U.S. patent application number 10/857877 was filed with the patent office on 2005-04-07 for use of perfluoroalkyl-containing metal complexes as contrast media in mr-imaging for visualization of plaque, tumors and necroses.
Invention is credited to Mareski, Peter, Misselwitz, Bernd, Niedballa, Ulrich, Platzek, Johannes, Raduechel, Bernd, Weinmann, Hanns-Joachim.
Application Number | 20050074409 10/857877 |
Document ID | / |
Family ID | 27214013 |
Filed Date | 2005-04-07 |
United States Patent
Application |
20050074409 |
Kind Code |
A1 |
Platzek, Johannes ; et
al. |
April 7, 2005 |
Use of perfluoroalkyl-containing metal complexes as contrast media
in MR-imaging for visualization of plaque, tumors and necroses
Abstract
The invention relates to the use of perfluoroalkyl-containing
metal complexes that have a critical micelle formation
concentration<10.sup.- -3 mol/l, a hydrodynamic micelle diameter
(2 Rh)>1 nm and a proton relaxivity in plasma (R.sup.1)>10
I/mmol.s) as contrast media in MR imaging for visualization of
plaque, lymph nodes, infarcted and necrotic tissue and for
independent visualization of necrotic tissue and tumor tissue.
Inventors: |
Platzek, Johannes; (Berlin,
DE) ; Mareski, Peter; (Berlin, DE) ;
Niedballa, Ulrich; (Berlin, DE) ; Raduechel,
Bernd; (Berlin, DE) ; Weinmann, Hanns-Joachim;
(Berlin, DE) ; Misselwitz, Bernd; (Glienicke,
DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
27214013 |
Appl. No.: |
10/857877 |
Filed: |
June 2, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10857877 |
Jun 2, 2004 |
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09925618 |
Aug 10, 2001 |
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6818203 |
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60235958 |
Sep 26, 2000 |
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Current U.S.
Class: |
424/9.35 ;
424/9.363 |
Current CPC
Class: |
A61K 49/10 20130101;
A61K 49/085 20130101 |
Class at
Publication: |
424/009.35 ;
424/009.363 |
International
Class: |
A61K 049/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 11, 2000 |
DE |
10040380.8 |
Claims
1-50. (canceled)
51. A method for MRI imaging comprising administring to a patient
an MRI contrast agent, comprising a perfluoroalkyl-containing metal
complex that has a critical micelle formation concentration
<10.sup.-3 mol/l, a hydrodynamic micelle diameter (2 Rh)>1 nm
and a proton relaxivity in plasma (R.sup.1)>10
l/mmol.multidot.s, wherein the perfluoroalkyl-containing metal
complex is a complex with a sugar radical, said complex being of
formula Ic is: 79in which R is a mono-or oligosaccharide radical
bonded by the 1-OH-- or 1-SH-position, R.sup.F is a perfluorinated,
straight-chain or branched carbon chain with the formula
--C.sub.nF.sub.2nE, in which E is a terminal fluorine, chlorine,
bromine, iodine or hydrogen atom, and n is a number from 4-30, K is
a metal complex of formula IIc, 80in which R.sup.1 is a hydrogen
atom or a metal ion equivalent of atomic numbers 23-29, 42-46 or
58-70, provided that at least two R.sup.1 stand for metal ion
equivalents, R.sup.2 and R.sup.3, independently of one another,
represent hydrogen, C.sub.1-C.sub.7 alkyl, benzyl, phenyl,
--CH.sub.2OH or --CH.sub.2CH.sub.3, and U is
--C.sub.6H.sub.4--O--CH.sub.2-.omega.-,
--(CH.sub.2).sub.1-5-.omega.), a phenylene group,
--CH.sub.2--NHCO--CH.su-
b.2--CH(CH.sub.2COOH)--C.sub.6H.sub.4-.omega.-,
--C.sub.6H.sub.4--(OCH.sub-
.2CH.sub.2).sub.0-1--N(CH.sub.2COOH)--CH.sub.2-.omega. or a
C.sub.1-C.sub.12 alkylene group or
C.sub.7-C.sub.12--C.sub.6H.sub.4--O group optionally interrupted by
one or more oxygen atoms, 1 to 3 --NHCO groups or 1 to 3 --CONH
groups and/or substituted with 1 to 3 --(CH.sub.2).sub.0-5COOH
groups, whereby .omega. is the binding site to --CO--, or of
formula IIIc 81in which R.sup.1 has the above-mentioned meaning,
R.sup.4 is hydrogen or a metal ion equivalent mentioned under
R.sup.1, and U.sup.1 is --C.sub.6H.sub.4--O--CH.sub.2-.omega.,
whereby (a is the binding site to --CO--, or of formula IVc 82in
which R.sup.1 and R.sup.2 have the above-mentioned meaning or of
formula VcA or VcB 83in which R.sup.1 has the above-mentioned
meaning, or of formula VIc 84in which R.sup.1 has the
above-mentioned meaning, or of formula VIIc 85in which R.sup.1 has
the above-mentioned meaning, and U.sup.1 is
--C.sub.6H.sub.4--O--CH.sub.2-.omega., whereby .omega. is the
binding site to --CO-- or of formula VIIIc 86in which R.sup.1 has
the above-mentioned meaning, and in radical K, optionally present
free acid groups optionally can be present as salts of organic
and/or inorganic bases or amino acids or amino acid amides, G for
the case that K is metal complexes IIc to VIIc is a radical that is
functionalized in at least three places and is selected from the
following radicals a) to j) 8788G for the case that K is metal
complex VIIIc is a radical that is functionalized in at least three
places and is selected from k) or l), 89whereby .alpha. is the
binding site of G to complex K, .beta. is the binding site of G to
radical Y, and .gamma. is the binding site of G to radical Z, Y is
--CH.sub.2, .delta.-(CH.sub.2).sub.(1-5)CO-.beta.,
.delta.-CH.sub.2--CHOH--CO-.beta. or
.delta.-CH(CHOH--CH.sub.2OH)--CHOH--- CHOH--CO-.beta., whereby
.delta. is the binding site to sugar radical R and .beta. is the
binding site to radical G, Z is 90whereby .gamma. is the binding
site of Z to radical G, and .epsilon. is the binding site of Z to
perfluorinated radical R.sup.F and l.sup.1, m.sup.l, independently
of one another, mean integers 1 or 2, and p.sup.1 is an integer
from 1 to 4 allowing the uptake of contrast agent in tissue,
conducting MRI imaging, and visualizing plaque, infarcted tissue,
or necrotic tissue in which contrast agent is uptaken, or
independently simultaneously visualizing necroses and tumors in
which contrast agent is uptaken.
52. A method according to claim 51, wherein the compound of formula
Ic, is a compound in which R is a monosaccharide radical with 5 to
6 C atoms or its deoxy compound.
53. A method according to claim 51, wherein the compound of formula
Ic, is a compound in which R.sup.2 and R.sup.3, independently of
one another, mean hydrogen or C.sub.1-C.sub.4 alkyl and/or E in
formula --C.sub.nF.sub.2n is a fluorine atom.
54. A method according to claim 51, wherein the compound of formula
Ic, is a compound in which G is lysine radical (a) or (b).
55. A method according to claim 51, wherein the compound of formula
Ic, is a compound in which Z is 91whereby .gamma. is the binding
site of Z to radical G, and .epsilon. is the binding site of Z to
perfluorinated radical R.sup.F, and/or Y is
.delta.-CH.sub.2CO-.beta., whereby .delta. is the binding site to
sugar radical R and .beta. is the binding site to radical G.
56. A method according to claim 51, wherein the compound of formula
Ic, is a compound in which U in metal complex K is --CH.sub.2-- or
--C.sub.6H.sub.4--O--CH.sub.2-.omega., whereby .omega. is the
binding site to --CO--.
57. A method according to claim 51, wherein the compound is a
gadolinium complex of
6-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododec-
ane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-2-N-[1-O-.alpha.-D-carbony-
lmethyl-mannopyranose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]--
amide.
58. A method for MRI imaging comprising administering to a patient
an MRI contrast agent, comprising a perfluoroalkyl-containing metal
complex that has a critical micelle formation
concentration<10.sup.-3 mol/l, a hydrodynamic micelle diameter
(2 Rh)>1 nm and a proton relaxivity in plasma (R.sup.1)>10
l/mmol.multidot.s wherein the perfluoroalkyl-containing metal
complex is a complex with a polar radical said complex being of
formula Id: 92in which R.sup.F is a perfluorinated, straight-chain
or branched carbon chain with formula --C.sub.nF.sub.2nE, in which
E is a terminal fluorine, chlorine, bromine, iodine or hydrogen
atom, and n is a number from 4-30, K is a metal complex of formula
IId, 93in which R.sup.1 is a hydrogen atom or a metal ion
equivalent of atomic numbers 23-29, 42-46 or 58-70, provided that
at least two R.sup.1 stand for metal ion equivalents, R.sup.2 and
R.sup.3, independently of one another, represent hydrogen,
C.sub.1-C.sub.7 alkyl, benzyl, phenyl, --CH.sub.2OH or
--CH.sub.2OCH.sub.3, and U is
--C.sub.6H.sub.4--O--CH.sub.2-.omega.-,
--(CH.sub.2).sub.1-5-.omega., a phenylene group,
--CH.sub.2--NHCO--CH.sub.2--CH(CH.sub.2COOH)--C.sub.6H.s-
ub.4-.omega.-,
--C.sub.6H.sub.4--(OCH.sub.2CH.sub.2).sub.0-1--N(CH.sub.2CO-
OH)--CH.sub.2-.omega., or a C.sub.1-C.sub.12 alkylene group or
C.sub.7-C.sub.12--C.sub.6H.sub.4--O group optionally interrupted by
one or more oxygen atoms, 1 to 3 --NHCO groups, 1 to 3 --CONH
groups and/or substituted with 1 to 3 --(CH.sub.2).sub.0-5COOH
groups, whereby .omega. is the binding site to --CO--, or of
formula IIId 94in which R.sup.1 has the above-mentioned meaning,
R.sup.4 is hydrogen or a metal ion equivalent mentioned under
R.sup.1, and U.sup.1 is C.sub.6H.sub.4--O--CH.sub.2-.omega. whereby
.omega. is the binding site to --CO--, or of formula IVd 95in which
R.sup.1 and R.sup.2 have the above-mentioned meaning, or of formula
VdA or VdB 96in which R.sup.1 has the above-mentioned meaning, or
of formula VId 97in which R.sup.1 has the above-mentioned meaning,
or of formula VIId 98in which R.sup.1 has the above-mentioned
meaning, and U.sup.1 is C.sub.6H.sub.4--O--CH.sub.2-.- omega.,
whereby t is the binding site to --CO--, and in radical K,
optionally present free acid groups optionally can be present as
salts of organic and/or inorganic bases or amino acids or amino
acid amides, G is a radical that is functionalized in at least
three-places and is selected from the following radicals a) to g)
99100whereby .alpha. is the binding site of G to complex K, .beta.
is the binding site of G to radical R, and .gamma. is the binding
site of G to radical Z Z is 101whereby .gamma. is the binding site
of Z to radical G and .epsilon. is the binding site of Z to
perfluorinated radical R.sub.f, R is a polar radical that is
selected from complexes K of formulas IId to VIId, whereby R.sup.1
here is a hydrogen atom or a metal ion equivalent of atomic numbers
20, 23-29, 42-46 or 58-70, and radicals R.sup.2, R.sup.3, R.sup.4,
U and U.sup.1 have the above-indicated meaning, or is the folic
acid radical or is a carbon chain with 2-30 C atoms that is bonded
to radical G via --CO-- or SO.sub.2-- and is straight or branched,
saturated or unsaturated, optionally interrupted by 1-10 oxygen
atoms, 1-5 --NHCO groups, 1-5 --CONH groups, 1-2 sulfur atoms, 1-5
--NH groups or 1-2 phenylene groups, which optionally can be
substituted with 1-2 OH groups, 1-2 NH.sub.2 groups, 1-2 --COOH
groups, or 1-2 --SO.sub.3H groups, or optionally substituted with
1-8 OH groups, 1-5 --COOH groups, 1-2 SO.sub.3H groups, 1-5
NH.sub.2 groups, 1-5 C.sub.1-C.sub.4 alkoxy groups, and l.sup.1,
m.sup.1, p.sup.2, independently of one another, mean integers 1 or
2
59. A method according to claim 58, wherein the-compound of formula
Id, is a compound in which K is a metal complex of formula IId,
IIId, VdB or VIId.
60. A method according to claim 58, wherein the compound of formula
Id, is a compound in which polar radical R is complex K.
61. A method according to claim 58, wherein the compound of formula
Id, is a compound in which polar radical R is:
--C(O)CH.sub.2CH.sub.2SO.sub.3H
--C(O)CH.sub.2OOH.sub.2CH.sub.2OCH.sub.2OCH.sub.2CH.sub.2OH
--C(O)CH.sub.2OCH.sub.2CH.sub.2OH
--C(O)CH.sub.2OOH.sub.2CH(OH)CH.sub.2OH
--C(O)CH.sub.2NH--C(O)CH.sub.2COOH --C(O)CH.sub.2CH(OH)CH.sub.2OH
--C(O)CH.sub.2OCH.sub.2COOH --SO.sub.2CH.sub.2CH.sub.2COOH
--C(O)--C.sub.6H.sub.3--(m-COOH).sub.2
--C(O)CH.sub.2O(CH.sub.2).sub.2-C.- sub.6H.sub.3-(m-COOH).sub.2
--C(O)CH.sub.2O--C.sub.6H.sub.4-m-SO.sub.3H
--C(O)CH.sub.2NHC(O)CH.sub.2NHC(O)CH.sub.2OCH.sub.2COOH
--C(O)CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2COOH
--C(O)CH.sub.2OCH.sub.2CH(OH- )CH.sub.2O--CH.sub.2CH.sub.2OH
--C(O)CH.sub.2OOH.sub.2CH(OH)CH.sub.2OCH.su-
b.2--CH(OH)--CH.sub.2OH --C(O)CH.sub.2SO.sub.3H
--C(O)CH.sub.2CH.sub.2COOH --C(O)CH(OH)CH(OH)CH.sub.2OH
--C(O)CH.sub.2O[(CH.sub.2).sub.2O].sub.1-9--- CH.sub.3
`3C(O)CH.sub.2O[(CH.sub.2).sub.2O].sub.1-9--H
--C(O)CH.sub.2OCH(CH.sub.2OH).sub.2
--C(O)CH.sub.2OCH(CH.sub.2OCH.sub.2CO- OH).sub.2
--C(O)--C.sub.6H.sub.3-(m-OCH.sub.2COOH).sub.2
--CO--CH.sub.2O--(CH.sub.2).sub.2O(CH.sub.2).sub.2O--(CH.sub.2).sub.2O(CH-
.sub.2).sub.2OCH.sub.3
62. A method according to claim 58, wherein the compound of formula
Id, is a compound in which polar radical R is a folic acid
radical.
63. A method according to claim 58, wherein the compound of formula
Id, is a compound in which G is lysine radical (a) or (b).
64. A method according to claim 58, wherein the compound of formula
Id, is a compound in which U is group --CH.sub.2-- or
C.sub.6H.sub.4--O--CH.sub.- 2-.omega. in metal complex K, whereby
.omega. is the binding site to --CO.
65. A method according to claim 58, wherein the compound is a
gadolinium complex of
2,6-N,N'-bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacy-
clododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-lysine-[1-(4-perfluo-
rooctylsulfonyl)-piperazine]-amide.
66. A method according to claim 51, wherein the
perfluoroalkyl-containing metal complex is a, galenical formulation
that contains a paramagnetic, perfluoroalkyl-containing metal
complex of formula I, and a diamagnetic perfluoroalkyl-containing
substance, optionally dissolved in an aqueous solvent.
67. A method according to claim 66, wherein the diamagnetic
perfluoroalkyl-containing substance is a conjugate that consist of
.alpha., .beta., or .gamma.-cyclodextrin and compounds of formula
XXII A.sup.1-L.sup.3-R.sup.F (XXII) in which A.sup.2 is an
adamantane, biphenyl or anthracene molecule, L.sup.3 is a linker,
and R.sup.F is a straight-chain or branched perfluoroalkyl radical
with 4 to 30 carbon atoms, and whereby linker L.sup.3 is a
straight-chain hydrocarbon chain with 1 to 20 carbon atoms, which
can be interrupted by one or more oxygen atoms, one or more CO--,
SO.sub.2--, CONH--, NHCO--, CONR.sup.10--, NR.sup.10CO--, NH-- or
NR.sup.10 groups or a piperazine, whereby R.sup.10 is a
C.sub.1-C.sub.5 alkyl radical.
68. A method according to claim 66, wherein the diamagnetic
perfluoroalkyl-containing substance is a compound of formula XXI:
R.sup.F--X.sup.1 (XXI) in which R.sup.F is a straight-chain or
branched perfluoroalkyl radical with 4 to 30 carbon atoms, and
X.sup.1 is a radical that is selected from the group of the
following radicals 102103and n is a number from 1 to 10.
69. A method according to claim 51, wherein the metal complexes
have a hydrodynamic micelle diameter of >3 nm.
70. A method according to claim 51, wherein the metal complexes
have a proton relaxivity in plasma of >13 l/mmol.multidot.s.
71. A method according to claim 52, wherein in the compound of
formula Ic, R is glucose, mannose or galactose.
72. A method according to claim 60, wherein complex K is of formula
IId, IIId, VdA or VIId.
73. A method according to claim 58, wherein in the compound of
formula Id, polar radical R is
--C(O)CH.sub.2O[(CH.sub.2).sub.2O].sub.4--CH.sub.3.
74. A method according to claim 51, wherein the
perfluoroalkyl-containing metal complex comprises galenical
formulations that contain paramagnetic, perfluoroalkyl-containing
metal complexes of formulas Ic and diamagnetic
perfluoroalkyl-containing substances, optionally dissolved in an
aqueous solvent.
75. A method according to claim 58, wherein the
perfluoroalkyl-containing metal complex comprises galenical
formulations that contain paramagnetic, perfluoroalkyl-containing
metal complexes of formula Id and diamagnetic
perfluoroalkyl-containing substances, optionally dissolved in an
aqueous solvent.
76. A method according to claim 58, wherein the metal complexes
have a hydrodynamic micelle diameter of >3 nm.
77. A method according to claim 58, wherein the metal complexes
have a proton relaxivity in plasma of >13 l/mmol.multidot.s.
Description
[0001] The invention relates to the use of
perfluoroalkyl-containing metal complexes that have a critical
micelle formation concentration of <10.sup.-3 mol/l, a
hydrodynamic micelle diameter (2 Rh)>1 nm and a proton
relaxivity in plasma (R.sup.1)>10 l/mmol.s as contrast media in
MR-imaging both for visualization of plaque, lymph nodes, infarcted
and necrotic tissue and for independent visualization of necrotic
tissue and tumor tissue. It has been shown that
perfluoroalkyl-containing metal complexes with the above-mentioned
properties are extremely well suited for the independent
visualization of plaque, tumors and necroses with the aid of
MR-imaging and simultaneously can also cover the diagnostically
important area of infarction and necrosis imaging.
[0002] Arteriosclerosis is the most important and most frequent
pathological alteration of arteries with hardening, thickening,
loss of elasticity and lumen constriction. It represents the most
frequent cause of death in Western industrialized countries.
Vascular wall alterations are produced by lipid retention,
connective tissue reproduction and calcification with irregular
dispersion for wall instability, vascular stenosis and for storage
of clots. Causes of disease are numerous exogenic and endogenic
noxae or diseases, e.g., hypertonia, hyperlipidemia,
hyperfibrinogenemia, diabetes mellitus, toxins, nicotine,
antigen-antibody complexes, inflammations, hypoxia, mental stress,
age and family stress. The latter result in the disruption of the
integrity of the vascular inside wall, in the disruption of growth
control of smooth muscle cells of the vascular wall and in
impairing the degradation of aged cell components. Treatment of
arteriosclerosis itself is not possible; the target of medical
efforts is prevention by reducing risk factors, e.g., using lipid
reducing agents.
[0003] The diagnosis of arteriosclerosis in clinical practice is
currently carried out mainly by angiography as a gold standard. The
limitation in all processes that are based on the measurement of
the reduction of the vascular lumen is, however, the early stage of
the disease, which is characterized by a thickening of the vascular
wall in the case of a normal vascular lumen (Glagov, S., Zarins, C.
K. Quantitating Atherosclerosis. In: Bond, M. G.; Insull, W.;
Glagov, S.; Chandler, A. B.; Cornhill, J. F. (eds.). Clinical
Diagnosis of Atherosclerosis. Quantitative Methods of Evaluation.
New York: Springer-Verlag, 1983, 11-35). Another method for
diagnostic assessment of vascular wall and vascular lumen is the
intravascular or percutaneous ultrasound.
[0004] Magnetic nuclear spin resonance tomography (MRT) is a
modern, non-invasive radiological process, which makes possible the
visualization of physiological and pathophysiological structures
with a very good space and time resolution. The use of specific
contrast media with selective concentration in certain tissues and
organs can increase the diagnostic value considerably in this case.
Contrast medium preparations with selective concentration in
arteriosclerotic plaque were able to detect location and degree of
the disease at an early time and thus to make possible a targeted
therapy and prophylaxis, and therefore the search for suitable
contrast media began early.
[0005] Thus, hematoporphyrin derivatives are claimed in U.S. Pat.
No. 4,577,636 as contrast media for the detection of
atherosclerotic plaque. As methods, scintigraphy, radiography,
fluorescence and, for paramagnetic metalloporphyrins, even
NMR-spectrometry, are mentioned. As paramagnetic ions, Gd, Cr, Co,
Ni, Ag and Eu are cited.
[0006] The disadvantage to these compounds is that the porphyrins
are stored in the skin and cause discolorations that can last up to
several weeks. Moreover, they result in a photosensitization. In
addition, the danger exists that in a long retention time in vivo,
the metalloporphyrin loses the metal.
[0007] In Application WO 95/09856, metalloporphyrins
(deuteroporphyrins) are claimed for diagnosis and therapy of
plaque. As a diagnostic method, MRI is mentioned. These porphyrins
also cause discolorations of the skin.
[0008] In Application WO 95/09013, conjugates that consist of
specifically binding polypeptides and metal complexes are claimed.
These compounds are also to bind to plaque and thus make possible
their diagnosis and therapy. As diagnostic methods, scintigraphy,
computer tomography, and MRI are mentioned. While scintigraphy is
confirmed by experiment, data is lacking for MRI.
[0009] Labeled phycocyanines are claimed as contrast media for the
imaging of plaque in U.S. Pat. No. 5,807,536. As diagnostic
methods, radiography, computer tomography, scintigraphy, SPECT and
MRI are mentioned here. Scintigraphy is confirmed by
experiment.
[0010] Numerous contrast media for infarction and necrosis imaging
are known from the literature. Tests were carried out early on to
improve the localization of infarctions and necroses by use of
contrast media in noninvasive processes such as scintigraphy or
nuclear spin tomography. The literature devotes a great deal of
space to attempts to use porphyrins for necrosis imaging. The
results that are achieved paint a contradictory picture, however.
Winkelman and Hoyes thus describe in Nature, 200, 903 (1967) that
manganese-5,10,15,20-tetrakis(4-sulfonatophe- nyl)-porphyrin (TPPS)
selectively accumulates in the necrotic portion of a tumor.
[0011] Lyon et al. (Magn. Res. Med. 4, 24 (1987)) observed,
however, that manganese-TPPS is dispersed into the body,
specifically into the kidney, liver, tumor and only in a small
portion to the muscles. It is advantageous in this case that the
concentration in the tumor reach its maximum only on the fourth day
and also only after the authors have increased the dose from 0.12
mmol/kg to 0.2 mmol/kg. The authors therefore also speak of a
non-specific uptake of TPPS in the tumor. Bockhurst et al. in turn
report in Acta Neurochir 60, 347 (1994, Suppl.) that MnTPPS binds
selectively to tumor cells.
[0012] Foster et al. (J. Nucl. Med. 26, 756 (1985)) in turn found
that
.sup.111In-5,10,15,20-tetrakis-(4-N-methyl-pyridinium)-porphyrin
(TMPyP) does not accumulate in the necrotic portion, but rather in
the living edge areas. It follows from the above that a
porphyrin-tissue interaction exists, is obvious but not
necessary.
[0013] In Circulation Vol. 90, No. 4, part 2, page 1468, Abstract
No. 2512 (1994), Ni et al. report that they can visualize
infarction areas with a manganese-tetraphenyl-porphyrin (Mn-TPP)
and a gadolinium-mesoporphyrin (Gd-MP). In International Patent
Application WO 95/31219, both substances were used for infarction
and necrosis imaging. The authors Marchal and Ni write (see Example
3) that for the compound Gd-MP, the metal content of the infarcted
kidney was as high as that of the non-infarcted organ, but that for
the myocardium in the infarcted tissue (Example 1), it was nine
times as high. It was surprising that the ratio of the signal
intensities during MRI for infarcted tissue in comparison to
healthy tissue was comparatively high in both cases, at 2.10 or
2.19. Other metalloporphyrins were described in Application DE
19835082 (Schering AG).
[0014] Porphyrins tend to be stored in the skin, which results in
photosensitization. The sensitization can last for days, and indeed
even weeks. This is an undesirable side effect when using
porphyrins as diagnostic agents. In addition, the therapeutic index
for porphyrins is only very small, since, e.g., for Mn-TPPS, an
action starts only at a dose of 0.2 mmol/kg, but the LD.sub.50 is
already approximately 0.5 mmol/kg.
[0015] Contrast media for necrosis and infarction imaging not
derived from the porphyrin skeleton have been described in DE
19744003 (Schering AG), DE 19744004 (Schering AG) and WO 99/17809
(EPIX).
[0016] In DE 19744003, oligomeric compounds, which consist of a
nucleus and are bonded to the 1-3 metal complexes, are claimed.
[0017] In Application 19744004, lipophilic metal complexes for
necrosis and infarction imaging are claimed. These compounds
include metal complexes of polyaminopolycarboxylic acids,
polyaminopolyphosphonic acids, porphyrins, texaphyrins, sapphyrins,
and peptides.
[0018] In EPIX-Application WO 99/17809, the use of DTPA derivatives
for necrosis imaging is claimed. The most prominent compound is the
gadolinium complex of a phosphodiester of hydroxymethyl-DTPA
(MS-325).
[0019] Perfluoroalkyl-containing metal complexes are also known as
contrast media for MR-imaging. WO 97/26017 (Schering) and WO
99/01161 (Schering) thus disclose the use of
perfluoroalkyl-containing metal complexes as lymphographic agents.
In addition, WO 99/01161 also describes the suitability of these
compounds for visualizing the vascular space (blood-pool
agents).
[0020] Contrast media were also described for the individual
visualization of tumors and necroses using MR-imaging.
[0021] In EP 417870 A1, compounds for tumor diagnosis and therapy
are disclosed. It is stated that infarctions and ischemias can also
be visualized. An experimental confirmation of this information
cannot be derived from the application, however. The claimed
compounds are chelates of complexes of N2S2 and N3S types with
radioisotopes. Scintigraphy is used as a diagnostic method.
[0022] In DE 19646762, scintigraphy is also used as a diagnostic
method. In the publication, metal chelates are claimed as
radiosensitizers for therapy of hypoxic tumors and for diagnosis of
hypoxic conditions and necroses. In the descriptive part,
NMR-diagnosis, x-ray diagnosis and radiodiagnosis are mentioned as
diagnostic processes.
[0023] In German Application DE 19824653, porphyrins are claimed as
necrosis-affine substances for the therapy of tumors. In the
application, it is explained that the compounds are concentrated in
the necrotic and hypoxic areas of the tumors. The compounds can be
used for diagnostic purposes in the form of their metal derivatives
with paramagnetic ions or radioisotopes.
[0024] It is common to both applications--DE 19646762 and DE
19824653--that the visualization of necroses and tumors does not
take place independently of one another, but rather that the
necrosis is part of the tumor.
[0025] The object of this invention was to make available contrast
media for MR-imaging, which are suitable both for visualization of
plaque, lymph nodes, infarcted and necrotic tissue and for
independent visualization of necroses and tumors.
[0026] Surprisingly enough, it was now found that
perfluoroalkyl-containin- g metal complexes, which have a critical
micelle formation concentration of <10.sup.-3 mol/l, a
hydrodynamic micelle diameter (2 Rh)>1 nm and a proton
relaxivity in plasma (R.sup.1)>10 l/mmol.s, are very well suited
as contrast media in MR imaging for visualization of plaque. In
addition, these compounds can be used both for visualization of
lymph nodes, infarcted and necrotic tissue and for independent
visualization of necrotic tissue and tumor tissue.
[0027] Amphiphilic compounds, which have a perfluoroalkyl side
chain in the molecule as a nonpolar portion that is optionally
connected to the total molecule via a lipophilic linker, are
defined as perfluoroalkyl-containing metal complexes that are
suitable for use according to the invention. The polar portion of
the compounds according to the invention is formed by one or more
metal complexes and optionally other existing polar groups.
[0028] In aqueous systems, these amphiphilic molecules show the
properties that are characteristic of standard surfactants (such
as, e.g., sodium dodecylsulfate, SDS). They thus reduce the surface
tension of water. By tensiometry, the so-called CMC (critical
micelle formation concentration in mol/l) can be determined. In
this respect, the surface tension is determined based on the
concentration of the substance to be measured. The CMC can be
calculated from the plot of the surface tension function (c) that
is obtained. The critical micelle formation concentration of the
compounds according to the invention must be <10.sup.-3 mol/l,
preferably <10.sup.-4 mol/l.
[0029] The amphiphilic compounds according to the invention are
combined in solution and are present as aggregates. The size (2 Rh)
of such aggregates (e.g., micelles, rods, wafers, etc.) can be
determined with the aid of photon-correction spectroscopy
(PCS).
[0030] As a second criterion, the hydrodynamic micelle diameter 2
Rh, which must be >1 nm, is therefore used. Those
perfluoroalkyl-containin- g metal complexes according to the
invention whose 2 RH is .gtoreq.3, quite especially preferably
>4 nm, are especially suitable.
[0031] Both the determination of the CMC and the photon correlation
spectroscopy are described in H.-D. Dorfler, "Grenzflchen-und
Kolloidchemie [Interface and Colloid Chemistry]," Weinheim, N.Y.,
Basel, Cambridge, Tokyo, VSH 1994.
[0032] As a third criterion, the proton-relaxivity in plasma
(R.sup.1) at 40.degree. C. and a field strength of 0.47 tesla is
used. The relaxivity, which is indicated in [1/mmol.s], is the
quantitative measurement for the shortening of relaxation time
T.sup.1 of the protons. For the purpose according to the invention,
the relaxivity must be as high as possible and >10 l/mmol.s,
preferably >13 l/mmol.s, especially preferably >15
l/mmol.s.
[0033] Relaxivity R.sup.1 [l/mmol.s] of the MR-contrast media
according to the invention was determined with the Minispec P 20
device of the Bruker Company. The measurements were taken at
40.degree. C. and a field strength of 0.47 tesla. Eight measuring
points were recorded by each T1-sequence:
180.degree.-TI-90.degree., inversion recovery. As a medium, bovine
plasma of the Kraeber Company was used. The contrast medium
concentrations [mmol/l] in the batches were between 0.30 and
1.16.
[0034] In an embodiment of this invention, the compounds of general
formula I according to claims 8 to 11 are used as preferred
compounds. In this case, these are known compounds that are
described in WO 97/26017. Their production can also be found in
this WO publication. Surprisingly enough, it has been shown that
these compounds are also very well suited as MRI-contrast media for
visualization of plaque. As quite especially preferred compounds,
metal complexes I-IV, VI and XI-XIII (cf. also Table 1) are
used.
[0035] In another embodiment of this invention, those compounds of
general formula Ia according to claims 12 to 21 are used as
preferred compounds. These compounds are known and are described in
WO 99/01161. Their use as MRI contrast media for visualization of
plaque still had not been described to date. Of these compounds,
quite especially preferably metal complex XIV (cf. Table 1) is
used.
[0036] The present invention includes a method for MRI imaging
comprising administering to a patient an MRI contrast agent,
comprising a perfluoroalkyl-containing metal complex that has a
critical micelle formation concentration <10.sup.-3 mol/l, a
hydrodynamic micelle diameter (2 Rh) >1 nm and a proton
relaxivity in plasma (R.sup.1)>10 l/mmol.s and conducting MRI
imaging whereby plaque, or necrotic tissue are visualized or
necroses and tumors are independently visualized.
[0037] In an embodiment the metal complex has a micelle formation
concentration of <10.sup.-4 mol/l.
[0038] In an embodiment the metal complex has a hydrodynamic
micelle diameter of >3 nm.
[0039] In an embodiment the metal complex has a proton relaxivity
in plasma of >13 l/mmol.s.
[0040] In an embodiment the perfluoroalkyl-containing metal complex
is a compound of formula I
R.sup.F-L-K
[0041] in which
[0042] R.sup.F is a perfluorinated, straight-chain or branched
carbon chain with formula --C.sub.nF.sub.2nE, in which
[0043] E is a terminal fluorine, chlorine, bromine, iodine or
hydrogen atom and n is a number from 4-30,
[0044] L is a direct bond, a methylene group, an NHCO-- group, a
group 1
[0045] whereby p is a number from 0 to 10, and q and n,
independently of one another, are 0 or 1, and R.sup.a is a hydrogen
atom, a methyl group, a --CH.sub.2--OH group, a
--CH.sub.2--CO.sub.2H group or a C.sub.2-C.sub.15 alkyl, which
optionally is interrupted by 1 to 3 oxygen atoms, 1 to 2 CO groups
or an optionally substituted aryl group and/or is substituted with
1 to 4 hydroxyl groups, 1 to 2 C.sub.1-C.sub.4 alkoxy groups, 1 to
2 carboxy groups, or a group --SO.sub.3H, or
[0046] L is a straight-chain, branched, saturated or unsaturated
C.sub.2-C.sub.30 carbon chain, which optionally contains 1 to 10
oxygen atoms, 1 to 3 --NR.sup.a groups, 1 to 2 sulfur atoms, a
piperazine group, a --CONR.sup.a group, an --NR.sup.aCO group, an
--SO.sub.2 group, an --NR.sup.a--CO.sub.2 group, 1 to 2 CO groups,
a group --CO--N-T-N(R.sup.a)--SO.sub.2--R.sup.F, or 1 to 2
optionally substituted aryls and/or is interrupted by these groups
and/or is optionally substituted with 1 to 3 --OR.sup.a groups, 1
to 2 oxo groups, 1 to 2 --NH--COR.sup.a groups, 1 to 2
--CONHR.sup.a groups, 1 to 2 --(CH.sub.2).sub.p--CO.sub.2H groups,
1 to 2 groups
--(CH.sub.2).sub.p--(O).sub.q--CH.sub.2CH.sub.2--R.sup.F,
[0047] whereby
[0048] R.sup.a, R.sup.F and p and q have the above-indicated
meanings, and
[0049] T is a C.sub.2-C.sub.10 chain, which optionally is
interrupted by 1 to 2 oxygen atoms or 1 to 2 --NHCO groups,
[0050] K is a complexing agent or metal complex of formula II 2
[0051] in which R.sup.c, R.sup.1 and B are independent of one
another, and
[0052] R.sup.c is R.sup.a or is --(CH.sub.2)m-L-R.sup.F, whereby m
is 0, 1 or 2, and L and R.sup.F have the above-mentioned
meaning,
[0053] R.sup.1, independently of one another, is a hydrogen atom or
a metal ion equivalent of atomic numbers 22-29, 42-46 or 58-70,
[0054] B is --OR.sup.1, 3
[0055] whereby R.sup.1, L, R and R.sup.c have the above-mentioned
meanings, or
[0056] K is a complexing agent or complex of formula III 4
[0057] in which R.sup.c and R have the above-mentioned meanings and
R.sup.b has the meaning of R.sup.a or
[0058] K is a complexing agent or complex of formula IV 5
[0059] in which R.sup.1 has the above-mentioned meaning or
[0060] K is a complexing agent or complex of formula V 6
[0061] in which R.sup.1 has the above-mentioned meaning, and o and
q stand for numbers 0 or 1, and yields the sum o+q=1, or
[0062] K is a complexing agent or complex of formula VI 7
[0063] in which R.sup.1 has the above-mentioned meaning or
[0064] K is a complexing agent or complex of formula VII 8
[0065] in which R.sup.1 and B have the above-mentioned meanings
or
[0066] K is a complexing agent or complex of formula VIII 9
[0067] in which R.sup.c and R.sup.1 have the above-mentioned
meanings, and R.sup.b is R.sup.a or
[0068] K is a complexing agent or complex of formula IX 10
[0069] in which R.sup.c and R.sup.1 have the above-mentioned
meanings, or
[0070] K is a complexing agent or complex of formula X 11
[0071] in which R.sup.c and R.sup.1 have the above-mentioned
meanings, or
[0072] K is a complexing agent or complex of formula XI 12
[0073] in which R.sup.1, p and q have the above-mentioned
meanings,
[0074] and R.sup.b has the meaning of R.sup.a, or
[0075] K is a complexing agent or complex of formula XII 13
[0076] in which L, R.sup.F and Z.sup.1 have the above-mentioned
meanings, or
[0077] K is a complexing agent or complex of formula XIII 14
[0078] in which R.sup.1 has the above-mentioned meaning, or
[0079] K is a salt of one of the complexing agents or complexes of
fomula II to XIII with an organic and/or inorganic base or amino
acid or amino acid amide.
[0080] In an embodiment the compound of formula I, is a compound in
which L is
.alpha.-CH.sub.2-.beta.
.alpha.-CH.sub.2CH.sub.2-.beta.
.alpha.-(CH.sub.2).sub.s-.beta. s=3-15
.alpha.-CH.sub.2--O--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2--(O--CH.sub.2--CH.sub.2--).sub.t-.beta. t=2-6
.alpha.-CH.sub.2--NH--CO-.beta.
.alpha.-CH.sub.2--NH--CO--CH.sub.2--N(CH.sub.2COOH)--SO.sub.2-.beta.
.alpha.-CH.sub.2--NH--CO--CH.sub.2--N(C.sub.2H.sub.5)--SO.sub.2-.beta.
.alpha.-CH.sub.2--NH--CO--CH.sub.2--N(C.sub.10H.sub.21)--SO.sub.2-.beta.
.alpha.-CH.sub.2--NH--CO--CH.sub.2--N(C.sub.6H.sub.13)--SO.sub.2-.beta.
.alpha.-CH.sub.2--NH--CO--(CH.sub.2).sub.10--N(C.sub.2H.sub.5)--SO.sub.2-.-
beta.
.alpha.-CH.sub.2--NH--CO--CH.sub.2--N(--CH.sub.2--C.sub.6H.sub.5)--SO.sub.-
2-.beta.
.alpha.-CH.sub.2--NH--CO--CH.sub.2--N(--CH.sub.2--CH.sub.2--OH)SO.sub.2-.b-
eta.
.alpha.-CH.sub.2--NHCO--(CH.sub.2).sub.10--S--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2NHCOCH.sub.2--O--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2NHCO(CH.sub.2).sub.10--O--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2--C.sub.6H.sub.4--O--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2--O--CH.sub.2--C(CH.sub.2--OCH.sub.2CH.sub.2--C.sub.6F.sub-
.13).sub.2--CH.sub.2--OCH.sub.2--CH.sub.2-.beta.
.alpha.-CH.sub.2--NHCOCH.sub.2CH.sub.2CON--CH.sub.2CH.sub.2NHCOCH.sub.2N(C-
.sub.2H.sub.5)SO.sub.2C.sub.8F.sub.17
CH.sub.2--CH.sub.2NHCOCH.sub.2N(C.sub.2H.sub.5)--SO.sub.2-.beta.
.alpha.-CH.sub.2--O--CH.sub.2--CH(OC.sub.10H.sub.21)--CH.sub.2--O--CH.sub.-
2CH.sub.2-.beta.
.alpha.-(CH.sub.2NHCO).sub.4--CH.sub.2O--CH.sub.2CH.sub.2-.beta.
.alpha.-(CH.sub.2NHCO).sub.3--CH.sub.2O--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2--OCH.sub.2C(CH.sub.2OH).sub.2--CH.sub.2--O--CH.sub.2CH.su-
b.2-.beta. 15
.alpha.-CH.sub.2NHCOCH.sub.2N(C.sub.6H.sub.5)--SO.sub.2-.bet-
a.
.alpha.-NHCO--CH.sub.2--CH.sub.2-.beta.
.alpha.-NHCO--CH.sub.2--O--CH.sub.2CH.sub.2-.beta.
.alpha.-NH--CO-.beta.
.alpha.-NH--CO--CH.sub.2--N(CH.sub.2COOH)--SO.sub.2-.beta.
.alpha.-NH--CO--CH.sub.2--N(C.sub.2H.sub.5)--SO.sub.2-.beta.
.alpha.-NH--CO--CH.sub.2--N(C.sub.10H.sub.21)--SO.sub.2-.beta.
.alpha.-NH--CO--CH.sub.2--N(C.sub.6H.sub.13)--SO.sub.2-.beta.
.alpha.-NH--CO--(CH.sub.2).sub.10--N(C.sub.2H.sub.5)--SO.sub.2-.beta.
.alpha.-NH--CO--CH.sub.2--N(--CH.sub.2--C.sub.6H.sub.5)--SO.sub.2-.beta.
.alpha.-NH--CO--CH.sub.2--N(--CH.sub.2--CH.sub.2--OH)SO.sub.2-.beta.
.alpha.-NH--CO--CH.sub.2-.beta.
.alpha.-CH.sub.2--O--C.sub.6H.sub.4--O--CH.sub.2--CH.sub.2-.beta.
.alpha.-CH.sub.2--C.sub.6H.sub.4--O--CH.sub.2--CH.sub.2-.beta.
.alpha.-N(C.sub.2H.sub.5)--SO.sub.2-.beta.
.alpha.-N(C.sub.6H.sub.5)--SO.sub.2-.beta.
.alpha.-N(C.sub.10H.sub.21)--SO.sub.2-.beta.
.alpha.-N(C.sub.6H.sub.13)--SO.sub.2-.beta.
.alpha.-N(C.sub.2H.sub.4OH)--SO.sub.2-.beta.
.alpha.-N(CH.sub.2COOH)--SO.sub.2-.beta.
.alpha.-N(CH.sub.2C.sub.6H.sub.5)--SO.sub.2-.beta.
.alpha.-N--[CH(CH.sub.2OH).sub.2]--SO.sub.2-.beta. or
.alpha.-N--[CH(CH.sub.2OH)CH(CH.sub.2OH)]--SO.sub.2-.beta.,
[0081] in which .alpha. is the binding site to the complexing agent
or metal complex K, and .beta. is the binding site to the fluorine
radical.
[0082] In an embodiment the compound of formula I, is a compound in
which n in formula --C.sub.nF.sub.2nE is a number from 4-15 and/or
E is a fluorine atom.
[0083] Also preferred are the following compounds of formula I:
[0084] Gadolinium complex of
10-[1-methyl-2-oxo-3-aza-5-oxo-{4-perfluorooc-
tylsulfonyl-piperazin-1-yl}-pentyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tet-
raazacyclododecane,
[0085] Gadolinium complex of
10-[2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,11,1-
2,12,13,13,14,14,15,15,16,16,17,17-heptadecafluoroheptadecyl]-1,4,7-tris(c-
arboxymethyl)-1,4,7,10-tetraazacyclododecane,
[0086] Gadolinium complex of
10-[2-hydroxy-4-aza-5,9-dioxo-9-{4-perfluoroo-
ctyl)-piperazin-1-yl}-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacy-
clododecane,
[0087] Gadolinium complex of
10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluoroo-
ctyl-sulfonyl)-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclodode-
cane,
[0088] Gadolinium complex of
10-[2-hydroxy-4-oxa-1H,1H,2H,3H,3H,5H,5H,6H,6-
H-perfluorotetradecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclodod-
ecane,
[0089] Gadolinium complex of
10-[2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,11,1-
2,12,13,13,14,14,15,15,-16,16,17,17,18,18,19,19-henicosafluoro-nonadecyl]--
1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane,
[0090] Gadolinium complex of
10-[2-hydroxy-4-aza-5-oxo-11-aza-11-(perfluor-
ooctylsulfonyl)-tridecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclo-
dodecane, or
[0091] Gadolinium complex of
10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluoroo-
ctylsulfonyl)-8-phenyl-octyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraaza--
cyclododecane.
[0092] In an embodiment the perfluoroalkyl-containing metal
complex, is a compound of formula Ia
A-R.sup.F (Ia)
[0093] in which
[0094] A is a group that contains 2 to 6 metal complexes, which are
bonded directly or via a linker to a nitrogen atom of an annular
skeleton chain, and
[0095] R.sup.F is a perfluorinated, straight-chain or branched
carbon chain with formula --C.sub.nF.sub.2nE, in which
[0096] E is a terminal fluorine, chlorine, bromine, iodine or
hydrogen atom, and n is a number from 4-30,
[0097] whereby A has the following structure: 16
[0098] whereby
[0099] q.sup.1 is 0, 1, 2 or 3,
[0100] K is a complexing agent or metal complex or a salts thereof
with an organic and/or inorganic base or amino acid or amino acid
amide,
[0101] X as the point of attachment to R.sup.F, is a direct bond, a
phenylene group or a C.sub.1-C.sub.10 alkylene chain, which
optionally contains 1-15 oxygen atoms, 1-5 sulfur atoms, 1-10
carbonyl groups, 10-10 (NR.sup.d) groups, 1-2 NR.sup.dSO.sub.2
groups, 1-10 CONR.sup.d groups, 1 piperidine group, 1-3 SO.sub.2
groups and/or 1-2 phenylene groups or optionally is substituted by
1-3 radicals R.sup.F, in which R.sup.d is a hydrogen atom, a phenyl
group, benzyl group or a C.sub.1-C.sub.15 alkyl group, which
optionally contains 1-2 NHCO, 1-2 CO groups, 1-5 oxygen atoms and
optionally is substituted by 1-5 hydroxy, 1-5 methoxy, 1-3 carboxy,
or 1-3 R.sup.F radicals, V is a direct bond or a chain of formula
Ia or IIIa: 17
[0102] in which
[0103] R.sup.e is a hydrogen atom, a phenyl group, a benzyl group
or a C.sub.1-C.sub.7 alkyl group, which optionally is substituted
with a carboxy group, a methoxy group or a hydroxy group,
[0104] W is a direct bond, a polyglycol ether group with up to 5
glycol units, or a group of formula IVa
--CH(R.sup.h)-- (IVa)
[0105] in which R.sup.h is a C.sub.1-C.sub.7 carboxylic acid, a
phenyl group, a benzyl group or a --(CH.sub.2).sub.1-5--NH--K
group,
[0106] .alpha. is the binding to the nitrogen atom of the skeleton
chain, .beta. is the binding to complexing agent or metal complex
K,
[0107] and in which variables k and m stand for natural numbers
between 0 and 10, and l is 0 or 1
[0108] and whereby
[0109] D is a CO or SO.sub.2 group.
[0110] Also preferred are compounds of formula Ia in which q.sup.1
is the number 1.
[0111] In an embodiment the compound of formula Ia is a compound in
which X is an alkylene chain, which contains 1-10
--CH.sub.2CH.sub.2O-- groups or 1-5 --COCH.sub.2NH-- groups, a
direct bond or one of the following structures 18
[0112] whereby
[0113] .gamma. binds to D, and .delta. binds to R.sup.F.
[0114] In an embodiment the compound of formula Ia, is a compound
in which V is a group with one of the following structures 19
[0115] In an embodiment the compound of formula Ia, is a compound
in which K is a complexing agent or complex of formula Va, VIa,
VIIa or VIIIa, 20
[0116] whereby
[0117] R.sup.1, independently of one another, are a hydrogen atom
or a metal ion equivalent of the elements of atomic numbers 23-29,
42-46 or 58-70,
[0118] R.sup.8 is a hydrogen atom or a straight-chain, branched,
saturated or unsaturated C.sub.1-C.sub.30 alkyl chain, which
optionally is substituted by 1-5 hydroxy, 1-3 carboxy or 1 phenyl
group(s) and/or optionally is interrupted by 1-10 oxygen atoms, 1
phenylene group or 1 phenylenoxy group,
[0119] R.sup.6 are independently a hydrogen atom, a straight-chain
or branched C.sub.1-C.sub.7 alkyl radical, a phenyl radical or
benzyl radical,
[0120] R.sup.7 is a hydrogen atom, a methyl group or ethyl group,
which optionally is substituted by a hydroxy group or carboxy
group,
[0121] U.sup.3 is a straight-chain, branched, saturated or
unsaturated C.sub.1-C.sub.20 alkylene group optionally containing
1-5 imino groups, 1-3 phenylene groups, 1-3 phenylenoxy groups, 1-3
phenylenimino groups, 1-5 amide groups, 1-2 hydrazide groups, 1-5
carbonyl groups, 1-5 ethylenoxy groups, 1 urea group, 1 thiourea
group, 1-2 carboxyalkylimino groups, 1-2 ester groups, 1-1-0 oxygen
atoms, 1-5 sulfur atoms and/or 1-5 nitrogen atoms, and/or
optionally substituted by 1-5 hydroxy groups, 1-2 mercapto groups,
1-5 oxo groups, 1-5 thioxo groups, 1-3 carboxy groups, 1-5
carboxyalkyl groups, 1-5 ester groups and/or 1-3 amino groups,
whereby the optionally contained phenylene groups can be
substituted by 1-2 carboxy groups, 1-2 sulfone groups or 1-2
hydroxy groups
[0122] T.sup.1 is a --CO-.beta., --NHCO-.beta. or --NHCS-.beta.
group, whereby .beta. is the binding site to V.
[0123] In an embodiment the compound of formula Ia is a
C.sub.1-C.sub.20 alkylene chain that is U.sup.3 contains the group
--CH.sub.2NHCO--, --NHCOCH.sub.2O--,
--NHCOCH.sub.2OC.sub.6H.sub.4--, --N(CH.sub.2CO.sub.2H)--,
--CH.sub.2OCH.sub.2--, --NHCOCH.sub.2C.sub.6H.s- ub.4--,
--NHCSNHC.sub.6H.sub.4--, --CH.sub.2OC.sub.6H.sub.4--, or
--CH.sub.2CH.sub.2O-- and/or is substituted by the group --COOH
and/or --CH.sub.2COOH.
[0124] In an embodiment the compound of formula Ia, U.sup.3 is a
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--C.sub.6H.sub.4--, --C.sub.6H.sub.10--,
--CH.sub.2C.sub.6H.sub.4--,
--CH.sub.2NHCOCH.sub.2CH(CH.sub.2CO.sub.2H)--C.sub.6H.sub.4--,
--CH.sub.2NHCOCH.sub.2OCH.sub.2--, or
--CH.sub.2NHCOCH.sub.2C.sub.6H.sub.- 4-- group.
[0125] In an embodiment the compound of formula Ia, is a compound
in which K has one of the following structures: 21
[0126] In an embodiment the compound of formula la is a compound in
which the perfluoroalkyl chain is R.sup.F is --C.sub.6F.sub.13,
--C.sub.8F.sub.17, --C.sub.10F.sub.21 or --C.sub.12F.sub.25.
[0127] In an embodiment the compound of formula Ia is
1,4,7-tris{1,4,7-tris(N-(carboxylatomethyl)-10-[N-1-methyl-3,6-diaza-2,5,-
8-trioxooctane-1,8-diyl)]-1,4,7,10-tetraazacyclododecane, Gd
complex}-10-[N-2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoyl]-1,4,7,10-tet-
raazacyclododecane.
[0128] In an embodiment the metal complex has a hydrodynamic
micelle diameter of >4 nm.
[0129] In an embodiment the metal complex has a proton relaxivity
in plasma of >15 l/mmol.s.
[0130] In an embodiment the perfluoroalkyl-containing metal complex
is in a galenical formulation that contains a paramagnetic,
perfluoroalkyl-containing metal complex of formula Ia and
diamagnetic perfluoroalkyl-containing substance, optionally
dissolved in an aqueous solvent.
[0131] In an embodiment the perfluoroalkyl-containing metal complex
is in a galenical formulations that contains a paramagnetic,
perfluoroalkyl-containing metal complex of formula Ib, and a
diamagnetic perfluoroalkyl-containing substance, optionally
dissolved in an aqueous solvent.
[0132] In another preferred embodiment of the invention, the
macrocyclic perfluoroalkyl compounds of general formula Ib 22
[0133] in which
[0134] K means a complexing agent or a metal complex of general
formula IIb 23
[0135] whereby
[0136] R.sup.1 stands for a hydrogen atom or a metal ion equivalent
of atomic numbers 23-29, 42-46 or 58-70,
[0137] R.sup.2 and R.sup.3 stand for a hydrogen atom, a
C.sub.1-C.sub.7 alkyl group, a benzyl group, a phenyl group,
--CH.sub.2OH or --CH.sub.2--OCH.sub.3, and
[0138] U.sup.2 stands for radical L.sup.1, whereby L.sup.1 and
U.sup.2, independently of one another, can be the same or
different,
[0139] A.sup.1 means a hydrogen atom, a straight-chain or branched
C.sub.1-C.sub.30-alkyl group, which optionally is interrupted by
1-15 oxygen atoms, and/or optionally is substituted with 1-10
hydroxy groups, 1-2 COOH groups, a phenyl group, a benzyl group
and/or 1-5 --OR.sup.9 groups, with R.sup.9 in the meaning of a
hydrogen atom or a C.sub.1-C.sub.7-alkyl radical, or
-L.sup.1-R.sup.F,
[0140] L.sup.1 means a straight-chain or branched
C.sub.1-C.sub.30-alkylen- e group, which optionally is interrupted
by 1-10 oxygen atoms, 1-5 --NH--CO groups, 1-5 --CO--NH groups, by
a phenylene group optionally substituted by a COOH group, 1-3
sulfur atoms, 1-2 --N(B.sup.1)--SO.sub.2 groups and/or 1-2
--SO.sub.2--N(B.sup.1) groups with B.sup.1 in the meaning of
A.sup.1, an NHCO group, a CONH group, an N(B.sup.1)--SO.sub.2 group
or an --SO.sub.2--N(B.sup.1) group and/or optionally is substituted
with radical R.sup.F, and
[0141] R.sup.F means a straight-chain or branched perfluorinated
alkyl radical of formula C.sub.nF.sub.2nE, whereby n stands for
numbers 4-30, and
[0142] E stands for a terminal fluorine atom, chlorine atom,
bromine atom, iodine atom or a hydrogen atom, and optionally
present acid groups optionally can be present as salts of organic
and/or inorganic bases or amino acids or amino acid amides, can be
used.
[0143] Since the compounds according to the invention are intended
for use in NMR diagnosis, the metal ion of the signaling group must
be paramagnetic. These are in particular the divalent and trivalent
ions of the elements of atomic numbers 23-29, 42-46 and 58-70.
Suitable ions are, for example, the chromium(III), iron(II),
cobalt(II), nickel(II), copper(II), praseodymium(III),
neodymium(III), samarium(III) and ytterbium(III) ions. Because of
their strong magnetic moments, gadolinium(III), terbium(III),
dysprosium(III), holmium(III), erbium(III), iron(III) and
manganese(II) ions are especially preferred.
[0144] Preferred are manganese(II), iron(II), iron(III),
praseodymium(III), neodymium(III), samarium(III), gadolinium(III)
and ytterbium(III) ions, especially dysprosium(III) ions.
[0145] Alkyl groups R.sup.2, R.sup.3, and R.sup.9 can be
straight-chain or branched. By way of example, methyl, ethyl,
propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl,
n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, and
1,2-dimethylpropyl can be mentioned.
[0146] Hydrogen and C.sub.1-C.sub.4 alkyl groups are preferred for
R.sup.2, R.sup.3 and R.sup.9; hydrogen and the methyl group are
especially preferred.
[0147] The benzyl group and phenyl group R.sup.2, A.sup.1 and
B.sup.1 can be substituted in the phenyl ring. The COOH group is
suitable as a substituent.
[0148] If the compound of formula Ib contains radicals L.sup.1 and
U.sup.2 at the same time, L.sup.1 and U.sup.2 can be different from
one another.
[0149] C.sub.1-C.sub.30 alkylene groups U.sup.2 can be
straight-chain or branched. By way of example, methylene, ethylene,
propylene, isopropylene, n-butylene, 1-methylpropylene,
2-methylpropylene, n-pentylene, 1-methylbutylene, 2-methylbutylene,
3-methylbutylene, and 1,2-dimethylpropylene can be mentioned.
[0150] For U.sup.2 in the meaning of alkylene, C.sub.1-C.sub.10
alkylene groups are preferred; C.sub.1-C.sub.4 alkylene groups are
especially preferred.
[0151] C.sub.1-C.sub.30 alkyl groups A.sup.1 can be straight-chain
or branched. By way of example, methyl, ethyl, propyl, isopropyl,
n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl,
2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, and n-hexyl can
be mentioned.
[0152] C.sub.1-C.sub.30 alkyl groups A.sup.1 can be interrupted by
1-15 oxygen atoms and/or substituted with 1-10 hydroxy groups, 1-5
alkoxy groups or 1-2 COOH groups, such as, e.g.,
C.sub.2H.sub.4--O--CH.sub.3, C.sub.3H.sub.6--O--CH.sub.3,
C.sub.2H.sub.4--O--(C.sub.2H.sub.4--O).sub.t--C.sub.2H.sub.4--OH,
C.sub.2H.sub.4--O--(C.sub.2H.sub.4--O).sub.t--C.sub.2H.sub.4--OCH.sub.3
with t=0 to 13
C.sub.2H.sub.4OH, C.sub.3H.sub.6OH, C.sub.4H.sub.8OH,
C.sub.5H.sub.10OH, C.sub.6H.sub.12OH, C.sub.7H.sub.14OH, as well as
their branched isomers,
CH(OH)CH.sub.2OH,
CH(OH)CH(OH)CH.sub.2OH, CH.sub.2[CH(OH)].sub.u.sup.1CH.sub.2OH,
with u.sup.1--=1-10
CH[CH.sub.2(OH)]CH(OH)CH.sub.2OH,
C.sub.2H.sub.4CH(OH)CH.sub.2OH,
(CH.sub.2).sub.sCOOH with s=1 to 15,
C.sub.2H.sub.4--O--(C.sub.2H.sub.4--O).sub.t--CH.sub.2COOH with t=0
to 13,
C.sub.2H.sub.4--O--(C.sub.2H.sub.4--O).sub.t--C.sub.2H.sub.4--C.sub.nF.sub-
.2nE with t=0 to 13, n=4 to 20 and
[0153] E=a fluorine, hydrogen, chlorine, bromine or iodine
atom.
[0154] Preferred meanings of A.sup.1 are hydrogen,
C.sub.1-C.sub.10-alkyl,
C.sub.2H.sub.4--O--CH.sub.3, C.sub.3H.sub.6--O--CH.sub.3,
C.sub.2H.sub.4--O--(C.sub.2H.sub.4--O).sub.x--C.sub.2H.sub.4--OH,
C.sub.2H.sub.4--O--(C.sub.2H.sub.4--O).sub.x--C.sub.2H.sub.4--OCH.sub.3
with x=0 to 5,
C.sub.2H.sub.4OH, C.sub.3H.sub.6OH,
CH.sub.2[CH(OH)].sub.yCH.sub.2OH, with y=1-6
CH[CH.sub.2(OH)]CH(OH)CH.sub.2OH,
(CH.sub.2).sub.wCOOH with w=1 to 10,
C.sub.2H.sub.4--O--(C.sub.2H.sub.4--O).sub.x--CH.sub.2COOH with x=0
to 5,
C.sub.2H.sub.4--O--(C.sub.2H.sub.4--O).sub.x--C.sub.2H.sub.4--C.sub.nF.sub-
.2nE with x=0 to 5, n=4 to 15, and
[0155] E=a fluorine atom.
[0156] If the compound of general formula Ib contains two radicals
L.sup.1-R.sup.F, these radicals can be different from one
another.
[0157] For radicals L.sup.1, there can be mentioned by way of
example, whereby .alpha. stands for the binding to the nitrogen
atom and .beta. stands for the binding to radical R.sup.F:
.alpha.-(CH.sub.2).sub.s-.beta. with s=1-15
.alpha.-CH.sub.2--CH.sub.2--(O--CH.sub.2--CH.sub.2--).sub.y-.beta.
with y=1-6
.alpha.-CH.sub.2--(O--CH.sub.2--CH.sub.2--).sub.y-.beta. with
y=1-6
.alpha.-CH.sub.2--NH--CO-.beta.
.alpha.-CH.sub.2--CH.sub.2--NH--SO.sub.2-.beta.
.alpha.-CH.sub.2--NH--CO--CH.sub.2--N(CH.sub.2COOH)--SO.sub.2-.beta.
.alpha.-CH.sub.2--NH--CO--CH.sub.2--N(C.sub.2H.sub.5)--SO.sub.2-.beta.
.alpha.-CH.sub.2--NH--CO--CH.sub.2--N(C.sub.10H.sub.21)--SO.sub.2-.beta.
.alpha.-CH.sub.2--NH--CO--CH.sub.2--N(C.sub.6H.sub.13)--SO.sub.2-.beta.
.alpha.-CH.sub.2--NH--CO--(CH.sub.2).sub.10--N(C.sub.2H.sub.5)--SO.sub.2-.-
beta.
.alpha.-CH.sub.2--NH--CO--CH.sub.2--N(--CH.sub.2--C.sub.6H.sub.5)--SO.sub.-
2-.beta.
.alpha.-CH.sub.2--NH--CO--CH.sub.2--N(--CH.sub.2--CH.sub.2--OH)SO.sub.2-.b-
eta.
.alpha.-CH.sub.2--NHCO--(CH.sub.2).sub.10--S--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2NHCOCH.sub.2--O--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2--CH.sub.2NHCOCH.sub.2--O--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2--(CH.sub.2--CH.sub.2--O).sub.y--(CH.sub.2).sub.3NHCO--CH.-
sub.2--O--CH.sub.2CH.sub.2--.beta. with y=1-6
.alpha.-CH.sub.2NHCO(CH.sub.2).sub.10--O--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2CH.sub.2NHCO(CH.sub.2).sub.10--O--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2--C.sub.6H.sub.4--O--CH.sub.2CH.sub.2--O, whereby
the phenylene group 1,4 or 1,3 is linked
.alpha.-CH.sub.2--O--CH.sub.2--C(CH.sub.2--OCH.sub.2CH.sub.2--C.sub.6F.sub-
.13).sub.2--CH.sub.2--OCH.sub.2--CH.sub.2-.beta.
.alpha.-CH.sub.2--NHCOCH.sub.2CH.sub.2CON--CH.sub.2CH.sub.2NHCOCH.sub.2N(C-
.sub.2H.sub.5)SO.sub.2C.sub.8F.sub.17.beta.
.alpha.-CH.sub.2--CH.sub.2NHCOCH.sub.2N(C.sub.2H.sub.5)--SO.sub.2-.beta.
.alpha.-CH.sub.2--O--CH.sub.2--CH(OC.sub.10H.sub.21)--CH.sub.2--O--CH.sub.-
2CH.sub.2-.beta.
.alpha.-(CH.sub.2NHCO).sub.4--CH.sub.2O--CH.sub.2CH.sub.2-.beta.
.alpha.-(CH.sub.2NHCO).sub.3--CH.sub.2O--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2--OCH.sub.2C(CH.sub.2OH).sub.2--CH.sub.2--O--CH.sub.2CH.su-
b.2-.beta. 24
.alpha.-CH.sub.2NHCOCH.sub.2N(C.sub.6H.sub.5)--SO.sub.2-.bet-
a.
.alpha.-NHCO--CH.sub.2--CH.sub.2-.beta.
.alpha.-NHCO--CH.sub.2--O--CH.sub.2CH.sub.2-.beta.
.alpha.-NH--CO-.beta.
.alpha.-NH--CO--CH.sub.2--N(CH.sub.2COOH)--SO.sub.2-.beta.
.alpha.-NH--CO--CH.sub.2--N(C.sub.2H.sub.5)--SO.sub.2-.beta.
.alpha.-NH--CO--CH.sub.2--N(C.sub.10H.sub.21)--SO.sub.2-.beta.
.alpha.-NH--CO--CH.sub.2--N(C.sub.6H.sub.13)--SO.sub.2-.beta.
.alpha.-NH--CO--(CH.sub.2).sub.10--N(C.sub.2H.sub.5)--SO.sub.2-.beta.
.alpha.-NH--CO--CH.sub.2--N(--CH.sub.2--C.sub.6H.sub.5)--SO.sub.2-.beta.
.alpha.-NH--CO--CH.sub.2--N(--CH.sub.2--CH.sub.2--OH)SO.sub.2-.beta.
.alpha.-NH--CO--CH.sub.2-.beta.
.alpha.-CH.sub.2--O--C.sub.6H.sub.4--O--CH.sub.2--CH.sub.2-.beta.
.alpha.-CH.sub.2--C.sub.6H.sub.4--O--CH.sub.2--CH.sub.2-.beta.
.alpha.-N(C.sub.2H.sub.5)--SO.sub.2-.beta.
.alpha.-N(C.sub.6H.sub.5)--SO.sub.2-.beta.
.alpha.-N(C.sub.10H.sub.21)--SO.sub.2-.beta.
.alpha.-N(C.sub.6H.sub.13)--SO.sub.2-.beta.
.alpha.-N(C.sub.2H.sub.4OH)--SO.sub.2-.beta.
.alpha.-N(CH.sub.2COOH)--SO.sub.2-.beta.
.alpha.-N(CH.sub.2C.sub.6H.sub.5)--SO.sub.2-.beta.
.alpha.-N--[CH(CH.sub.2OH).sub.2]--SO.sub.2-.beta.
.alpha.-N--[CH(CH.sub.2OH)CH(OH)(CH.sub.2OH)]--SO.sub.2-.beta.
[0158] Preferred are:
.alpha.-CH.sub.2--O--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2--CH.sub.2--(O--CH.sub.2--CH.sub.2--).sub.y-.beta.
with y=1-6
.alpha.-CH.sub.2--(O--CH.sub.2--CH.sub.2--).sub.y-.beta. with
y=1-6
.alpha.-CH.sub.2--CH.sub.2--NH--SO.sub.2-.beta. Example 10
.alpha.-CH.sub.2NHCOCH.sub.2--O--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2--CH.sub.2NHCOCH.sub.2--O--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2--(CH.sub.2--CH.sub.2--O).sub.y--(CH.sub.2).sub.3NHCO--CH.-
sub.2--O--CH.sub.2CH.sub.2--.beta. with y=1-6
.alpha.-CH.sub.2NHCO(CH.sub.2).sub.10--O--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2CH.sub.2NHCO(CH.sub.2).sub.10--O--CH.sub.2CH.sub.2-.beta.
.alpha.-CH.sub.2--O--CH.sub.2--CH(OC.sub.10H.sub.21)--CH.sub.2--O--CH.sub.-
2CH.sub.2-.beta.
.alpha.-CH.sub.2--O--C.sub.6H.sub.4--O--CH.sub.2--CH.sub.2-.beta.
.alpha.-CH.sub.2--C.sub.6H.sub.4--O--CH.sub.2--CH.sub.2-.beta.
[0159] According to the invention, radicals L.sup.1 of the
compounds mentioned in the examples of the description of this
invention are quite especially preferred.
[0160] U.sup.2 is considered to stand for the above-cited radicals
for L.sup.1 and the radicals that are characterized as preferred
and especially preferred, and the above-cited and optionally
preferred and especially preferred radicals are considered to stand
for the meaning of alkylene, provided that no .alpha.-position
nitrogen atom and no terminal (P-position) SO.sub.2 or CO group
must be present.
[0161] Preferred radicals B.sup.1 are hydrogen, straight-chain or
branched C.sub.1-C.sub.10-alkyl radicals, which optionally are
interrupted by 1-5 oxygen atoms and/or optionally are substituted
with 1-5 hydroxy groups, 1-2 COOH groups, a phenyl group optionally
substituted by a COOH group, a benzyl group and/or 1-5 OR.sup.9
groups, with R.sup.9 in the meaning of a hydrogen atom or a
C.sub.1-C.sub.3 alkyl radical.
[0162] Preferred radicals R.sup.F are straight-chain or branched
perfluorinated alkyl radicals of formula C.sub.nF.sub.2nE, whereby
n stands for numbers 4 to 15 and E stands for a terminal fluorine
atom.
[0163] The production of the compounds of general formula Ib
according to the invention 25
[0164] with
[0165] K in the meaning of a complexing agent or a metal complex of
general formula IIb 26
[0166] can be carried out according to the following process:
[0167] Process A.
[0168] The carboxylic acid of Formula IIIb already contains metal
ion equivalent R.sup.1. 27
[0169] Carboxylic acid IIIb that is optionally activated in situ
with R.sup.1 in the meaning of a metal ion equivalent is reacted
with an amine IVb in a coupling reaction to form an amide Ib.
[0170] This process for the production of metal complex carboxylic
acid amides is known from DE 196 52 386.
[0171] The mixture of metal complex carboxylic acid IIIb that is
used in the coupling reaction and that contains optionally present
carboxy and/or hydroxy groups in protected form and at least one
solubilizing substance in an amount up to 5, preferably 0.5-2 molar
equivalents relative to the metal complex carboxylic acid, can both
be produced in an upstream reaction stage and isolated (e.g., by
concentration by evaporation, freeze-drying or spray-drying of an
aqueous or water-miscible solution of components or by
precipitation with an organic solvent from such a solution) and
then can be reacted in DMSO with dehydrating reagent and optionally
a coupling adjuvant and can be formed in situ optionally by the
addition of solubilizing substance(s) for DMSO-suspension of metal
complex carboxylic acid, dehydrating reagent and optionally a
coupling adjuvant.
[0172] The reaction solution that is produced according to one of
these processes is kept for pretreatment (acid activation) for 1 to
24 hours, preferably 3 to 12 hours at temperatures of 0 to
50.degree. C., preferably at room temperature.
[0173] Then, an amine of general formula IVb 28
[0174] in which radicals R.sup.3, L.sup.1, R.sup.F and A have the
above-indicated meanings, is added without solvent or dissolved in,
for example, dimethyl sulfoxide, alcohols, such as, e.g., methanol,
ethanol, isopropanol or mixtures thereof, formamide,
dimethylformamide, water or mixtures of the cited solvents,
preferably in dimethyl sulfoxide, in water or in solvents that are
mixed with water. For amide coupling, the thus obtained reaction
solution is kept at temperatures of 0 to 70.degree. C., preferably
30 to 60.degree. C., for 1 to 48 hours, preferably 8 to 24
hours.
[0175] In some cases, it has proven advantageous to use the amine
in the form of its salts, e.g., as hydrobromide or hydrochloride,
in the reaction. To release the amine, a base such as, e.g.,
triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine,
tripropylamine, tributylamine, lithium hydroxide, lithium
carbonate, sodium hydroxide or sodium carbonate is added.
[0176] The optionally still present protective groups are then
cleaved off.
[0177] The isolation of the reaction product is carried out
according to the methods that are known to one skilled in the art,
preferably by precipitation with organic solvents, preferably
acetone, 2-butanone, diethyl ether, ethyl acetate,
methyl-t-butylether, isopropanol or mixtures thereof. Further
purification can be carried out by, for example, chromatography,
crystallization or ultrafiltration.
[0178] As solubilizing substances, alkali salts, alkaline-earth
salts, trialkylammonium salts, tetraalkylammonium salts, ureas,
N-hydroxyimides, hydroxyaryltriazoles, substituted phenols and
salts of heterocyclic amines are suitable. By way of example, there
can be mentioned: lithium chloride, lithium bromide, lithium
iodide, sodium bromide, sodium iodide, lithium methanesulfonate,
sodium methanesulfonate, lithium-p-toluenesulfonate,
sodium-p-toluenesulfonate, potassium bromide, potassium iodide,
sodium chloride, magnesium bromide, magnesium chloride, magnesium
iodide, tetraethylammonium-p-toluenesulfonate,
tetramethylammonium-p-toluenesulfonate,
pyridinium-p-toluenesulfonate, triethylammonium-p-toluenesulfonate,
2-morpholinoethylsulfonic acid, 4-nitrophenol, 3,5-dinitrophenol,
2,4-dichlorophenol, N-hydroxysuccinimide, N-hydroxyphthalimide,
urea, tetramethylurea, N-methylpyrrolidone, formamide, as well as
cyclic ureas, whereby the five first-mentioned are preferred.
[0179] As dehydrating reagents, all agents that are known to one
skilled in the art are used. By way of example, carbodiimides and
onium reagents, such as, e.g., dicyclohexylcarbodiimide (DCCI),
1-ethyl-3-(3-dimethylamin- opropyl)-carbodiimide-hydroxychloride
(EDC), benzotriazol-1-yloxytris(dime- thylamino)-phosphonium
hexafluorophosphate (BOP) and
O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate
(HBTU), preferably DCCI, can be mentioned.
[0180] In the literature, for example, the following suitable
processes are described:
[0181] Aktivierung von Carbonsuren. bersicht in Houben-Weyl,
Methoden der Organischen Chemie [Activation of Carboxylic Acids.
Survey in Houben-Weyl, Methods of Organic Chemistry], Volume XV/2,
Georg Thieme Verlag Stuttgart, 1974 (and J. Chem. Research (S)
1996, 302).
[0182] Aktivierung mit Carbodiimiden [Activation with
Carbodiimides]. R. Schwyzer and H. Kappeler, Helv. 46: 1550
(1963).
[0183] E. Wunsch et al., Vol. 100: 173 (1967).
[0184] Aktivierung mit Carbodiimiden/Hydroxysuccinimid [Activation
with Carbodiimides/Hydroxysuccinimide]: J. Am. Chem. Soc. 86: 1839
(1964) and J. Org. Chem. 53: 3583 (1988). Synthesis 453 (1972).
[0185] Anhydridmethode,
2-Ethoxy-1-ethoxycarbonyl-1,2-dihydrochinolin [Anhydride Methods,
2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline]: B. Belleau et al.,
J.
[0186] Am. Chem. Soc., 90: 1651 (1986), H. Kunz et al., Int. J.
Pept. Prot. Res., 26: 493 (1985) and J. R. Voughn, Am. Soc. 73:
3547 (1951).
[0187] Imidazolid-Methode [Imidazolide Methods]: B. F. Gisin; R. B.
Menifield; D. C. Tosteon, Am. Soc. 91: 2691 (1969).
[0188] Surechlorid-Methoden, Thionylchlorid [Acid Chloride Methods,
Thionyl Chloride]: Helv., 42: 1653 (1959).
[0189] Oxalylchlorid [Oxalyl Chloride]: J. Org. Chem., 29: 843
(1964).
[0190] As coupling adjuvants that are optionally to be used, all
that are known to one skilled in the art are suitable (Houben-Weyl,
Methoden der organischen Chemie, Volume XV/2, Georg Thieme-Verlag,
Stuttgart, 1974). By way of example, 4-nitrophenol,
N-hydroxysuccinimide, 1-hydroxybenzotriazole,
1-hydroxy-7-aza-benzotriazole, 3,5-dinitrophenol and
pentafluorophenol can be mentioned. Preferred are 4-nitrophenol and
N-hydroxysuccinimide; especially preferred in this case is the
first-mentioned reagent.
[0191] The cleavage of the protective groups is carried out
according to the processes that are known to one skilled in the
art, for example by hydrolysis, hydrogenolysis, alkaline
saponification of esters with alkali in aqueous-alcoholic solution
at temperatures of 0.degree. to 50.degree. C., acid saponification
with mineral acids or in the case of, e.g., tert-butylesters with
the aid of trifluoroacetic acid [Protective Groups in Organic
Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, John Wiley
and Sons, Inc. New York, 1991], in the case of benzyl ethers with
hydrogen/palladium/carbon.
[0192] The production of the starting material, the compounds of
Formula IIIb, 29
[0193] is known from DE 196 52 386.
[0194] The amines of general formula IVb 30
[0195] are commercially available products (Fluorochem, ABCR) or
can be obtained according to the following process from compounds
of general formula Vb by reaction with an amine of general formula
VIb and subsequent reduction of the compounds of general formula
VIIb: 31
[0196] in which
[0197] R.sup.F, A.sup.1, L.sup.1 and R.sup.3 have the
above-mentioned meaning, and L' has the meaning of group L.sup.1,
in which the .alpha.-CH.sub.2-group is still missing, and
[0198] R.sup.9 stands for hydrogen or a methyl group.
[0199] According to the process described in the literature that
was already disclosed above for the activation of carboxylic acid
IIIb, acid Vb is activated with amine VIb before the reaction. For
R.sup.9 in the meaning of a methyl group, an aminolysis is
performed.
[0200] The compounds of general formula Vb are commercially
available products (Fluorochem, ABCR) or are produced as disclosed
in DE 196 03 033.
[0201] The compounds of general formula VIb are commercially
available products (Fluorochem, ABCR) or can be produced as
described in Houben-Weyl, Methoden der organischen Chemie, XI/2
Stickstoffverbindungen [XI/2 Nitrogen Compounds], Georg Thieme
Verlag Stuttgart, 1957, p. 680; J. E. Rickman and T. Atkins, Am.
Chem. Soc., 96:2268, 1974, 96: 2268; F. Chavez and A. D. Sherry. J.
Org. Chem. 1989, 54: 2990.
[0202] The compounds of general formula IVb are obtained in a way
that is known in the art [Helv. Chim. Acta. 77: 23 (1994)] by
reduction of the compounds of general formula VII, for example,
with diborane or lithium aluminum hydride and cleavage of the
protective groups.
[0203] Process B.
[0204] As starting material, the carboxylic acid of formula IIIx is
used with R.sup.1 in the meaning of hydrogen--it still does not
contain any metal ion equivalent R.sup.1. The carboxyl groups are
protected according to the processes that are known to one skilled
in the art, and a compound of Formula IIIy is obtained, whereby
R.sup.5 stands for any protective group and R.sup.5' stands for its
precursor. 32
[0205] As carboxyl protective groups, e.g., straight-chain or
branched C.sub.1-C.sub.6 alkyl, aryl and aralkyl groups, for
example, the methyl, ethyl, propyl, butyl, phenyl, benzyl,
diphenylmethyl, triphenylmethyl, bis(p-nitrophenyl)-methyl group
and trialkylsilyl groups are suitable. The t-butyl group is
preferred. 33
[0206] The reaction of the protected carboxylic acid IIIy with the
amine of formula IVb and the cleavage of the protective groups is
carried out as described under process A and in a subsequent step,
the obtained carboxylic acid Ix is reacted with at least one metal
oxide or metal salt of an element of the desired atomic number as
is disclosed in, e.g., DE 195 25 924.
[0207] If the metal complex that is obtained from process A or B
still contains free COOH groups, these groups can also be present
as salts of physiologically compatible inorganic or organic
bases.
[0208] The neutralization of optionally still present free carboxy
groups is then carried out with the aid of inorganic bases (for
example, hydroxides, carbonates or bicarbonates) of, for example,
sodium, potassium, lithium, magnesium, or calcium and/or organic
bases such as, i.a., primary, secondary and tertiary amines, such
as, for example, ethanolamine, morpholine, glucamine, N-methyl- and
N,N-dimethylglucamine, as well as basic amino acids, such as, for
example, lysine, arginine, and ornithine, or amides of originally
neutral or acidic amino acids.
[0209] According to the invention, quite especially preferably
metal complexes V, VII, VIII, IX and X (cf. Table 1) are used.
[0210] These compounds of general formula Ib are very well suited
as MRI contrast media for visualization of plaque.
[0211] In another preferred embodiment of the invention, the
perfluoroalkyl-containing complexes with sugar radicals of general
formula Ic
(K).sub.l.sup.1-G-(Z-R.sup.F).sub.m.sup.1
(Y--R).sub.p.sup.1 (Ic)
[0212] in which
[0213] R represents a mono-or oligosaccharide radical bonded by the
1-OH-- or 1-SH-position,
[0214] R.sup.F is a perfluorinated, straight-chain or branched
carbon chain with the formula --C.sub.nF.sub.2nE, in which E
represents a terminal fluorine, chlorine, bromine, iodine or
hydrogen atom, and n stands for numbers 4-30,
[0215] K stands for a metal complex of general formula IIc, 34
[0216] in which
[0217] R.sup.1 means a hydrogen atom or a metal ion equivalent of
atomic numbers 23-29, 42-46 or 58-70,
[0218] provided that at least two R.sup.1 stand for metal ion
equivalents,
[0219] R.sup.2 and R.sup.3, independently of one another, represent
hydrogen, C.sub.1-C.sub.7 alkyl, benzyl, phenyl, --CH.sub.2OH or
--CH.sub.2OCH.sub.3, and
[0220] U represents --C.sub.6H.sub.4--O--CH.sub.2-.omega.,
--(CH.sub.2).sub.1-5-.omega., a phenylene group,
--CH.sub.2--NHCO--CH.sub-
.2--CH(CH.sub.2COOH)--C.sub.6H.sub.4-.omega.,
--C.sub.6H.sub.4--(OCH.sub.2-
CH.sub.2).sub.0-1--N(CH.sub.2COOH)--CH.sub.2-.omega., or a
C.sub.1-C.sub.12 alkylene group or
C.sub.7-C.sub.12--C.sub.6H.sub.4--O group optionally interrupted by
one or more oxygen atoms, 1 to 3 --NHCO groups or 1 to 3 --CONH
groups and/or substituted with 1 to 3 --(CH.sub.2).sub.0-5COOH
groups, whereby (o stands for the binding site to --CO--, or
[0221] of general formula IIIc 35
[0222] in which R.sup.1 has the above-mentioned meaning, R.sup.4
represents hydrogen or a metal ion equivalent mentioned under
R.sup.1, and U.sup.1 represents
--C.sub.6H.sub.4--O--CH.sub.2-.omega., whereby .omega. means the
binding site to --CO--, or of general formula IVc 36
[0223] in which R.sup.1 and R.sup.2 have the above-mentioned
meaning
[0224] or of general formula VcA or VcB 37
[0225] in which R.sup.1 has the above-mentioned meaning,
[0226] or of general formula VIc 38
[0227] in which R.sup.1 has the above-mentioned meaning,
[0228] or of general formula VIIc 39
[0229] in which R.sup.1 has the above-mentioned meaning, and
[0230] U.sup.1 represents --C.sub.6H.sub.4--O--CH.sub.2-.omega.,
whereby .omega. means the binding site to --CO-- or of general
formula VIIc 40
[0231] in which R.sup.1 has the above-mentioned meaning,
[0232] and in radical K, optionally present free acid groups
optionally can be present as salts of organic and/or inorganic
bases or amino acids or amino acid amides,
[0233] G for the case that K means metal complexes IIc to VIc,
represents a radical that is functionalized in at least three
places and is selected from the following radicals a) to j)
4142
[0234] G for the case that K means metal complex VIIc, represents a
radical that is functionalized in at least three places and is
selected from k) or l) 43
[0235] whereby .alpha. means the binding site of G to complex K,
.beta. is the binding site of G to radical Y, and .gamma.
represents the binding site of G to radical Z,
[0236] Y means --CH.sub.2, .delta.-(CH.sub.2).sub.1-5CO-.beta.,
.delta.-CH.sub.2--CHOH--CO--.beta. or
6-CH(CHOH--CH.sub.2OH)--CHOH--CHOH-- -CO-.beta., whereby .delta.
represents the binding site to sugar radical R, and .beta. is the
binding site to radical G,
[0237] Z stands for 44
.gamma.-COCH.sub.2--N(C.sub.2H.sub.5)--SO.sub.2-.e- psilon.,
.gamma.-COCH.sub.2--O--(CH.sub.2).sub.2--SO.sub.2-.epsilon., 45
[0238] or
.gamma.-NHCH.sub.2CH.sub.2--O--CH.sub.2CH.sub.2-.epsilon.
[0239] whereby .gamma. represents the binding site of Z to radical
G, and .epsilon. means the binding site of Z to perfluorinated
radical R.sup.F and
[0240] l.sup.1, m.sup.1, independently of one another, mean integer
1 or 2, and
[0241] p.sup.1 means integers 1 to 4, can be used.
[0242] Since the compounds according to the invention are intended
for use in NMR-diagnosis, the metal ion of the signaling group must
be paramagnetic. These are especially the divalent and trivalent
ions of the elements of atomic numbers 23-29, 42-46 and 58-70.
Suitable ions are, for example, the chromium(III), iron(II),
cobalt(II), nickel(II), copper(II), praseodymium(III),
neodymium(III), samarium(III) and ytterbium(III) ion. Because of
their strong magnetic moment, gadolinium(III), terbium(III),
dysprosium(III), holmium(III), erbium(III), iron(III) and
manganese(II) ions are especially preferred.
[0243] Preferred are manganese(II), iron(II), iron(III),
praseodymium(III), neodymium(III), samarium(III), gadolinium(III)
and ytterbium(III) ions, especially dysprosium(III) ions.
[0244] In R.sup.1, optionally present acidic hydrogen atoms, i.e.,
those that have not been substituted by the central ion, can
optionally be replaced completely or partially by cations of
inorganic and/or organic bases or amino acids or amino acid
amides.
[0245] Suitable inorganic cations are, for example, the lithium
ion, the potassium ion, the calcium ion and especially the sodium
ion. Suitable cations of organic bases are, i.a., 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 as well as
the amides of otherwise acidic or neutral amino acids.
[0246] Especially preferred compounds of general formula Ic are
those with macrocyclic compound K of general formula IIc.
[0247] Radical U in metal complex K means preferably --CH.sub.2--
or C.sub.6H.sub.4--O--CH.sub.2-.omega., whereby .omega. stands for
the binding site to --CO--.
[0248] Alkyl groups R.sup.2 and R.sup.3 in the macrocyclic compound
of general formula IIc can be straight-chain or branched. By way of
example, methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl,
2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl,
3-methylbutyl, and 1,2-dimethylpropyl can be mentioned. R.sup.2 and
R.sup.3, independently of one another, preferably mean hydrogen or
C.sub.1-C.sub.4-alkyl. In a quite especially preferred embodiment,
R.sup.2 stands for methyl and R.sup.3 stands for hydrogen.
[0249] The benzyl group or phenyl group R.sup.2 or R.sup.3 in
macrocyclic compound K of general formula IIc can also be
substituted in the ring.
[0250] Radical R in general formula Ic means a mono- or
oligosaccharide radical or thiosugar radical that is bonded via the
1-OH-- or 1-SH-position, whereby in this connection according to
the invention, this can be a deoxy sugar, which contains an H atom
instead of one or more OH groups. In a preferred embodiment of the
invention, R means a monosaccharide radical with 5 or 6 C atoms,
preferably glucose, mannose, galactose, ribose, arabinose or xylose
or their deoxy sugars, such as, for example, 6-deoxygalactose
(fucose) or 6-deoxymannose (rhamnose) or their thiosugars, whereby
glucose, mannose and galactose are especially preferred.
[0251] Of the compounds of general formula Ic according to the
invention, in addition those are preferred in which R.sup.F means
--C.sub.nF.sub.2n+1. n preferably stands for numbers 4-15. Quite
especially preferred are radicals --C.sub.4F.sub.9,
--C.sub.6F.sub.13, --C.sub.8F.sub.17, --C.sub.12F.sub.25 and
--C.sub.14F.sub.29 as well as the compounds that are mentioned in
the examples.
[0252] Radical G that is functionalized in at least three places in
general formula Ic, which represents the "skeleton," means lysine
radical (a) or (b) in a preferred embodiment of the invention.
[0253] Y and Z mean the linkers indicated in general formula Ic,
whereby independently of one another, radical 46
[0254] is preferred for Z, and radical .delta.-CH.sub.2CO-.beta. is
preferred for Y.
[0255] The perfluoroalkyl-containing metal complexes with sugar
radicals of general formula Ic 47
[0256] with K in the meaning of a metal complex of general formulas
IIc to VIc and G in the meaning of formulas a) to j), whereby Y, Z,
R, R.sup.F, m.sup.1, p.sup.1 and l.sup.1 have the above-mentioned
meaning, are produced by a carboxylic acid of general formula IIi
48
[0257] in which R.sup.5 means a metal ion equivalent of atomic
numbers 23-29, 42-46, or 58-70 or a carboxyl protective group, and
R.sup.2, R.sup.3 and U have the above-mentioned meaning,
[0258] or a carboxylic acid of general formula IIIi 49
[0259] in which R.sup.4, R.sup.5 and U.sup.1 have the
above-mentioned meaning
[0260] or a carboxylic acid of general formula IVi 50
[0261] in which R.sup.5 and R.sup.2 have the above-mentioned
meaning
[0262] or a carboxylic acid of general formula Vi or Vii 51
[0263] in which R.sup.5 has the above-mentioned meaning
[0264] or a carboxylic acid of general formula VIi 52
[0265] in which R.sup.5 has the above-mentioned meaning
[0266] or a carboxylic acid of general formula VIIi 53
[0267] in which R.sup.5 and U.sup.1 have the above-mentioned
meanings,
[0268] being reacted in a way that is known in the art in
optionally activated form with an amine of general formula IXc
54
[0269] in which G has the meaning of formulas a) to j), and R,
R.sup.F, Y, Z, m.sup.1 and p.sup.1 have the indicated meaning, in a
coupling reaction and optionally subsequent cleavage of optionally
present protective groups to form a metal complex of general
formula Ic or
[0270] if R.sup.5 has the meaning of a protective group, after
cleavage of these protective groups in a subsequent step being
reacted in a way that is known in the art with at least one metal
oxide or metal salt of an element of atomic numbers 23-29, 42-46 or
58-70, and then, if desired, optionally present acidic hydrogen
atoms being substituted by cations of inorganic and/or organic
bases, amino acids or amino acid amides.
[0271] The compounds of general formula Ic according to the
invention with K in the meaning of a metal complex of general
formula VIIc and G in the meaning of formulas k) or l) are produced
by an amine of general formula VIIIi 55
[0272] in which R.sup.5 means a metal ion equivalent of atomic
numbers 23-29, 42-46 or 58-70 or a carboxyl protective group,
[0273] being reacted in a way that is known in the art with an
optionally activated carboxylic acid of general formula Xc 56
[0274] in which G has the meaning of formula k) or l) and R,
R.sup.F, Y, Z, m.sup.1 and p.sup.1 have the indicated meanings, in
a coupling reaction and optionally subsequent cleavage of
optionally present protective groups to form a metal complex of
general formula Ic or
[0275] if R.sup.5 has the meaning of a protective group, after
cleavage of these protective groups in a subsequent step, being
reacted in a way that is known in the art with at least one metal
oxide or metal salt of an element of atomic numbers 23-29, 42-46 or
58-70, and then, if desired, optionally present acidic hydrogen
atoms being substituted by cations of inorganic and/or organic
bases, amino acids or amino acid amides.
[0276] The carboxylic acids of general formulas IIi to VIIi that
are used are either known compounds or are produced according to
the processes that are described in the examples. Thus, the
production of carboxylic acids of general formula IIi is known from
DE 196 52 386. The production of the carboxylic acids of general
formula IVi can be found in DE 197 28 954.
[0277] A precursor for compounds of general formula VcA is the
N.sup.3-(2,6-dioxomorpholinoethyl)-N.sup.6-(ethoxycarbonylmethyl)-3,6-dia-
za-octanedioic acid, which is described in EP 263 059.
[0278] The compounds of general formula VcB are derived from the
isomeric diethylenetriamine-pentaacetic acid, which binds via
acetic acid on the center N atom. This DTPA is described in Patents
DE 195 07 819 and DE 195 08 058.
[0279] Compounds of general formula VIc are derived from
N-(carboxymethyl)-N-[2-(2,6-dioxo-4-morpholinyl)-ethyl]-glycine,
whose production is described in J. Am. Oil. Chem. Soc. (1982), 59
(2), 104-107.
[0280] Compounds of general formula VIc are derived from the
1-(4-carboxymethoxybenzyl)-ethylenediamine-tetraacetic acid, which
is described in Patent U.S. Pat. No. 4,622,420.
[0281] The perbenzylated sugar acids that are used as starting
substances can be produced analogously to Lockhoff, Angew. Chem.
1998, 110 No. 24, p. 3634 ff. For example, the production of
1-O-acetic acid from perbenzyl-glucose is carried out over 2
stages, via trichloroacetimidate and reaction with hydroxyacetic
acid ethyl ester, BF.sub.3-catalysis in THF and subsequent
saponification with NaOH in MeOH/THF.
[0282] In a more advantageous process, the perbenzylated sugar
acids that are used as starting substances can also be produced by
the perbenzylated 1-OH-sugar being dissolved in a water-immiscible
organic solvent and being reacted with an alkylating reagent of
general formula XIc
Nu-L-COO-Sg (XIc),
[0283] in which Nu means a nucleofuge, L is --(CH.sub.2).sub.(1-5),
--CH.sub.2--CHOH--,
[0284] --CH(CHOH--CH.sub.2OH)--CHOH--CHOH--, and Sg represents a
protective group,
[0285] in the presence of a base and optionally a phase transfer
catalyst. As a nucleofuge, for example, the radicals --Cl, --Br,
--I, --OTs, --OMs, --OSO.sub.2CF.sub.3, --OSO.sub.2C.sub.4F.sub.9
or --OSO.sub.2C.sub.8F.sub- .17 can be contained in the alkylating
reagent of general formula XIc.
[0286] The protective group is a common acid protective group.
These protective groups are well known to one skilled in the art
(Protective Groups in Organic Syntheses, Second Edition, T. W.
Greene and P. G. M. Wuts, John Wiley & Sons, Inc., New York
1991).
[0287] The reaction according to the invention can be carried out
at temperatures from 0-50.degree. C., preferably from 0.degree. C.
to room temperature. The reaction times are 10 minutes to 24 hours,
preferably 20 minutes to 12 hours.
[0288] The base is added either in solid form, preferably
fine-powder, or as 10-70%, preferably 30-50%, aqueous solution.
NaOH and KOH are used as preferred bases.
[0289] As organic, water-immiscible solvent, for example, toluene,
benzene, CF.sub.3-benzene, hexane, cyclohexane, diethyl ether,
tetrahydrofuran, dichloromethane, MTB or mixtures thereof can be
used in the alkylating process according to the invention.
[0290] As phase-transfer catalysts, the quaternary ammonium or
phosphonium salts or else crown ethers, such as, e.g., [15]-crown-5
or [18]-crown-6, that are known for this purpose are used in the
process according to the invention. Quaternary ammonium salts with
four identical or different hydrocarbon groups at the cation,
selected from methyl, ethyl, propyl, isopropyl, butyl or isobutyl,
are preferably suitable. The hydrocarbon groups at the cation must
be large enough to ensure good solubility of the alkylating reagent
in the organic solvent. According to the invention,
N(butyl).sub.4.sup.+-Cl.sup.-, N(butyl).sub.4.sup.+-HSO.sub.4.-
sup.-, but also N(methyl).sub.4.sup.+-Cl.sup.- are especially
preferably used.
[0291] As quite especially preferred compounds of general formula
Ic, metal complex XV of Table 1 (Example 1) according to the
invention is used.
[0292] In another preferred embodiment of the invention, the
perfluoroalkyl-containing complexes with polar radicals of general
formula Id are used 57
[0293] in which
[0294] R.sup.F is a perfluorinated, straight-chain or branched
carbon chain with formula --C.sub.nF.sub.2nE, in which E represents
a terminal fluorine, chlorine, bromine, iodine or hydrogen atom,
and n stands for numbers 4-30,
[0295] K stands for a metal complex of general formula IId, 58
[0296] in which
[0297] R.sup.1 means a hydrogen atom or a metal ion equivalent of
atomic numbers 23-29, 42-46 or 58-70,
[0298] provided that at least two R.sup.1 stand for metal ion
equivalents,
[0299] R.sup.2 and R.sup.3, independently of one another, represent
hydrogen, C.sub.1-C.sub.7-alkyl, benzyl, phenyl, --CH.sub.2OH or
--CH.sub.2OCH.sub.3, and
[0300] U represents --C.sub.6H.sub.4--O--CH.sub.2-.omega.,
--(CH.sub.2).sub.1-5-.omega., a phenylene group,
--CH.sub.2--NHCO--CH.sub-
.2--CH(CH.sub.2COOH)--C.sub.6H.sub.4-.omega.-,
--C.sub.6H.sub.4--(OCH.sub.-
2CH.sub.2).sub.0-1--N(CH.sub.2COOH)--CH.sub.2-.omega., or a
C.sub.1-C.sub.12-alkylene group or
C.sub.7-C.sub.12-C.sub.6H.sub.4--O group optionally interrupted by
one or more oxygen atoms, 1 to 3 --NHCO groups, 1 to 3 --CONH
groups and/or substituted with 1 to 3 --(CH.sub.2).sub.0-5COOH
groups, whereby .omega. stands for the binding site to --CO--,
or
[0301] of general formula IIId 59
[0302] in which R.sup.1 has the above-mentioned meaning, R.sup.4
represents hydrogen or a metal ion equivalent mentioned under
R.sup.1, and U.sup.1 represents
--C.sub.6H.sub.4--O--CH.sub.2-.omega., whereby .omega. means the
binding site to --CO--,
[0303] or of general formula IVd 60
[0304] in which R.sup.1 and R.sup.2 have the above-mentioned
meaning,
[0305] or of general formula VdA or VdB 61
[0306] in which R.sup.1 has the above-mentioned meaning,
[0307] or of general formula VId 62
[0308] in which R.sup.1 has the above-mentioned meaning,
[0309] or of general formula VIId 63
[0310] in which R.sup.1 has the above-mentioned meaning, and
[0311] U.sup.1 represents --C.sub.6H.sub.4--O--CH.sub.2-.omega.-,
whereby .omega. means the binding site to --CO--,
[0312] and in radical K, optionally present free acid groups
optionally can be present as salts of organic and/or inorganic
bases or amino acids or amino acid amides,
[0313] G represents a radical that is functionalized in at least
three places and is selected from the following radicals a) to g)
6465
[0314] (h)
[0315] whereby .alpha. means the binding site of G to complex K,
.beta. is the binding site of G to radical R, and .gamma.
represents the binding site of G to radical Z
[0316] Z stands for 66
.gamma.-C(O)CH.sub.2O(CH.sub.2).sub.2-.epsilon.,
[0317] whereby .gamma. represents the binding site of Z to radical
G and .epsilon. means the binding site of Z to perfluorinated
radical R.sup.F,
[0318] R represents a polar radical that is selected from complexes
K of general formulas IId to VId, whereby R.sup.1 here means a
hydrogen atom or a metal ion equivalent of atomic numbers 20,
23-29, 42-46 or 58-70,
[0319] and radicals R.sup.2, R.sup.3, R.sup.4, U and U.sup.1 have
the above-indicated meaning, or
[0320] the folic acid radical or
[0321] R means a carbon chain with 2-30 C atoms that is bonded to
radical G via --CO-- or SO.sub.2-- and is straight or branched,
saturated or unsaturated, optionally interrupted by 1-10 oxygen
atoms, 1-5 --NHCO groups, 1-5 --CONH groups, 1-2 sulfur atoms, 1-5
--NH groups or 1-2 phenylene groups, which optionally can be
substituted with 1-2 OH groups, 1-2 NH.sub.2 groups, 1-2 --COOH
groups, or 1-2 --SO.sub.3H groups, or
[0322] optionally substituted with 1-8 OH groups, 1-5 --COOH
groups, 1-2 SO.sub.3H groups, 1-5 NH.sub.2 groups, 1-5
C.sub.1-C.sub.4-alkoxy groups, and
[0323] l.sup.1, m.sup.1, p.sup.2, independently of one another,
mean integer 1 or 2.
[0324] Since the compounds according to the invention are intended
for use in NMR diagnosis, the metal ion of the signaling group must
be paramagnetic. These are in particular the divalent and trivalent
ions of the elements of atomic numbers 23-29, 42-46 and 58-70.
Suitable ions are, for example, the chromium(III), iron(II),
cobalt(II), nickel(II), copper(II), praseodymium(III),
neodymium(III), samarium(III) and ytterbium(III) ions. Because of
their strong magnetic moment, gadolinium(III), terbium(III),
dysprosium(III), holmium(III), erbium(III), iron(III) and
manganese(II) ions are especially preferred.
[0325] Preferred are manganese(II), iron(II), iron(III),
praseodymium(III), neodymium(III), samarium(III), gadolinium(III)
and ytterbium(III) ions, especially dysprosium(III) ions.
[0326] In R.sup.1, optionally present acidic hydrogen atoms, i.e.,
those that have not been substituted by the central ion, can be
replaced optionally completely or partially by cations of inorganic
and/or organic bases or amino acids or amino acid amides.
[0327] Suitable inorganic cations are, for example, the lithium
ion, the potassium ion, the calcium ion and especially the sodium
ion. Suitable cations of organic bases are, i.a., 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 as well as
the amides of otherwise acidic or neutral amino acids.
[0328] Especially preferred compounds of general formula Id are
those with macrocyclic compound K of general formulas IId, IIId,
VdB or VId.
[0329] Radical U in metal complex K preferably means --CH.sub.2--
or C.sub.6H.sub.4--O--CH.sub.2-.omega.-, whereby .omega. stands for
the binding site to --CO--.
[0330] Alkyl groups R.sup.2 and R.sup.3 in the macrocyclic compound
of general formula IId can be straight-chain or branched. By way of
example, methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl,
2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl,
3-methylbutyl, and 1,2-dimethylpropyl can be mentioned. R.sup.2 and
R.sup.3, independently of one another, preferably mean hydrogen or
C.sub.1-C.sub.4-alkyl.
[0331] In a quite especially preferred embodiment, R.sup.2 stands
for methyl and R.sup.3 stands for hydrogen.
[0332] The benzyl group or phenyl group R.sup.2 or R.sup.3 in
macrocyclic compound K of general formula IId can also be
substituted in the ring.
[0333] In a preferred embodiment, polar radical R in general
formula Id means complex K, whereby the latter preferably in
addition to a Gd.sup.3++-- or Mn.sup.2+ complex also can be a
Ca.sup.2+ complex. As polar radicals R, complexes K of general
formulas IId, IIId, VdA or VId are especially preferred. The latter
as R.sup.1 quite especially preferably have a metal ion equivalent
of atomic numbers 20, 25, 39 or 64.
[0334] In another preferred embodiment, polar radical R has the
following meanings:
--C(O)CH.sub.2CH.sub.2SO.sub.3H
--C(O)CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OH
--C(O)CH.sub.2OCH.sub.2CH.sub.2OH
--C(O)CH.sub.2OCH.sub.2CH(OH)CH.sub.2OH
--C(O)CH.sub.2NH--C(O)CH.sub.2COOH
--C(O)CH.sub.2CH(OH)CH.sub.2OH
--C(O)CH.sub.2OCH.sub.2COOH
--SO.sub.2CH.sub.2CH.sub.2COOH
--C(O)--C.sub.6H.sub.3-(m-COOH).sub.2
--C(O)CH.sub.2O(CH.sub.2).sub.2--C.sub.6H.sub.3-(m-COOH).sub.2
--C(O)CH.sub.2O--C.sub.6H.sub.4-m-SO.sub.3H
--C(O)CH.sub.2NHC(O)CH.sub.2NHC(O)CH.sub.2OCH.sub.2COOH
--C(O)CH.sub.2OCH.sub.2CH.sub.2OCH.sub.2COOH
--C(O)CH.sub.2OCH.sub.2CH(OH)CH.sub.2O--CH.sub.2CH.sub.2OH
--C(O)CH.sub.2OCH.sub.2CH(OH)CH.sub.2OCH.sub.2--CH(OH)--CH.sub.2OH
--C(O)CH.sub.2SO.sub.3H
--C(O)CH.sub.2CH.sub.2COOH
--C(O)CH(OH)CH(OH)CH.sub.2OH
--C(O)CH.sub.2O[(CH.sub.2).sub.2O].sub.1-9--CH.sub.3
--C(O)CH.sub.2O[(CH.sub.2).sub.2O].sub.1-9--H
--C(O)CH.sub.2OCH(CH.sub.2OH).sub.2
--C(O)CH.sub.2OCH(CH.sub.2OCH.sub.2COOH).sub.2
--C(O)--C.sub.6H.sub.3--(m-OCH.sub.2COOH).sub.2
--CO--CH.sub.2O--(CH.sub.2).sub.2O(CH.sub.2).sub.2O--(CH.sub.2).sub.2O(CH.-
sub.2).sub.2OCH.sub.3
preferably --C(O)CH.sub.2O[(CH.sub.2).sub.2O].sub.4--CH.sub.3.
[0335] In another preferred embodiment, polar radical R means the
folic acid radical.
[0336] Of the compounds of general formula Id according to the
invention, in addition those are preferred in which R.sup.F means
--C.sub.nF.sub.2n+1. n preferably stands for numbers 4-15. Quite
especially preferred are the radicals --C.sub.4F.sub.9,
--C.sub.6F.sub.13, --C.sub.8F.sub.17, --C.sub.12F.sub.25 and
--C.sub.14F.sub.29.
[0337] Radical G that is functionalized in at least three places in
general formula Id, which represents the "skeleton," means lysine
radical (a) or (b) in a preferred embodiment of the invention.
[0338] Z means the linker that is indicated in general formula Id,
whereby radical 67
[0339] is preferred.
[0340] The perfluoroalkyl-containing metal complexes with polar
radicals of general formula Id 68
[0341] in which K, G, R, Z, R.sup.F, I.sup.1, m.sup.1, and p.sup.2
have the above-indicated meaning, are produced by a carboxylic acid
of general formula IIk 69
[0342] in which R.sup.5 means a metal ion equivalent of atomic
numbers 23-29, 42-46 or 58-70 or a carboxyl protective group, and
R.sup.2, R.sup.3 and U have the above-mentioned meaning,
[0343] or a carboxylic acid of general formula IIIk 70
[0344] in which R.sup.4, R.sup.5 and U.sup.1 have the
above-mentioned meaning
[0345] or a carboxylic acid of general formula IVk 71
[0346] in which R.sup.5 and R.sup.2 have the above-mentioned
meaning
[0347] or a carboxylic acid of general formula Vk or Vm 72
[0348] in which R.sup.5 has the above-mentioned meaning
[0349] or a carboxylic acid of general formula VIk 73
[0350] in which R.sup.5 has the above-mentioned meaning
[0351] or a carboxylic acid of general formula VIk 74
[0352] in which R.sup.5 and U.sup.1 have the above-mentioned
meanings,
[0353] being reacted in a way that is known in the art in
optionally activated form with an amine of general formula VIIId
75
[0354] in which G, R, Z, R.sup.F, m.sup.1 and p.sup.2 have the
above-indicated meaning, in a coupling reaction and optionally
subsequent cleavage of optionally present protective groups to form
a metal complex of general formula Id or
[0355] if R.sup.5 has the meaning of a protective group, being
reacted after cleavage of these protective groups in a subsequent
step in a way that is known in the art with at least one metal
oxide or metal salt of an element of atomic numbers 23-29, 42-46 or
58-70, and then, if desired, optionally present acidic hydrogen
atoms being substituted by cations of inorganic and/or organic
bases, amino acids or amino acid amides.
[0356] The carboxylic acids of general formulas IIk to VIIk that
are used are either known compounds or are produced according to
the processes that are described in the examples. Thus, the
production of the carboxylic acids of general formula IIk is known
from DE 196 52 386. The production of the carboxylic acids of
general formula IVk can be found in DE 197 28 954.
[0357] A precursor of compounds of general formula VdA is the
N.sup.3-(2,6-dioxomorpholinoethyl)-N.sup.6-(ethoxycarbonylmethyl)-3,6-dia-
za-octanedioic acid, which is described in EP 263 059.
[0358] The compounds of general formula VdB are derived from the
isomeric diethylenetriamine-pentaacetic acid, which binds via
acetic acid on the center N-atom. This DTPA is described in Patents
DE 195 07 819 and DE 195 08 058.
[0359] Compounds of general formula VId are derived from
N-(carboxymethyl)-N-[2-(2,6-dioxo-4-morpholinyl)-ethyl]-glycine,
whose production is described in J. Am. Oil. Chem. Soc. (1982), 59
(2), 104-107.
[0360] Compounds of general formula VId are derived from
1-(4-carboxymethoxybenzyl)-ethylenediamine-tetraacetic acid, whose
production was described in Patent U.S. Pat. No. 4,622,420.
[0361] Metal complex XVI of Table 1 according to the invention is
used as a quite especially preferred compound of general formula
Id.
[0362] In another preferred embodiment of the invention, galenical
formulations can be used that contain paramagnetic and diamagnetic
perfluoroallkyl-containing substances. The paramagnetic and
diamagnetic substances are preferably present in a dissolved state
in an aqueous solvent.
[0363] As paramagnetic, perfluoroalkyl-containing compounds, all
above-mentioned metal complexes of general formulas I, Ia, Ib, Ic
and/or Id according to the invention can be used in the
formulations.
[0364] The diamagnetic perfluoroalkyl-containing substances are
those of general formula XX:
R.sup.F-L.sup.2-B.sup.2 (XX)
[0365] in which R.sup.F represents a straight-chain or branched
perfluoroalkyl radical with 4 to 30 carbon atoms, L.sup.2 stands
for a linker and B.sup.2 stands for a hydrophilic group. Linker
L.sup.2 is a direct bond, an --SO.sub.2 group, or a straight-chain
or branched carbon chain with up to 20 carbon atoms, which can be
substituted with one or more --OH, --COO--, --SO.sub.3 groups
and/or optionally contains one or more --O--, --S--, --CO--,
--CONH--, --NHCO--, --CONR.sup.9--, --NR.sup.9CO--, --SO.sub.2--,
--PO.sub.4.sup.---, --NH-- or --NR.sup.9 groups, an aryl ring or a
piperazine, whereby R.sup.9 stands for a C.sub.1- to C.sub.20-alkyl
radical, which in turn can contain one or more O atoms, and/or can
be substituted with --COO.sup.- or SO.sub.3 groups.
[0366] Hydrophilic group B is a mono- or disaccharide, one or more
adjacent --COO.sup.- or --SO.sub.3 groups, a dicarboxylic acid, an
isophthalic acid, a picolinic acid, a benzenesulfonic acid, a
tetrahydropyrandicarboxylic acid, a 2,6-pyridinedicarboxylic acid,
a quaternary ammonium ion, an aminopolycarboxylic acid, an
aminodipolyethylene glycolsulfonic acid, an aminopolyethylene
glycol group, an SO.sub.2--(CH.sub.2).sub.2--OH group, a
polyhydroxyalkyl chain with at least two hydroxyl groups or one or
more polyethylene glycol chains with at least two glycol units,
whereby the polyethylene glycol chains are terminated by an --OH or
--OCH.sub.3 group. Such substances are partially already known;
such substances for the production of formulations according to the
invention were partially newly synthesized. Known
perfluoroalkyl-containing substances and their production are
described in the following publications:
[0367] J. G. Riess, Journal of Drug Targeting, 1994, Vol. 2, pp.
455-468;
[0368] J. B. Nivet et al., Eur. J. Med. Chem., 1991, Vol. 26, pp.
953-960;
[0369] M.-P. Krafft et al., Angew. Chem., 1994, Vol. 106, No. 10,
pp. 1146-1148;
[0370] M. Lanier et al., Tetrahedron Letters, 1995, Vol. 36, No.
14, pp. 2491-2492;
[0371] F. Guillod et al., Carbohydrate Research, 1994, Vol. 261,
pp. 37-55;
[0372] S. Achilefu et al., Journal of Fluorine Chemistry, 1995,
Vol. 70, pp. 19-26;
[0373] L. Clary et al., Tetrahedron, 1995, Vol. 51, No. 47, pp.
13073-13088;
[0374] F. Szoni et al., Journal of Fluorine Chemistry, 1989, Vol.
42, pp. 59-68;
[0375] H. Wu et al., Supramolecular Chemistry, 1994, Vol. 3, pp.
175-180;
[0376] F. Guileri et al., Angew. Chem. 1994, Vol. 106, No. 14, pp.
1583-1585;
[0377] M.-P. Krafft et al., Eur. J. Med. Chem., 1991, Vol. 26, pp.
545-550;
[0378] J. Greiner et al., Journal of Fluorine Chemistry, 1992, Vol.
56, pp. 285-293;
[0379] A. Milius et al., Carbohydrate Research, 1992, Vol. 229, pp.
323-336;
[0380] J. Riess et al., Colloids and Surfaces A, 1994, Vol. 84, pp.
33-48;
[0381] G. Merhi et al., J. Med. Chem., 1996, Vol. 39, pp.
4483-4488;
[0382] V. Cirkva et al., Journal of Fluorine Chemistry, 1997, Vol.
83, pp. 151-158;
[0383] A. Ould Amanetoullah et al., Journal of Fluorine Chemistry,
1997, Vol. 84, pp. 149-153;
[0384] J. Chen et al., Inorg. Chem., 1996, Vol. 35, pp.
1590-161;
[0385] L. Clary et al., Tetrahedron Letters, 1995, Vol. 36, No. 4,
pp. 539-542;
[0386] M. M. Chaabouni et al., Journal of Fluorine Chemistry, 1990,
Vol. 46, pp. 307-315;
[0387] A. Milius et al., New J. Chem., 1991, Vol. 15, pp.
337-344;
[0388] M.-P. Krafft et al., New J. Chem., 1990, Vol. 14, pp.
869-875;
[0389] J.-B. Nivet et al., New J. Chem., 1994, Vol. 18, pp.
861-869;
[0390] C. Santaella et al., New J. Chem., 1991, Vol. 15, pp.
685-692;
[0391] C. Santaella et al., New J. Chem., 1992, Vol. 16, pp.
399-404;
[0392] A. Milius et al., New J. Chem., 1992, Vol. 16, pp.
771-773;
[0393] F. Szonyi et al., Journal of Fluorine Chemistry, 1991, Vol.
55, pp. 85-92;
[0394] C. Santaella et al., Angew. Chem., 1991, Vol. 103, No. 5,
pp. 584-586;
[0395] M.-P. Krafft et al., Angew. Chem., 1993, Vol. 105, No. 5,
pp. 783-785;
[0396] EP 0 548 096 B1.
[0397] The production of the new perfluoroalkyl-containing
substances is carried out analogously to the above-mentioned
compounds that are known in the literature and is described in the
examples. In this case, these are substances of general formula
XXI
R.sup.F--X.sup.1 (XXI)
[0398] in which R.sup.F represents a straight-chain or branched
perfluoroalkyl radical with 4 to 30 carbon atoms, and X.sup.1 is a
radical that is selected from the group of the following radicals
(n in this case is a number between 1 and 10): 7677
[0399] Preferred diamagnetic perfluoroalkyl-containing substances
are those with a monosaccharide as hydrophilic group B.sup.2.
[0400] Especially preferred diamagnetic perfluoroalkyl-containing
compounds contain a perfluoroalkyl radical R.sub.f with 6 to 12
carbon atoms, a linker L.sup.2, which represents an --SO.sub.2
group, or a straight-chain or branched carbon chain with up to 20
carbon atoms, which in turn contains one or more --O--, --CO--,
--CONH--, --NHCO--, --CONR--, --NRCO--, or --SO.sub.2 groups or a
piperazine, in which R has the above-indicated meaning, and a
monosaccharide as hydrophilic group B.sup.2.
[0401] Other suitable diamagnetic perfluoroalkyl-containing
compounds are conjugates that consist of cyclodextrin and
perfluoroalkyl-containing compounds. These conjugates consist of
.alpha.-, .beta.- or .gamma.-cyclodextrin and compounds of general
formula XXII
A.sup.1-L.sup.3-R.sup.F (XXII)
[0402] in which A.sup.1 stands for an adamantan, biphenyl or
anthracene molecule, L.sup.3 stands for a linker, and R.sup.F
stands for a straight-chain or branched perfluoroalkyl radical with
4 to 30 carbon atoms. Linker L.sup.3 is a straight-chain
hydrocarbon chain with 1 to 20 carbon atoms, which can be
interrupted by one or more oxygen atoms, one or more CO--,
SO.sub.2--, CONH--, NHCO--, CONR--, NRCO--, NH-- or NR groups or a
piperazine, whereby R is a C.sub.1-C.sub.5-alkyl radical.
[0403] Preferred compounds are the following compounds: 78
[0404] The galenical formulations of this invention contain the
paramagnetic and diamagnetic perfluoroalkyl-containing compounds in
a mixing ratio of between 5:95 and 95:5. Preferred are mixing
ratios of between 40:60 and 60:40 of the two substances. Both
substances are used in millimolar concentrations. Concentrations of
between 0.5 and 1000 mmol/l of solvent are achieved. The solvent is
preferably water. The metal concentration of the formulations is
preferably in a range of 50-250 mmol/l.
[0405] Preferred are mixtures that consist of paramagnetic and
diamagnetic perfluoroalkyl-containing compounds, in which the
perfluoroalkyl chains have a length of 6 to 12 carbon atoms.
Especially preferred are mixtures in which both the paramagnetic
and the diamagnetic perfluoroalkyl-containing compounds have a
perfluoroalkyl chain with 8 carbon atoms.
[0406] The production of the galenical formulations is carried out
in that the paramagnetic perfluoroalkyl-containing compounds
(components A) and the diamagnetic perfluoroalkyl-containing
substances (components B) are weighed in fractions of a mol of
between 0.05 and 0.95 in components A or B and are dissolved in a
suitable solvent. An especially well suited solvent is water.
Common galenical additives, such as, e.g., buffer solutions and the
Ca-salt of the complexing agent, are then added in excess to this
solution. At 10 to 100.degree. C., the solutions are stirred
vigorously. As an alterative, the solutions can be treated in an
ultrasound bath at 10 to 100.degree. C. Another alternative
consists in that the solutions are treated with microwaves.
[0407] In substances that do not dissolve in water as individual
components, it proves advantageous to add a solubilizer such as
alcohol (e.g., methanol or ethanol) or another water-miscible
solvent, and the latter can then be distilled off slowly. The
distillation can be carried out under a vacuum. The residue is then
dissolved in water, and the solution is filtered. It is also
possible to dissolve each component separately in one solvent each,
then to combine them and proceed as indicated above. It has proven
advantageous to introduce a relatively strongly concentrated
solution (>100 mmol) of the metal complex (component A) and then
to add component B in the pure state, and, as mentioned above, to
stir the solution or to treat it with ultrasound or microwaves.
[0408] In summary, it has been determined that as quite especially
preferred compounds, gadolinium complexes I-XVI that are presented
in Table 1 meet the criteria according to the invention. The
physical parameters of these metal complexes I-XVI are presented in
Table 2.
[0409] Both the paramagnetic compounds of general formulas I, Ia,
Ib, Ic and Id according to the invention and the formulations that
consist of paramagnetic and diamagnetic perfluoroalkyl-containing
substances according to the invention are extremely well suited as
contrast media in MR-imaging for visualization of plaque, tumors
and necroses.
BRIEF DESCRIPTION OF THE FIGURES
[0410] FIG. 1 depicts the localization of plaque at baseline, 24
hours p.i and 48 hours p.i, especially in aortic arches and in
vascular passages by means of Sudan-III staining, with
visualization after administration of metal complex XV 25
.mu.mol/kg.; 3D-T1-MPRage, TR/TE 11.1/4.3 ms, .alpha. 15.degree.
(Watanabe rabbits; A:Aorta; H: Heart; Arrow: vascular passages; MPR
Projection:)
[0411] FIG. 2A presents MR images of the aorta at baseline and
after 35 min., 60 min. and 24 hours, with visualization after
administration of metal complex XV 10 .mu.mol/kg i.v.;
3D-T1-MPRage, TR/TE 11.1/4.3 ms, .alpha. 15.degree.. (Watanabe
rabbits; A:Aorta; H: Heart; Arrow: arteriosclerotic plaque; MPR
Projection: Histology after Sudan-III staining)
[0412] FIG. 2B depicts post mortem MRI of agar-embedded aorta with
visualization after administration of metal complex XV 10
.mu.mol/kg i.v.; SE, TR/TE 400/15 ms, and 3D-T1-MPRage, TR/TE
11.1/4.3 ms .alpha. 15.degree.. (Watanabe rabbits; 24 hour p.i.
preparation of Aorta; Histology after Sudan-III staining)
[0413] FIG. 3 shows myocardial infarction visualization 24 hours
p.i. after administration of metal complex XV, 100 .mu.mol/kg i.v.;
T1-SE, TR/TE 400/6 ms.
[0414] FIG. 4 shows myocardial infarction visualization 24 hours
p.i. after administration of metal complex 1, 100 .mu.mol/kg i.v.;
SE, TR/TE 400/6 ms.
[0415] FIG. 5A arrow points to metastasis. Visualization is after
administration of metal complex XV, 200 .mu.mol/kg i.v.;
3D-T1-MPRange, TR/TE 11.1/4.3 ms, .alpha. 15.degree.., T:
tumor.
[0416] FIG. 5B arrow points to metastasis, with visualization after
administration of metal complex XV, 200 .mu.mol/kg i.v.; TRITE
11.1/4.3 ms, .alpha. 15.degree..
[0417] FIG. 6 closed arrow points to lymph nodes and open arrow
points to late enhancement, with visualization after administration
of metal complex 1, 100 .mu.mol/kg i.v.; 3D-T1-MPRange, TR/TE
11.1/4.3 ms, .alpha. 15.degree..
[0418] FIG. 7 depicts imaging of myocardial infarct, with
visualization after administration of metal complex X;, 100
.mu.mol/kg i.v.; SE, TR/TE 400/12 ms.
[0419] FIG. 8 depicts the visualization of popliteal lymph nodes
after administration of metal complex X, 100 .mu.mol/kg i.v.;
3D-T1-MPRange, TR/TE 11.1/4.3 ms, .alpha. 15.degree.
[0420] FIG. 9 depicts the visualization of metastases and tumors
after administration of metal complex X, 200 .mu.mol/kg i.v.;
3D-T1-MPRange, TR/TE 11.1/4.3 ms, .alpha. 15.degree.
[0421] FIG. 10 depicts the visualization of myocardial infarct
after administration of metal complex V, 100 .mu.mol/kg i.v.; SE,
TR/TE 400/12 ms.
[0422] FIG. 11 depicts the visualization of popliteal lymph nodes
after administration of metal complex III, 200 .mu.mol/kg i.v.;
3D-T1-MPRange, TR/TE 11.1/4.3 ms, .alpha. 15.degree..
[0423] FIG. 12 depicts the visualization of metastasis after
administration of metal complex V, 200 .mu.mol/kg i.v.;
3D-T1-MPRange, TR/TE 11.1/4.3 ms, .alpha. 15.degree.., T:
tumor.
[0424] FIG. 13 depicts the visualization of myocardial infarct
after administration of metal complex XIV, 100 .mu.mol/kg i.v.; SE,
TR/TE 400/12 ms.
[0425] FIG. 14 closed arrow points to inguinal and iliacal lymph
nodes. Visualization after administration of metal complex XIV ,
flash outphase, TR/TE 10/5 ms, .alpha. 40.degree..
[0426] FIG. 15 depicts the visualization of inguinal and iliacal
lymph nodes after administration of metal complex XIV, flash
outphase, TR/TE 10/5 ms, .alpha. 40.degree..
[0427] FIG. 16 depicts the visualization of myocardial infarct
after administration of metal complex III, 100 .mu.mol/kg i.v.; SE,
TR/TE 400/12 ms.
[0428] FIG. 17 depicts the visualization of popliteal lymph nodes
after administration of metal complex 111, 200 .mu.mol/kg i.v.;
3D-T1-MPRange, TR/TE 11.1/4.3 ms, .alpha. 15.degree..
[0429] FIG. 18 depicts visualization of matastases and tumors after
administration of metal complex III, 200 .mu.mol/kg i.v.;
3D-T1-MPRange, TR/TE 11.1/4.3 ms, .alpha. 15.degree..
1TABLE 1 Metal Complexes that are Quite Especially Preferably Used
According to the Invention Complex Bibliographic Reference, Name I
WO 97/26017, Example 33f Gadolinium complex of
10-[1-methyl-2-oxo-3-aza-5-oxo-{4-perfluorooc- tylsulfonyl-
piperazin-1-yl}-pentyl]-1,4,7-tris(carboxymethyl)-1,4- ,7,10-
tetraazacyclododecane II WO 97/26017, Example 2c Gadolinium complex
of 10-[2-hydroxy-4-aza-5-oxo-7-oxa-
10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17-heptadecafluoroheptadecyl-
]- 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane III WO
97/26017, Example 34b Gadolinium complex of
10-[2-hydroxy-4-aza-5,9-dioxo-9-{4-perfluorooctyl)-
piperazin-1-yl}-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-
tetraazacyclododecane IV WO 97/26017, Example 1c Gadolinium complex
of 10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctylsu- lfonyl)-
nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclodo- decane V
Example 2c, this application
1,4,7-Tris(carboxylatomethyl)-10-(3-aza-4-oxo-hexan-5-ylic)-acid-N-(2,3-
dihydroxypropyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotride-
cyl)- amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex VI
WO 97/26017, Example 3c Gadolinium complex of 10-[2-hydroxy-4-oxa-
1H,1H,2H,2H,3H,3H,5H,5H,6H,6H-perfluorotetra- decyl]-1,4,7-
tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane VII Example 5e,
this application 1,4,7-Tris(carboxylatomethy-
l)-10-{(3-aza-4-oxo-hexan-5-ylic)acid-[N- (3,6,9,12,15-pentaoxa)-h-
exadecyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-
perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane,
gadolinium complex VIII Example 3c, this application
1,4,7-Tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-N-(5-
hydroxy-3-oxa-pentyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-
perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane,
gadolinium complex IX Example 6b, this application
1,4,7-Tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N-
3,6,9,16-tetraoxa-13-aza-14-oxo-C.sub.19-C.sub.26-hepta-decafluoro)he-
xacosyl]-amide}- 1,4,7,10-tetraazacyclododecane, gadolinium complex
X Example 1c, this application
1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic]-acid-N-(2-
methoxyethyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl]-
amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex XI WO
97/26017, Example 32c Gadolinium complex of
10-[2-hydroxy-4-aza-5-oxo-7-oxa- 10,10,11,11,12,12,13,13,14,14,15-
,15,16,16,17,17,18,18,19,19-henicosafluorononadecyl]-
1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane XII WO
97/26017, Example 38d Gadolinium complex of
10-[2-hydroxy-4-aza-5-oxo-11-aza-11-(perfluorooctylsulfonyl)-
tridecyl]-1-4-7-tris(carboxymethyl) 1,4,7,10-tetraazacyclododecane
XIII WO 97/26017, Example 35d Gadolinium complex of
10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctylsulfonyl)-
8-phenyl-octyl]-1-4-7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane
XIV WO 99/01161, Example 1g 1,4,7-Tris{1,4,7-tris(N-(carbo-
xylatomethyl)-10-[N-1-methyl-3,6-diaza-2,5,8-
trioxooctane-1,8-diyl]-1,4,7,10-tetraazacyclododecane, Gd
complex}-10-N-
2H,2H,4H,4H,5H,5H-3-oxa-perfluoro-tridecanoyl]-1,4,7,10-tetraazac-
yclododecane, Gd complex XV Example 21f, this application
6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-
0-N- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-2-N-[1-O-.alpha.-D-car-
bonylmethylmannopyranose]- L-lysine-[1-(4-perfluorooctylsulfonyl)--
piperazine]-amide, Gd complex XVI Example 54b, this application
2,6-N,N'-Bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-t-
etraazacyclododecane-10- (pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-ly-
sine-[1-(4-perfluorooctylsulfonylpiperazine]- amide, Gd complex
[0430]
2TABLE 2 Physicochemical Parameters of the Complexes of Table 1
that are Used According to the Invention R.sup.1 Plasma Complex No.
CMC (mol/l) 2 Rh (nm) (l/mmol .multidot. s) I 1.86 .multidot.
10.sup.-6 4.6 35.7 II 2.30 .multidot. 10.sup.-5 14 33 III 7.06
.multidot. 10.sup.-6 3.2 24.9 IV 1.0 .multidot. 10.sup.-6 31.5 29.7
V 3.9 .multidot. 10.sup.-6 4.4 19.6 VI 1.44 .multidot. 10.sup.-5
3.2 27.5 VII 5.20 .multidot. 10.sup.-5 3.0 30.3 VIII 2.92
.multidot. 10.sup.-5 25 21.2 IX 2.65 .multidot. 10.sup.-6 6.0 13.3
X 7.90 .multidot. 10.sup.-6 5.4 25.7 XI 2.88 .multidot. 10.sup.-6
35.5 24.8 XII 1.07 .multidot. 10.sup.-5 7.4 30.5 XIII 3.25
.multidot. 10.sup.-6 4.3 34.0 XIV 8.90 .multidot. 10.sup.-4 2.2
19.5 XV 2.50 .multidot. 10.sup.-6 4.4 15.9 XVI 3.90 .multidot.
10.sup.-5 4.9 21.3 CMC: Critical micelle formation concentration 2
Rh: Hydrodynamic micelle diameter R.sup.1: Relaxivity
EMBODIMENTS
EXAMPLE 1
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic
acid-N-(2-methoxy)-ethyl-a- mide
[0431] 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45
mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300
ml of dichloromethane, and it is stirred for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 100 ml of dichloromethane and added in
drops at 0.degree. C. to a solution that consists of 4.51 g (60
mmol) of 2-methoxyethylamine and 6.07 g (60 mmol) of triethylamine,
dissolved in 200 ml of dichloromethane. It is stirred for 3 hours
at 0.degree. C., then for 6 hours at room temperature. 300 ml of 5%
aqueous hydrochloric acid is added, and it is thoroughly stirred
for 15 minutes. The organic phase is separated, dried on magnesium
sulfate and evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/acetone=20:1).
[0432] Yield: 30.28 g (91% of theory) of a colorless solid
[0433] Elementary analysis: Cld: C, 31.10; H, 2.44; N, 2.42; F,
55.76. Fnd: C, 30.87; H, 2.58; N, 2.35; F, 55.51.
b)
N-(2-Methoxyethyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyla-
mine
[0434] 30 g (51.79 mmol) of the title compound of Example la is
dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 200 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is
stirred for 8 hours at 40.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 300 ml of 5% aqueous
sodium hydroxide solution, and it is extracted 3 times with 300 ml
of dichloromethane each. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/2-propanol=20:1).
[0435] Yield: 26.93 g (92% of theory) of a colorless solid
[0436] Elementary analysis (relative to anhydrous substance): Cld:
C, 31.87; H, 2.85; N, 2.48; F, 57.14. Fnd: C, 31.69; H, 3.10; N,
2.27; F, 56.88.
c)
1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(2--
methoxyethyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amide]--
1,4,7,10-tetraazacyclododecane, gadolinium complex (metal complex
X)
[0437] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 8.98 g (15.88 mmol) of the title
compound of Example 1b is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water, and it is
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0438] Yield: 15.14 g (81% of theory) of a colorless, amorphous
powder
[0439] Water content: 5.7%
[0440] Elementary analysis (relative to anhydrous substance): Cld:
C, 34.70; H, 3.77; N, 7.14; F, 27.44; Gd, 13.36. Fnd: C, 34.51; H,
3.94; N, 7.02; F, 27.25; Gd, 13.18.
EXAMPLE 2
a) 2H,2H,4H,4H,5H,5H-3-Oxa)-perfluorotridecanoic
acid-N-(2,3-dihydroxyprop- yl)-amide
[0441] 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45
mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300
ml of dichloromethane, and it is stirred for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 100 ml of dichloromethane and added in
drops at 0.degree. C. to a solution that consists of 5.47 g (60
mmol) of 2,3-dihydroxypropylamine and 6.07 g (60 mmol) of
triethylamine, dissolved in 200 ml of dichloromethane. It is
stirred for 3 hours at 0.degree. C., then for 6 hours at room
temperature. 300 ml of 5% aqueous hydrochloric acid is added, and
it is thoroughly stirred for 15 minutes. The organic phase is
separated, dried on magnesium sulfate and evaporated to the dry
state in a vacuum. The residue is chromatographed on silica gel
(mobile solvent: dichloromethane/ethanol=15:1).
[0442] Yield: 29.70 g (87% of theory) of a colorless solid
[0443] Elementary analysis: Cld: C, 30.32; H, 2.20; N, 2.36; F,
54.35. Fnd: C, 30.12; H, 2.41; N, 2.18; F, 54.15.
b)
N-(2,3-Dihydroxypropyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotride-
cyl)-amine
[0444] 30 g (48.8 mmol) of the title compound of Example 2a is
dissolved in 300 ml of tetrahydrofuran, and 50 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 300 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is
stirred for 8 hours at 60.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 300 ml of 5% aqueous
sodium hydroxide solution and extracted 3 times with 300 ml of
dichloromethane each. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/methanol=1- 5:1).
[0445] Yield: 24.07 g (85% of theory) of a colorless solid
[0446] Elementary analysis: Cld: C, 31.05; H, 2.61; N, 2.41; F,
55.66. Fnd: C, 31.91; H, 2.78; N, 2.33; F, 55.47.
c)
1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(2,-
3-dihydroxypropyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-am-
ide]-1,4,7,10-tetraazacyclododecane, gadolinium complex (metal
complex V)
[0447] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved in 100 ml of dimethyl sulfoxide at 60.degree. C. It is
cooled to 15.degree. C., and 9.21 g (15.88 mmol) of the title
compound of Example 2b is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water, and it is
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0448] Yield: 16.09 g (85% of theory) of a colorless, amorphous
powder
[0449] Water content: 6.3%
[0450] Elementary analysis (relative to anhydrous substance): Cld:
C, 34.26; H, 3.64; N, 7.05; F, 27.10; Gd, 13.19. Fnd: C, 34.12; H,
3.83; N, 6.91; F, 26.88; Gd, 12.93.
EXAMPLE 3
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic
acid-N-(5-hydroxy-3-oxa-pe- ntyl)-amide
[0451] 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45
mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300
ml of dichloromethane, and it is stirred for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 100 ml of dichloromethane and added in
drops at 0.degree. C. to a solution that consists of 6.25 g (60
mmol) of 5-hydroxy-3-oxa-pentylamine and 6.07 g (60 mmol) of
triethylamine, dissolved in 200 ml of dichloromethane. It is
stirred for 3 hours at 0.degree. C., then for 6 hours at room
temperature. 300 ml of 5% aqueous hydrochloric acid is added, and
it is thoroughly stirred for 15 minutes. The organic phase is
separated, dried on magnesium sulfate and evaporated to the dry
state in a vacuum. The residue is chromatographed on silica gel
(mobile solvent: dichloromethane/acetone=15:1).
[0452] Yield: 32.20 g (92% of theory) of a colorless solid
[0453] Elementary analysis: Cld: C, 31.54; H, 2.65; N, 2.30; F,
53.01. Fnd: C, 31.61; H, 2.84; N, 2.14; F, 52.85.
b) N-(5-Hydroxy-3-oxa-pentyl)-N-(1H,
1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorot- ridecyl)-amine
[0454] 30 g (49.24 mmol) of the title compound of Example 3a is
dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 200 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is
stirred for 10 hours at 50.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 300 ml of 5% aqueous
sodium hydroxide solution and extracted 3 times with 300 ml of
dichloromethane each. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/2-propanol- =20:1).
[0455] Yield: 26.09 g (89% of theory) of a colorless solid
[0456] Elementary analysis: Cld: C, 32.28; H, 3.05; N, 2.35; F,
54.25. Fnd: C, 32.12; H, 3.21; N, 2.18; F, 54.09.
c)
1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(5--
hydroxy-3-oxa-pentyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-
-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex (metal
complex VIII)
[0457] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 9.45 g (15.88 mmol) of the title
compound of Example 3b is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water, and it is
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0458] Yield: 16.10 g (84% of theory) of a colorless, amorphous
powder
[0459] Water content: 5.7%
[0460] Elementary analysis (relative to anhydrous substance): Cld:
C, 34.83; H, 3.84; N, 6.96; F, 26.76; Gd, 13.03. Fnd: C, 34.65; H,
3.96; N, 6.84; F, 26.62; Gd, 12.91.
EXAMPLE 4
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic
acid-N-(2-hydroxyethyl)-am- ide
[0461] 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45
mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300
ml of dichloromethane, and it is stirred for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 100 ml of dichloromethane and added in
drops at 0.degree. C. to a solution that consists of 3.66 g (60
mmol) of 2-aminoethanol and 6.07 g (60 mmol) of triethylamine,
dissolved in 200 ml of dichloromethane. It is stirred for 3 hours
at 0.degree. C., then for 6 hours at room temperature. 300 ml of 5%
aqueous hydrochloric acid is added, and it is thoroughly stirred
for 15 minutes. The organic phase is separated, dried on magnesium
sulfate and evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/acetone=20:1).
[0462] Yield: 28.90 g (89% of theory)
[0463] Elementary analysis: Cld: C, 29.75; H, 2.14; N, 2.48; F,
57.14. Fnd: C, 29.61; H, 2.29; N, 2.37; F, 57.01.
b)
N-(2-Hydroxyethyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-
-amine
[0464] 28 g (49.54 mmol) of the title compound of Example 4a is
dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 200 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is
stirred for 10 hours at 50.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 300 ml of 5% aqueous
sodium hydroxide solution, and it is extracted 3 times with 300 ml
of dichloromethane each. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/2-propanol=15:1).
[0465] Yield: 25.12 g (92% of theory) of a colorless solid
[0466] Elementary analysis (relative to anhydrous substance): Cld:
C, 30.50; H, 2.56; N, 2.54; F, 58.59. Fnd: C, 30.32; H, 2.71; N,
2.48; F, 58.43.
c)
1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(2--
hydroxyethyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amine-a-
mide]-1,4,7,10-tetraazacyclododecane, gadolinium complex
[0467] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 8.75 g (15.88 mmol) of the title
compound of Example 4b is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water, and it is
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0468] Yield: 16.81 g (91% of theory) of a colorless, amorphous
powder
[0469] Water content: 7.2%
[0470] Elementary analysis (relative to anhydrous substance): Cld:
C, 34.08; H, 3.64; N, 7.23; F, 27.77; Gd, 13.52. Fnd: C, 33.91;
H3.82; N, 7.14; F, 27.58; Gd, 13.41.
EXAMPLE 5
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid amide
[0471] 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45
mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300
ml of dichloromethane, and it is stirred for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 200 ml of dichloromethane. Ammonia gas is
then directed into the solution for about 2 hours at 0.degree. C.
It is stirred for 4 more hours at 0.degree. C., then for 2 hours at
room temperature. 300 ml of 5% aqueous hydrochloric acid is added,
and it is thoroughly stirred for 15 minutes. The organic phase is
separated, dried on magnesium sulfate and evaporated to the dry
state in a vacuum. The residue is chromatographed on silica gel
(mobile solvent: dichloromethane/acetone=20:1).
[0472] Yield: 27.85 g (93% of theory)
[0473] Elementary analysis: Cld: C, 27.66; H, 1.55; N, 2.69; F,
61.97. Fnd: C, 27.49; H, 1.72; N, 2.54; F, 61.81.
b) 1H,1H,2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecylamine,
hydrochloride
[0474] 27 g (51.8 mmol) of the title compound of Example 5a is
dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 200 ml of
methanol is added, then it is evaporated to the dry state in a
vacuum. The residue is taken up in a mixture that consists of 400
ml of ethanol/100 ml of 10% aqueous hydrochloric acid, and it is
stirred for 8 hours at 60.degree. C. It is evaporated to the dry
state in a vacuum, and the residue is recrystallized from a little
ethanol/diethyl ether.
[0475] Yield: 26.75 g (95% of theory) of a colorless, crystalline
solid
[0476] Elementary analysis: Cld: C, 26.51; H, 2.04; N, 2.58; F,
59.41; Cl, 6.52. Fnd: C, 26.37; H, 2.21; N, 2.46; F, 59.25; Cl,
6.38.
c) 3,6,9,12,15-Pentaoxahexadecanoic
acid-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-
-perfluorotridecyl)-amide
[0477] 14.24 g (50 mmol) of 3,6,9,12,15-pentaoxahexadecanoic acid
chloride is added at 0.degree. C. to 26.5 g (48.74 mmol) of the
title compound of Example 5b and 14.8 g (146.2 mmol) of
triethylamine, dissolved in 300 ml of dichloromethane, and it is
stirred for 3 hours at 0.degree. C. 300 ml of 5% aqueous
hydrochloric acid is added, and it is thoroughly stirred for 30
minutes. The organic phase is separated, dried on magnesium sulfate
and evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/acetone: 20:1).
[0478] Yield: 32.03 g (87% of theory) of a colorless oil
[0479] Elementary analysis: Cld: C, 36.57; H, 4.00; N, 1.85; F,
42.75. Fnd: C, 36.46; H, 4.12; N, 1.76; F, 42.53.
d)
N-(3,6,9,12,15-Pentaoxahexadecyl)-N-(1H,1H,2H,2H,4H,4H-3-oxa)-perfluoro-
tridecyl)-amine
[0480] 31 g (41.03 mmol) of the title compound of Example 5c is
dissolved in 300 ml of tetrahydrofuran, and 25 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 200 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is
stirred for 8 hours at 40.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 300 ml of 5% aqueous
sodium hydroxide solution, and it is extracted 3 times with 300 ml
of dichloromethane each. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/2-propanol=15:1).
[0481] Yield: 27.68 g (91% of theory)
[0482] Elementary analysis: Cld: C, 37.26; H, 4.35; N, 1.89; F,
43.56. Fnd: C, 37.11; H, 4.51; N, 1.73; F, 43.41.
e)
1,4,7-Tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N-3,-
6,9,12,15-pentaoxa)-hexadecyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluoro-
tridecyl)-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex
(metal complex VII)
[0483] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 11.77 g (15.88 mmol) of the title
compound of Example 5d is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water and chromatographed
on silica gel RP-18 (mobile solvent: gradient that consists of
tetrahydrofuran/acetonitrile/water).
[0484] Yield: 18.05 g (84% of theory) of a colorless, amorphous
powder
[0485] Water content: 6.2%
[0486] Elementary analysis (relative to anhydrous substance): Cld:
C, 37.28; H, 4.47; N, 6.21; F, 23.87; Gd, 11.62. Fnd: C, 37.11; H,
4.61; N, 6.03; F, 23.64; Gd, 11.42.
EXAMPLE 6
a)
1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(12-
-amino-3,6,9-trioxa-dodecyl)-amide]-1,4,7,10-tetraazacyclododecane,
gadolinium complex
[0487] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride and
3.66 g (31.76 mmol) of N-hydroxysuccinimide are dissolved at
60.degree. C. in 100 ml of dimethyl sulfoxide. It is cooled to
15.degree. C., and 3.51 g (17 mmol) of
N,N'-dicyclohexyl-carbodiimide is added, and it is stirred for 5
hours at 15.degree. C. To separate the urea, the solution is
filtered. 14.66 g (60 mmol) of 1,12-diamino-3,6,9-trioxa-dodecane
and 2.02 g (20 mmol) of triethylamine are added to the filtrate,
and it is stirred for 12 hours at room temperature. The solution is
poured into 1500 ml of diethyl ether/50 ml of n-butanol, and it is
stirred for 30 minutes. The precipitated solid is filtered and
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0488] Yield: 12.66 g (69% of theory) of a colorless, amorphous
powder
[0489] Water content: 3.5%
[0490] Elementary analysis (relative to anhydrous substance): Cld:
C, 30.16; H, 4.54; N, 8.49; F, 27.96; Gd, 13.61. Fnd: C, 30.02; H,
4.68; N, 8.35; F, 27.81; Gd, 13.45.
b)
1,4,7-Tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N-3,-
6,9,16-tetraoxa-13-aza-14-oxo-C.sub.19-C.sub.26-hepta-decafluoro)-hexacosy-
l]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex (metal
complex IX)
[0491] 11.3 g (21.64 mmol) of
2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid, 0.85 g (20 mmol)
of lithium chloride and 4.95 g (43 mmol) of N-hydroxysuccinimide
are dissolved at 25.degree. C. in 150 ml of dimethyl sulfoxide. It
is cooled to 15.degree. C., and 6.19 g (30 mmol) of
N,N'-dicyclohexylcarbodiimide is added, and it is stirred for 5
hours at 15.degree. C. To separate the urea, the solution is
filtered. 12.5 g (10.82 mmol) of the title compound of Example 6a
and 3.29 g (32.47 mmol) of triethylamine are added to the filtrate,
and it is stirred for 12 hours at room temperature. The solution is
poured into 1300 ml of diethyl ether/100 ml of acetone, and it is
stirred for 30 minutes. The precipitated solid is filtered off and
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonit- rile/water).
[0492] Yield: 13.01 g (90% of theory)
[0493] Water content: 6.7%
[0494] Elementary analysis (relative to anhydrous substance): Cld:
C, 36.86; H, 4.30; N, 7.34; F, 24.17; Gd, 11.77. Fnd: C, 36.68; H,
4.41; N, 7.25; F, 24.03; Gd, 11.55.
EXAMPLE 7
1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(1H,1H-
,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amide]-1,4,7,10-tetraaza-cyclo-
dodecane, gadolinium complex
[0495] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride and
3.66 g (31.76 mmol) of N-hydroxysuccinimide are dissolved at
60.degree. C. in 100 ml of dimethyl sulfoxide. It is cooled to
15.degree. C., and 3.51 g (17 mmol) of
N,N'-dicyclohexylcarbodiimide is added, and it is stirred for 5
hours at 15.degree. C. To separate the urea, the solution is
filtered. 8.63 g (15.88 mmol) of the title compound of Example 5b
and 5.06 g (50 mmol) of triethylamine are added to the filtrate,
and it is stirred for 12 hours at room temperature. The solution is
poured into 1500 ml of diethyl ether/100 ml of acetone, and it is
stirred for 30 minutes. The precipitated solid is filtered off and
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0496] Yield: 13.86 g (78% of theory) of a colorless, amorphous
powder
[0497] Water content: 9.3%
[0498] Elementary analysis (relative to anhydrous substance): Cld:
C, 33.28; H, 13.42; N, 7.51; F, 28.87; Gd, 14.05. Fnd: C, 33.12; H,
3.61; N, 7.37; F, 28.69; Gd, 13.89.
EXAMPLE 8
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic
acid-N-(2,3,4,5,6-pentahyd- roxy)-hexylamide
[0499] 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45
mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300
ml of dichloromethane, and it is stirred for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 100 ml of dichloromethane and added in
drops at 0.degree. C. to a solution that consists of 10.87 g (60
mmol) of glucamine and 6.07 g (60 mmol) of triethylamine, dissolved
in 150 ml of dichloromethane/1 50 dioxane. It is stirred for 3
hours at 0.degree. C., then for 8 hours at room temperature. 400 ml
of 5% aqueous hydrochloric acid is added, and it is thoroughly
stirred for 15 minutes. The organic phase is separated, dried on
magnesium sulfate and evaporated to the dry state in a vacuum. The
residue is chromatographed on silica gel (mobile solvent:
dichloromethane/methanol=5:1).
[0500] Yield: 30.71 g (78% of theory)
[0501] Elementary analysis: Cld: C, 31.55; H, 12.94; N, 2.04; F,
47.13. Fnd: C, 31.44; H, 13.09; N, 1.97; F, 47.01.
b)
N-(2,3,4,5,6-Pentahydroxyhexyl)-N-1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluo-
rotridecyl)-amine
[0502] 30 g (43.77 mmol) of the title compound of Example 8a is
dissolved in 300 ml of tetrahydrofuran, and 50 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 48 hours. It is cooled to 0.degree. C., and 500 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
500 ml of ethanol/100 ml of 10% aqueous hydrochloric acid, and it
is stirred for 15 hours at 60.degree. C. It is evaporated to the
dry state in a vacuum, the residue is taken up in 400 ml of 5%
aqueous sodium hydroxide solution and extracted 5 times with 400 ml
of chloroform each. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/methanol=3- :1).
[0503] Yield: 19.69 g (67% of theory) of a colorless solid
[0504] Elementary analysis: Cld: C, 32.20; H, 3.30; N, 2.09; F,
48.11. Fnd: C, 32.05; H, 3.43; N, 1.97; F, 47.93.
c)
1,4,7-Tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N-2,-
3,5,6-pentahydroxy)-hexyl-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridec-
yl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex
[0505] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 15.88 g (15.88 mmol) of the title
compound of Example 8b is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water, and it is
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0506] Yield: 16.10 g (79% of theory) of a colorless, amorphous
powder
[0507] Water content: 6.3%
[0508] Elementary analysis (relative to anhydrous substance): Cld:
C, 36.64; H, 3.93; N, 6.55; F, 25.17; Gd, 12.26. Fnd: C, 34.49; H,
4.13; N, 6.48; F, 25.03; Gd, 12.11.
EXAMPLE 9
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic
acid-N-(2,2-dimethyl-5-hyd- roxy-1,3-dioxepan-6-yl)-amide
[0509] 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45
mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300
ml of dichloromethane, and it is stirred for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 100 ml of dichloromethane and added in
drops at 0.degree. C. to a solution that consists of 9.67 g (60
mmol) of 5-amino-2,2-dimethyl-1,3-di- oxepan-6-ol and 6.07 g (60
mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It
is stirred for 3 hours at 0.degree. C., then for 5 hours at room
temperature. 300 ml of water is added, and it is thoroughly stirred
for 15 minutes. The organic phase is separated, dried on magnesium
sulfate and evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/acetone=15:1).
[0510] Yield: 27.62 g (85% of theory)
[0511] Elementary analysis: Cld: C, 34.30; H, 3.03; N, 2.11; F,
48.54. Fnd: C, 34.15; H, 3.19; N, 2.04; F, 48.37.
b)
N-(1-Hydroxymethyl-2,3-dihydroxypropyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-ox-
a-perfluorotridecyl)-amine
[0512] 27 g (40.58 mmol) of the title compound of Example 9a is
dissolved in 300 ml of tetrahydrofuran, and 26 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 20 hours. It is cooled to 0.degree. C., and 300 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
300 ml of ethanol/100 ml of 10% aqueous hydrochloric acid, and it
is stirred for 6 hours at 60.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 400 ml of 5% aqueous
sodium hydroxide solution, and it is extracted 5 times with 250 ml
of chloroform each. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/methanol=6- :1).
[0513] Yield: 20.09 g (81% of theory) of a colorless solid
[0514] Elementary analysis: Cld: C, 31.44; H, 2.97; N, 2.29; F,
52.83. Fnd: C, 31.26; H, 3.11; N, 2.18; F, 52.67.
c)
1,4,7-Tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N-1--
hydroxymethyl-2,3-dihydroxypropyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perflu-
orotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium
complex
[0515] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 9.71 g (15.88 mmol) of the title
compound of Example 9b is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water, and it is
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0516] Yield: 13.40 g (69% of theory) of a colorless, amorphous
powder
[0517] Water content: 9.1%
[0518] Elementary analysis (relative to anhydrous substance): Cld:
C, 34.37; H, 3.79; N, 6.87; F, 24.41; Gd, 12.86. Fnd: C, 34.18; H,
3.95; N, 6.71; F, 24.25; Gd, 12.70.
EXAMPLE 10
a) Perfluorooctylsulfonic
acid-N-[(2-benzyloxycarbonylamino)-ethyl]-amide
[0519] 40 g (173.4 mmol) of 1-benzyloxycarbonylamino-2-aminoethane,
hydrochloride, 87.1 g (173.4 mmol) of perfluorooctylsulfofluoride
and 35.42 g (350 mmol) of triethylamine are heated for 10 hours to
80.degree. C. It is cooled to room temperature and added directly
to a silica gel column for chromatographic purification (mobile
solvent: dichloromethane/acetone=20:1).
[0520] Yield: 42.22 g (36% of theory) of a colorless solid
[0521] Elementary analysis: Cld: C, 31.97; H, 1.94; N, 4.14; F,
47.75; S, 4.74. Fnd: C, 31.83; H, 2.11; N, 4.03; F, 47.63; S,
4.63.
b) Perfluorooctylsulfonic acid-N-[(2-amino)-ethyl]-amide
[0522] 30 g (44.36 mmol) of the title compound of Example 10a is
dissolved in 300 ml of methanol, and 5 g of palladium catalyst (10%
Pd/C) is added, and it is hydrogenated overnight at room
temperature. Catalyst is filtered off, and the filtrate is
evaporated to the dry state in a vacuum.
[0523] Yield: 24.05 g (quantitative) of a colorless solid
[0524] Elementary analysis: Cld: C, 22.15; H, 1.30; N, 5.17; F,
59.57. Fnd: C, 22.04; H, 1.41; N, 5.05; F, 59.62.
c)
1,4,7-Tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-N-[(2-
-perfluorooctylsulfonylamino)-ethyl]-amide}-1,4,7,10-tetraazacyclododecane-
, gadolinium complex
[0525] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride and
3.66 g (31.76 mmol) of N-hydroxysuccinimide are dissolved at
60.degree. C. in 100 ml of dimethyl sulfoxide. It is cooled to
15.degree. C., and 3.51 g (17 mmol) of
N,N'-dicyclohexylcarbodiimide is added, and it is stirred for 5
hours at 15.degree. C. To separate the urea, the solution is
filtered. 8.61 g (15.88 mmol) of the title compound of Example 10b
and 2.02 g (20 mmol) of triethylamine are added to the filtrate,
and it is stirred for 12 hours at room temperature. The solution is
poured into 1500 ml of diethyl ether/100 ml of acetone, and it is
stirred for 30 minutes. The precipitated solid is filtered off and
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0526] Yield: 15.76 g (86% of theory) of a colorless, amorphous
powder
[0527] Water content: 6.5%
[0528] Elementary analysis (relative to anhydrous substance): Cld:
C, 30.19; H, 3.06; N, 8.50; F, 27.99; Gd, 13.63 S, 2.78. Fnd: C,
30.03; H, 3.18; N, 8.41; F, 27.81; Gd, 13.50; S, 2.61.
EXAMPLE 11
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic
acid-N-(2-benzyloxy-carbox- ylamino-ethyl]-amide
[0529] 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45
mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300
ml of dichloromethane, and it is stirred for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 100 ml of dichloromethane and added in
drops at 0.degree. C. to a solution that consists of 13.84 g (60
mmol) of 1-benzyloxycarbonylamine-2- -amino-ethane, hydrochloride
and 12.14 g (120 mmol) of triethylamine, dissolved in 200 ml of
dichloromethane. It is stirred for 3 hours at 0.degree. C., then
for 5 hours at room temperature. 300 ml of 5% aqueous hydrochloric
acid is added, and it is thoroughly stirred for 15 minutes. The
organic phase is separated, dried on magnesium sulfate and
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/acetone=20:1).
[0530] Yield: 33.30 g (83% of theory) of a colorless solid
[0531] Elementary analysis: Cld: C, 37.84; H, 2.74; N, 4.01; F,
46.25. Fnd: C, 37.67; H, 2.89; N, 3.88; F, 46.11.
b) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic
acid-N-[(2-amino)-ethyl]-a- mide
[0532] 30 g (42.96 mmol) of the title compound of Example 11a is
dissolved in 500 ml of methanol, and 5 g of palladium catalyst (10%
Pd/C) is added, and it is hydrogenated overnight at room
temperature. It is filtered off in the catalyst, and the filtrate
is evaporated to the dry state in a vacuum.
[0533] Yield: 24.24 g (quantitative) of a colorless solid
[0534] Elementary analysis: Cld: C, 29.80; H, 2.32; N, 4.96; F,
57.24. Fnd: C, 29.67; H, 2.41; N, 4.88; F, 57.15.
c)
1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-N-[3-
-aza-6-oxa-4-oxo-(C.sub.19-C.sub.16-heptadecafluoro)-hexadecyl]-amide}-1,4-
,7,10-tetraazacyclododecane-gadolinium complex
[0535] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride and
3.66 g (31.76 mmol) of N-hydroxysuccinimide are dissolved at
60.degree. C. in 100 ml of dimethyl sulfoxide. It is cooled to
15.degree. C., 3.51 g (17 mmol) of N,N'-dicyclohexylcarbodiimide is
added, and it is stirred for 5 hours at 15.degree. C. To separate
the urea, the solution is filtered. 8.96 g (15.88 mmol) of the
title compound of Example 11b and 2.02 g (20 mmol) of triethylamine
are added to the filtrate and stirred for 12 hours at room
temperature. The solution is poured into 1500 ml of diethyl
ether/100 ml of acetone, and it is stirred for 30 minutes. The
precipitated solid is filtered off and chromatographed on silica
gel RP-18 (mobile solvent: gradient that consists of
tetrahydrofuran/acetonit- rile/water).
[0536] Yield: 15.31 g (82% of theory) of a colorless, amorphous
powder
[0537] Water content: 6.3%
[0538] Elementary analysis (relative to anhydrous substance): Cld:
C, 33.71; H, 3.51; N, 8.34; F, 27.46; Gd, 13.37. Fnd: C, 33.61; H,
3.63; N, 8.17; F, 27.31; Gd, 13.20.
EXAMPLE 12
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluoroundecanoic
acid-N-[(2-hydroxy)-ethyl]-- amide
[0539] 8.90 g (70 mmol) of oxalyl chloride is added to 24.25 g
(57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid
in 300 ml of dichloromethane, and it is stirred for 12 hours at
room temperature. It is evaporated to the dry state in a vacuum.
The residue is dissolved in 100 ml of dichloromethane and added in
drops at 0.degree. C. to a solution that consists of 3.66 g (60
mmol) of ethanolamine and 6.07 g (60 mmol) of triethylamine,
dissolved in 200 ml of dichloromethane. It is stirred for 3 hours
at 0.degree. C., then for 6 hours at room temperature. 300 ml of 5%
aqueous hydrochloric acid is added, and it is thoroughly stirred
for 15 minutes. The organic phase is separated, dried on magnesium
sulfate and evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/acetone=20:1).
[0540] Yield: 24.86 g (93% of theory) of a colorless solid
[0541] Elementary analysis: Cld: C, 30.98; H, 2.60; N, 3.01; F,
53.09. Fnd: C, 30.71; H, 2.81; N, 2.87; F, 52.82.
b)
N-(2-Hydroxyethyl)-N-1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluoroundecyl)-am-
ine
[0542] 24 g (51.59 mmol) of the title compound of Example 12a is
dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 12 hours. It is cooled to 0.degree. C., and 200 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is
stirred for 8 hours at 40.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 300 ml of 5% aqueous
sodium hydroxide solution, and it is extracted 3 times with 300 ml
of dichloromethane each. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/2-propanol=20:1).
[0543] Yield: 20.95 g (90% of theory) of a colorless solid
[0544] Elementary analysis: Cld: C, 31.94; H, 3.13; N, 3.10; F,
54.73. Fnd: C, 31.71; H, 3.31; N, 3.01; F, 54.58.
c)
1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-N-[(-
2-hydroxy)-ethyl-N-(1H,1H,2H,2H,4H,4H,5H,5H-3oxa)-perfluoroundecyl]-amide}-
-1,4,7,10-tetraazacyclododecane-gadolinium complex
[0545] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 8.98 g (15.88 mmol) of the title
compound of Example 12b is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water, and it is
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0546] Yield: 14.01 g (83% of theory) of a colorless, amorphous
powder
[0547] Elementary analysis: Cld: C, 35.03; H, 3.98; N, 7.91; F,
23.24; Gd, 14.79. Fnd: C, 34.85; H, 4.19; N, 7.75; F, 23.05; Gd,
14.58.
EXAMPLE 13
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluoroundecanoic
acid-N-(3,6,9,12-tetraoxa-t- ridecyl)-amide
[0548] 8.90 g (70 mmol) of oxalyl chloride is added to 24.25 g
(57.45 mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluoroundecanoic acid in
300 ml of dichloromethane, and it is stirred for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 100 ml of dichloromethane and added in
drops at 0.degree. C. to a solution that consists of 12.44 g (60
mmol) of 3,6,9,12-tetraoxa-tridecyl- amine and 6.07 g (60 mmol) of
triethylamine, dissolved in 200 ml of dichloromethane. It is
stirred for 3 hours at 0.degree. C., then for 6 hours at room
temperature. 300 ml of 5% aqueous hydrochloric acid is added, and
it is thoroughly stirred for 15 minutes. The organic phase is
separated, dried on magnesium sulfate and evaporated to the dry
state in a vacuum. The residue is chromatographed on silica gel
(mobile solvent: dichloromethane/acetone=15:1).
[0549] Yield: 31.61 g (90% of theory) of a colorless solid
[0550] Elementary analysis: Cld: C, 37.33; H, 4.29; N, 2.29; F,
40.40. Fnd: C, 37.15; H, 4.41; N, 2.12; F, 40.18.
b)
N-(3,6,9,12-Tetraoxatridecyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluor-
oundecyl)-amine
[0551] 31 g (50.7 mmol) of the title compound of Example 13a is
dissolved in 300 ml of tetrahydrofuran, and 32 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 200 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is
stirred for 8 hours at 40.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 300 ml of 5% aqueous
sodium hydroxide solution, and it is extracted 3 times with 300 ml
of dichloromethane each. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/2-propanol=20:1).
[0552] Yield: 28.17 g (93% of theory) of a colorless solid
[0553] Elementary analysis (relative to anhydrous substance): Cld:
C, 38.20; H, 4.72; N, 2.34; F, 41.34. Fnd: C, 38.05; H, 4.83; N,
2.40; F, 41.50.
c)
1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-N-[(-
3,6,9,12-tetraoxa)-tridecyl-N-(1H,1H,2H,2H,4H,4H,5H,5H-3oxa)-perfluorounde-
cyl]-amide}-1,4,7,10-tetraazacyclododecane-gadolinium complex
[0554] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 9.49 g (15.88 mmol) of the title
compound of Example 13b is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water, and it is
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0555] Yield: 16.13 g (84% of theory)
[0556] Elementary analysis: Cld: C, 37.75; H, 4.67; N, 6.95; F,
20.43; Gd, 13.01. Fnd: C, 37.91; H, 4.81; N, 6.83; F, 20.60; Gd,
13.15.
EXAMPLE 14
a)
2-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecyl)-amino-acetic
acid-t-butyl ester
[0557] 6.523 g (40 mmol) of bromoacetic acid-t-butyl ester is added
in drops at 50.degree. C. to 32.0 g (58.65 mmol) of the title
compound of Example 5b and 24.89 g (180 mmol) of potassium
carbonate in 300 ml of acetonitrile, and it is stirred for 3 hours
at this temperature. 300 ml of dichloromethane is added,
precipitated salts are filtered out, and the filtrate is evaporated
to the dry state in a vacuum. The residue is chromatographed on
silica gel (mobile solvent: dichloromethane/2-propanol- =20:1).
[0558] Yield: 28.11 g (57% of theory) of a colorless solid
[0559] Elementary analysis: Cld: C, 34.80; H, 3.24; N, 2.25; F,
51.98. Fnd: C, 34.98; H, 3.31; N, 2.20; F, 52.16.
b)
1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-N-[(-
t.butyloxycarbonylmethyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3oxa)-perfluorotridec-
yl]-amide}-1,4,7,10-tetraazacyclododecane-gadolinium complex
[0560] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 9.87 g (15.88 mmol) of the title
compound of Example 14a is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water, and it is
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0561] Yield: 16.64 g (85% of theory)
[0562] Elementary analysis: Cld: C, 36.04; H, 3.92; N, 6.82; F,
26.19; Gd, 12.72. Fnd: C, 35.92; H, 3.83; N, 6.91; F, 26.29; Gd,
12.84.
c)
1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-N-[(-
carboxymethyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3oxa)-perfluorotridecyl]-amide}--
1,4,7,10-tetraazacyclododecane-gadolinium complex
[0563] 10 g (8.11 mmol) of the title compound of Example 14b is
dissolved in 50 ml of trifluoroacetic acid, and it is stirred for 5
hours at room temperature. It is evaporated to the dry state in a
vacuum, and the residue is chromatographed on silica gel RP-18
(mobile solvent: gradient that consists of
tetrahydrofuran/acetonitrile/water). After the product-containing
fractions are concentrated by evaporation, the residue is dissolved
in water and set at pH, 7.2 with 5% aqueous sodium hydroxide
solution. The solution is filtered, and the filtrate is
freeze-dried.
[0564] Yield: 10.48 g (91% of theory)
[0565] Elementary analysis (relative to anhydrous substance): Cld:
C, 33.06; H, 3.28; N, 7.01; F, 26.94; Gd, 13.12; Na, 1.92. Fnd: C,
33.19; H, 3.40; N, 7.20; F, 27.14; Gd, 13.25; Na2.00.
EXAMPLE 15
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic
acid-N-(2-hydroxyethyl)-am- ide
[0566] 2.96 g (74 mmol) of sodium hydride (that consists of 60%
sodium hydride in paraffin oil) in 300 ml of tetrahydrofuran is
added to 32 g (56.61 mmol) of the title compound of Example 4a, and
it is stirred for 3 hours at room temperature under nitrogen. 7.67
g (74 mmol) of bromoacetic acid-t.butylester, dissolved in 20 ml of
tetrahydrofuran, is added in drops, and it is stirred for 5 hours
at 50.degree. C. 50 ml of methanol is added, and it is evaporated
to the dry state in a vacuum. The residue is chromatographed on
silica gel (mobile solvent: dichloromethane(/2-prop-
anol=20:1).
[0567] Yield: 23.46 g (61% of theory)
[0568] Elementary analysis: Cld: C, 35.36; H, 3.26; N, 2.06; F,
47.54. Fnd: C, 35.52; H, 3.40; N, 2.17; F, 47.40.
b)
N-(1H,1H,2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecyl)-N-[4-t.butyloxycarb-
onyl-3-oxa)-butyl]-amine
[0569] 35.0 g (51.52 mmol) of the title compound of Example 15a is
dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 200 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is
stirred for 8 hours at 40.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 300 ml of 5% aqueous
sodium hydroxide solution, and it is extracted 3 times with 300 ml
of dichloromethane each. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/2-propanol=20:1).
[0570] Yield: 31.88 g (93% of theory)
[0571] Elementary analysis: Cld: C, 36.10; H, 3.64; N, 2.11; F,
48.54. Fnd: C, 35.90; H, 3.75; N, 2.20; F, 48.71.
c)
1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-N-[(-
4-t.butyloxycarbonyl-3-oxa)-butyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3oxa)-perflu-
orotridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium
complex
[0572] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 10.57 g (15.88 mmol) of the title
compound of Example 15b is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water, and it is
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0573] Yield: 16.63 g (82% of theory)
[0574] Elementary analysis: Cld: C, 36.68; H, 4.10; N, 6.58; F,
25.29; Gd, 12.31. Fnd: C, 36.81; H, 4.20; N, 6.41; F, 25.40; Gd,
12.19.
d)
1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N-(-
4-carboxy-3-oxa)-butyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3oxa)-perfluorotridecyl-
]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex
[0575] 12 g (9.40 mmol) of the title compound of Example 15c is
dissolved in 50 ml of trifluoroacetic acid, and it is stirred for 5
hours at room temperature. It is evaporated to the dry state in a
vacuum, and the residue is chromatographed on silica gel RP-18
(mobile solvent: gradient that consists of
tetrahydrofuran/acetonitrile/water). After the product-containing
fractions are concentrated by evaporation, the residue is dissolved
in water and set at pH, 7.2 with 5% aqueous sodium hydroxide
solution. The solution is filtered, and the filtrate is
freeze-dried.
[0576] Yield: 11.41 g (92% of theory)
[0577] Water content: 5.8%
[0578] Elementary analysis (relative to anhydrous substance): Cld:
C, 33.82; H, 3.49; N, 6.76; F, 25.98; Gd, 12.65; Na, 1.85. Fnd: C,
33.95; H, 3.60; N, 6.88; F, 26.15; Gd, 12.49; Na, 1.93.
EXAMPLE 16
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic
acid-N-(2H,2H,4H,4H,5H,5H-- 3-oxa-perfluorotridecyl)-amide
[0579] 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45
mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300
ml of dichloromethane, and it is stirred for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 100 ml of dichloromethane, and it is added
in drops at 0.degree. C. to a solution that consists of 32.62 g (60
mmol) of the title compound of Example 5b and 6.07 g (60 mmol) of
triethylamine, dissolved in 200 ml of dichloromethane. It is
stirred for 3 hours at 0.degree. C., then for 6 hours at room
temperature. 300 ml of 5% aqueous hydrochloric acid is added, and
it is thoroughly stirred for 15 minutes. The organic phase is
separated, dried on magnesium sulfate and evaporated to the dry
state in a vacuum. The residue is chromatographed on silica gel
(mobile solvent: dichloromethane/acetone=15:1).
[0580] Yield: 52.87 g (91% of theory)
[0581] Elementary analysis: Cld: C, 28.50; H, 1.49; N, 1.38; F,
63.87. Fnd: C, 28.65; H, 1.61; N, 1.50; F, 64.01.
b)
N-Bis-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amine
[0582] 52 g (51.42 mmol) of the title compound of Example 16a is
dissolved in 500 ml of tetrahydrofuran, and 31 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 200 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
400 ml of ethanol/70 ml of 10% aqueous hydrochloric acid, and it is
stirred for 8 hours at 40.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 400 ml of 5% aqueous
sodium hydroxide solution and extracted 3 times with 400 ml of
dichloromethane each. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/2-propanol- =20:1).
[0583] Yield: 47.18 g (92% of theory) of a colorless solid
[0584] Elementary analysis: Cld: C, 28.90; H, 1.72; N, 1.40; F,
64.77. Fnd: C, 30.03; H, 1.81; N, 1.55; F, 65.00.
c)
1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-bis-
-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amide]-1,4,7,10-tetraaz-
acyclododecane, gadolinium complex
[0585] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetrazacyclododecane-1,4,-
7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 15.84 g (15.88 mmol) of the title
compound of Example 16b is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water, and it is
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0586] Yield: 20.95 g (82% of theory)
[0587] Elementary analysis: Cld: C, 32.10; H, 2.82; N, 5.22; F,
40.14; Gd, 9.77. Fnd: C, 29.87; H, 2.91; N, 5.09; F, 40.28; Gd,
9.98.
EXAMPLE 17
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic
acid-N-(5-hydroxy-3-oxa-pe- ntyl)-amide
[0588] 2.80 g (70 mmol) of sodium hydride (that consists of 60%
sodium hydride in paraffin oil) in 300 ml of tetrahydrofuran is
added to 32 g (52.52 mmol) of the title compound of Example 3a, and
it is stirred for 3 hours at room temperature under nitrogen. 9.68
g (70 mmol) of bromoacetic acid-t.butyl ester, dissolved in 20 ml
of tetrahydrofuran, is added in drops, and it is stirred for 5
hours at 50.degree. C. 50 ml of methanol is added, and it is
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane(/2-prop- anol=20:1).
[0589] Yield: 19.31 g (59% of theory)
[0590] Elementary analysis: Cld: C, 32.76; H, 2.91; N, 2.25; F,
51.82. Fnd: C, 32.98; H, 2.99; N, 2.36; F, 51.98.
b)
N-(3,6-Dioxa-heptyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl-
)-amine
[0591] 32 g (51.34 mmol) of the title compound of Example 17a is
dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 200 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is
stirred for 8 hours at 40.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 300 ml of 5% aqueous
sodium hydroxide solution, and it is extracted 3 times with 300 ml
of dichloromethane each. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/2-propanol=20:1).
[0592] Yield: 28.47 g (91% of theory)
[0593] Elementary analysis: Cld: C, 33.51; H, 3.31; N, 2.30; F,
53.01. Fnd: C, 33.63; H, 3.41; N, 2.21; F, 52.87.
c)
1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(3,-
6-dioxa)-heptyl-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amide]-
-1,4,7,10-tetraazacyclododecane, gadolinium complex
[0594] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 9.68 g (15.88 mmol) of the title
compound of Example 17b is added. It is stirred for 10 minutes and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water, and it is
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0595] Yield: 16.09 g (83% of theory)
[0596] Elementary analysis: Cld: C, 35.41; H, 3.96; N, 6.88; F,
26.45; Gd, 12.88. Fnd: C, 35.57; H, 4.11; N, 6.72; F, 26.58; Gd,
12.97.
EXAMPLE 18
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic
acid-N-(hexyl)-amide
[0597] 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45
mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300
ml of dichloromethane, and it is stirred for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 100 ml of dichloromethane and added in
drops at 0.degree. C. to a solution that consists of 6.07 g (60
mmol) of nhexylamine and 6.07 g (60 mmol) of triethylamine,
dissolved in 200 ml of dichloromethane. It is stirred for 3 hours
at 0.degree. C., then for 6 hours at room temperature. 300 ml of 5%
aqueous hydrochloric acid is added, and it is thoroughly stirred
for 15 minutes. The organic phase is separated, dried on magnesium
sulfate and evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/acetone=20:1).
[0598] Yield: 30.95 g (89% of theory)
[0599] Elementary analysis: Cld: C, 35.72; H, 3.33; N, 2.31; F,
53.35. Fnd: C, 35.60; H, 3.45; N, 2.43; F, 53.63.
b)
N-(Hexyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amine
[0600] 31 g (51.21 mmol) of the title compound of Example 18a is
dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 200 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is
stirred for 8 hours at 40.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 300 ml of 5% aqueous
sodium hydroxide solution, and it is extracted 3 times with 300 ml
of dichloromethane each. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/2-propanol=20:1).
[0601] Yield: 28.16 g (93% of theory)
[0602] Elementary analysis: Cld: C, 36.56; H, 3.75; N, 2.37; F,
54.62. Fnd: C, 36.40; H, 3.82; N, 2.27; F, 54.81.
c)
1,4,7-Tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N-(h-
exyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl]-amide}-1,4,7,10--
tetraazacyclododecane, gadolinium complex
[0603] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 10.98 g (15.88 mmol) of the title
compound of Example 18b is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water, and it is
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0604] Yield: 16.29 g (84% of theory)
[0605] Elementary analysis: Cld: C, 36.94; H, 4.19; N, 6.99; F,
26.85; Gd, 13.07. Fnd: C, 37.18; H, 4.31; N, 7.18; F, 26.67; Gd,
13.19.
EXAMPLE 19
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic
acid-N-[(10-t.butyloxycarb- onyl)-decyl]-amide
[0606] 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45
mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300
ml of dichloromethane, and it is stirred for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 100 ml of dichloromethane, and it is added
in drops at 0.degree. C. to a solution that consists of 15.45 g (60
mmol) of 1 1-amino-undecanoic acid-t.butylester and 6.07 g (60
mmol) of triethylamine, dissolved in 200 ml of dichloromethane. It
is stirred for 3 hours at 0.degree. C., then for 6 hours at room
temperature. 300 ml of 5% aqueous hydrochloric acid is added, and
it is thoroughly stirred for 15 minutes. The organic phase is
separated, dried on magnesium sulfate and evaporated to the dry
state in a vacuum. The residue is chromatographed on silica gel
(mobile solvent: dichloromethane/acetone=20:1).
[0607] Yield: 42.04 g (92% of theory)
[0608] Elementary analysis: Cld: C, 42.58; H, 4.76; N, 1.84; F,
42.41. Fnd: C, 42.74; H, 4.90; N, 1.73; F, 42.61.
b)
N-(10-t.Butyloxycarbonyl-decyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perflu-
orotridecyl)-amine
[0609] 39 g (51.21 mmol) of the title compound of Example 19a is
dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 200 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
400 ml of ethanol/70 ml of 10% aqueous hydrochloric acid, and it is
stirred for 8 hours at 40.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 350 ml of 5% aqueous
sodium hydroxide solution, and it is extracted 3 times with 400 ml
of dichloromethane each. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/2-propanol=20:1).
[0610] Yield: 34.84 g (91% of theory)
[0611] Elementary analysis: Cld: C, 43.38; H, 5.12; N, 1.87; F,
43.20. Fnd: C, 43.22; H, 5.23; N, 1.96; F, 43.33.
c)
1,4,7-Tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N-(1-
0-t.butyloxycarbonyl)-decyl-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotrid-
ecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium complex
[0612] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 11.87 g (15.88 mmol) of the title
compound of Example 19b is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water, and it is
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0613] Yield: 17.92 g (83% of theory)
[0614] Elementary analysis: Cld: C, 40.65; H, 4.89; N, 6.18; F,
23.76; Gd, 11.57. Fnd: C, 40.81; H, 4.99; N, 6.32; F, 23.94; Gd,
11.73.
d)
1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N-(-
10-carboxy)-decyl-N-(1H,1H,2H,2H,4H,4H,5H,5H-3oxa)-perfluorotridecyl]-amid-
e}-1,4,7,10-tetraazacyclododecane, gadolinium complex, sodium
salt
[0615] 12 g (8.83 mmol) of the title compound of Example 19c is
dissolved in 50 ml of trifluoroacetic acid, and it is stirred for 5
hours at room temperature. It is evaporated to the dry state in a
vacuum, and the residue is chromatographed on silica gel RP-18
(mobile solvent: gradient that consists of
tetrahydrofuran/acetonitrile/water). After the product-containing
fractions are concentrated by evaporation, the residue is dissolved
in water and set at pH, 7.2 with 5% aqueous sodium hydroxide
solution. The solution is filtered, and the filtrate is
freeze-dried.
[0616] Yield: 12.48 g (92% of theory)
[0617] Water content: 6.2%
[0618] Elementary analysis (relative to anhydrous substance): Cld:
C, 38.07; H, 4.34; N, 6.34; F, 24.37; Gd, 11.87 Na, 1.73. Fnd: C,
37.89; H, 4.44; N, 6.22; F, 24.51; Gd, 12.01; Na, 1.80.
EXAMPLE 20
a) 15-Benzyl-3,6,9,12,15-pentaoxa-hexadecylic
acid-N-(1H,1H,2H,2H,4H,4H,5H-
,5H-3oxa)-perfluorotridecyl)-amide
[0619] 8.90 g (70 mmol) of oxalyl chloride is added to 19.67 g
(57.45 mmol) of 15-benzyl-3,6,9,12,15-pentaoxahexadecylic acid in
250 ml of dichloromethane, and it is stirred for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 100 ml of dichloromethane and added in
drops at 0.degree. C. to a solution that consists of 32.62 g (60
mmol) of 1H,1H,2H,2H,4H,4H,5H,5H-3-- oxa-perfluoro-tridecylamine,
hydrochloride and 6.07 g (60 mmol) of triethylamine, dissolved in
200 ml of dichloromethane. It is stirred for 3 hours at 0.degree.
C., then for 6 hours at room temperature. 300 ml of 5% aqueous
hydrochloric acid is added, and it is thoroughly stirred for 15
minutes. The organic phase is separated, dried on magnesium sulfate
and evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/acetone=20- :1).
[0620] Yield: 44.91 g (94% of theory) of a colorless solid
[0621] Elementary analysis: Cld: C, 41.89; H, 4.12; N, 1.68; F,
38.84. Fnd: C, 42.02; H, 4.25; N, 1.83; F, 39.07.
b)
N-15-Benzyl-3,6,9,12,15-pentaoxa-hexadecyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H--
3oxa)-perfluorotridecyl)-amine
[0622] 43 g (51.72 mmol) of the title compound of Example 20a) is
dissolved in 400 ml of tetrahydrofuran, and 31 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 200 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
400 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is
stirred for 8 hours at 40.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 350 ml of 5% aqueous
sodium hydroxide solution, and it is extracted 3 times with 400 ml
of dichloromethane each. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/2-propanol=20:1).
[0623] Yield: 39.32 g (93% of theory)
[0624] Elementary analysis: Cld: C, 42.60; H, 4.12; N, 1.68; F,
38.84. Fnd: C, 42.45; H, 4.23; N, 1.57; F, 38.99.
c)
1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N-(-
15-benzyl-3,6,9,12,15-pentaoxa)-hexadecyl-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-
)-tridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium
complex
[0625] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 12.98 g (15.88 mmol) of the title
compound of Example 20b) is added. It is stirred for 10 minutes,
and then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water, and it is
chromatographed on silica gel RP-18 (mobile solvent: gradient that
consists of tetrahydrofuran/acetonitrile/water).
[0626] Yield: 18.84 g (83% of theory)
[0627] Elementary analysis: Cld: C, 40.34; H, 4.51; N, 5.88; F,
22.60; Gd, 11.00. Fnd: C, 40.50; H, 4.62; N, 5.76; F, 22.73; Gd
11.16.
d)
1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N-(-
14-hydroxy-3,6,9,12-tetraoxa)-tetradecyl-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-
-perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane,
gadolinium complex
[0628] 12 g (8.40 mmol) of the title compound of Example 20c is
dissolved in 150 ml of methanol, and 1.0 g of palladium catalyst
(10% Pd/C) is added, and it is hydrogenated overnight at room
temperature. It is filtered off in the catalyst, and the filtrate
is evaporated to the dry state in a vacuum.
[0629] Yield: 10.13 g (95% of theory)
[0630] Elementary analysis: Cld: C, 38.80; H, 4.61; N, 1.10; F,
25.45; Gd, 12.39. Fnd: C, 38.87; H, 4.73; N, 1.20; F, 25.58; Gd,
12.50.
EXAMPLE 21
a) 2-N-Trifluoroacetyl-6-N-benzyloxycarbonyl-L-lysine
[0631] 100.0 g (356.7 mmol) of 6-N-benzyloxycarbonyl-L-lysine is
dissolved in a mixture that consists of 1000 ml of trifluoroacetic
acid ethyl ester and 500 ml of ethanol, and it is stirred for 24
hours at room temperature. It is evaporated to the dry state, and
the residue is crystallized from diisopropyl ether.
[0632] Yield: 128.9 g (96% of theory) of a colorless, crystalline
powder.
[0633] Melting point: 98.5.degree. C.
[0634] Elementary analysis: Cld: C, 51.07; H, 5.09; N, 7.44; F,
15.14. Fnd: C, 51.25; H, 5.18; N, 7.58; F, 15.03.
b) 2-N-Trifluoroacetyl-6-N-benzyloxycarbonyl-L-lysine
[1-(4-perfluorooctylsulfonyl)-piperazine]-amide
[0635] 164.2 g (0.664 mmol) of EEDQ
(2-ethoxy-1,2-dihydroquinoline-1-carbo- xylic acid ethyl ester) is
added at 0.degree. C. to 125.0 g (332.0 mmol) of the title compound
of Example 21a) and 188.7 g (332.0 mmol) of
1-perfluorooctylsulfonylpiperazine (produced according to DE
19603033) in 750 ml of tetrahydrofuran, and it is stirred overnight
at room temperature. It is evaporated to the dry state in a vacuum,
and it is chromatographed on silica gel (mobile solvent:
dichloromethane/methanol=2- 0:1).
[0636] Yield: 286.0 g (93% of theory) of a colorless solid.
[0637] Melting point: 92.degree. C.
[0638] Elementary analysis: Cld: C, 36.30; H, 2.83; N, 6.05; F,
41.01; S, 3.46. Fnd: C, 36.18; H, 2.94; N, 5.98; F, 40.87; S,
3.40.
c)
6-N-Benzyloxycarbonyl-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine-
]-amide
[0639] Ammonia gas is introduced at 0.degree. C. for one hour into
a solution that consists of 280.0 g (302.2 mol) of the title
compound of Example 21b) in 2000 ml of ethanol. It then is stirred
for 4 hours at 0.degree. C. It is evaporated to the dry state, and
the residue is absorptively precipitated from water. The solid is
filtered off and dried in a vacuum at 50.degree. C.
[0640] Yield: 243.5 g (97% of theory) of an amorphous solid.
[0641] Elementary analysis: Cld: C, 37.60; H, 3.28; N, 6.75; F,
38.89; S, 3.86. Fnd: C, 37.55; H, 3.33; N, 6.68; F, 38.78; S,
3.81.
d)
6-N-Benzyloxycarbonyl-2-N-[1-O-.alpha.-D-carbonylmethyl-(2,3,4,6-tetra--
O-benzyl-mannopyranose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-
-amide
[0642] 41.27 g (200.0 mmol) of N,N-dicyclohexylcarbodiimide is
added at 0.degree. C. to a solution that consists of 100.0 g (120.4
mol) of the title compound of Example 21c), 72.1 g (120.4 mol) of
1-O-.alpha.-D-carboxymethyl-2,3,4,6-tetra-O-benzyl-mannopyranose
and 13.86 g (120.4 mol) of N-hydroxysuccinimide, dissolved in 500
ml of dimethylformamide. It is stirred for 3 hours at 0.degree. C.
and then overnight at room temperature. Precipitated urea is
filtered out, the filtrate is evaporated to the dry state in a
vacuum and chromatographed on silica gel.
[0643] (Mobile solvent: dichloromethane/ethanol=20:1).
[0644] Yield: 136.1 g (87% of theory) of a viscous oil.
[0645] Elementary analysis: Cld: C, 57.32; H, 4.89; N, 4.31; F,
24.86; S, 2.47. Fnd: C, 57.38; H, 5.07; N, 4.22; F, 24.78; S,
2.39.
e)
2-N-[1-O-.alpha.-D-Carbonylmethyl-mannopyranose]-L-lysine-1-[(4-perfluo-
rooctylsulfonyl)-piperazine]-amide
[0646] 130.0 g (100.0 mmol) of the title compound of Example 21d)
is dissolved in 2000 ml of ethanol, and 10.0 g of palladium
catalyst (10% Pd/C) is added. It is hydrogenated for 12 hours at
room temperature. Catalyst is filtered out, and the filtrate is
evaporated to the dry state in a vacuum.
[0647] Yield: 91.7 g (quantitative) of a colorless solid.
[0648] Elementary analysis: Cld: C, 34.07; H, 3.63; N, 6.11; S,
3.50; F, 35.24. Fnd: C, 33.91; H, 3.72; N, 6.04; S, 3.40; F,
35.31.
f)
6-N-[1,4,7-Tris(carboxylatomethyl)]-1,4,7,10-tetraazacyclododecane-10-N-
-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-2-N-[1-O-.alpha.-D-carbonylmethyl--
mannopyranose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide,
Gd complex (metal complex XV)
[0649] 50.0 g (54.55 mmol) of the title compound of Example 21e),
6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of
lithium chloride and 34.35 g (54.55 mol) of
1,4,7-tris(carboxylatomethyl)-10-(car-
boxy-3-aza-4-oxo-5-methyl-pent-5-yl)-1,4,7,10-tetraazacyclododecane,
Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while
being heated slightly. At 10.degree. C., 16.88 g (81.8 mol) of
N,N-dicyclohexylcarbodi- imide is added, and it is then stirred
overnight at room temperature. The solution is poured into 3000 ml
of acetone, and it is stirred for 10 minutes. The precipitated
solid is filtered off and then purified by chromatography (LP-18
mobile solvent: gradient that consists of
water/ethanol/acetonitrile).
[0650] Yield: 75.9 g (91.0% of theory) of a colorless solid.
[0651] Water content: 8.6%.
[0652] Elementary analysis (relative to anhydrous substance): Cld:
C, 35.34; H, 4.09; N, 8.24; S, 2.10; F, 21.12; Gd, 10.28. Fnd: C,
35.28; H, 4.15; N, 8.19; S, 2.15; F, 21.03; Gd, 10.14.
EXAMPLE 22
a)
6-N-[1,4,7-Tris(carboxylatomethyl]-1,4,7,10-tetraazacyclododecane-10-N--
(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-2-N-[1-O-.alpha.-D-carbonylmethyl-m-
annopyranose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide,
Gd complex
[0653] 50.0 g (54.55 mmol) of the title compound of Example 21e),
6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of
lithium chloride and 34.35 g (54.55 mol) of
1,4,7-tris(carboxylatomethyl)-10-(car-
boxy-3-aza-4-oxo-5-methyl-pent-5-yl)-1,4,7,10-tetraazacyclododecane,
Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while
being heated slightly. At 10.degree. C., 16.88 g (81.8 mmol) of
N,N-dicyclohexylcarbodiimide is added, and it then is stirred
overnight at room temperature. The solution is poured into 3000 ml
of acetone and stirred for 10 minutes. The precipitated solid is
filtered off, and then it is purified by chromatography (RP-18
mobile solvent: gradient that consists of
water/ethanol/acetonitrile).
[0654] Yield: 76.0 g (92.0% of theory) of a colorless solid.
[0655] Water content: 6.88%.
[0656] Elementary analysis (relative to anhydrous substance): Cld:
C, 34.90; H, 3.93; N, 8.32; S, 2.12; F, 21.33; Gd, 10.38. Fnd: C,
34.81; H, 4.02; N, 8.27; S, 2.09; F, 21.22; Gd, 10.19.
EXAMPLE 23
a) 2-[4-3-Oxapropionic acid ethyl ester]-phenylacetic acid methyl
ester
[0657] 233.8 g (1400.0 mmol) of 2-bromoacetic acid ethyl ester is
added to 200.0 g (1204.0 mmol) of 4-hydroxyphenylacetic acid methyl
ester and 212.0 g (2000.0 mmol) of sodium carbonate in 2000 ml of
acetone, and it is refluxed for 5 hours. The solid is filtered off
and evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel. (Mobile solvent: n-hexane/ethyl
acetate=15:1).
[0658] Yield: 288.5 g (95.0% of theory) of a colorless oil.
[0659] Elementary analysis: Cld: C, 61.90; H, 6.39. Fnd: C, 61.75;
H, 6.51.
b) 2-[4-3-Oxapropionic acid ethyl ester)]-phenyl-2-bromoacetic acid
methyl ester
[0660] 201.0 g (1130.0 mmol) of N-bromosuccinimide and 100.0 mg of
dibenzoyl peroxide are added to 285.0 g (1130.0 mmol) of the title
compound of Example 23a), dissolved in 2000 ml of carbon
tetrachloride, and it is refluxed for eight hours. It is cooled in
an ice bath, the precipitated succinimide is filtered off, and the
filtrate is evaporated to the dry state in a vacuum. The residue is
purified on silica gel (mobile solvent: n-hexane/acetone=15:1).
[0661] Yield: 359.2 g (96.0% of theory) of a colorless, viscous
oil.
[0662] Elementary analysis: Cld: C, 47.28; H, 4.57; Br, 24.16. Fnd:
C, 47.19; H, 4.71; Br, 24.05.
c) 2-[4-(3-Oxapropionic acid ethyl
ester)]-phenyl-2-[1-(1,4,7,10-tetraazac- yclododecan-1-yl]-acetic
acid methyl ester
[0663] 350.0 g (1057.0 mmol) of the title compound of Example 23b)
is added to 603.0 g (3500.0 mmol) of
1,4,7,10-tetraazacyclododecane, in 6000 ml of chloroform, and it is
stirred overnight at room temperature. It is extracted 3 times with
3000 ml of water in each case, the organic phase is dried on
magnesium sulfate and evaporated to the dry state in a vacuum. The
residue is used without further purification in the next reaction
(Example 23d).
[0664] Yield: 448.0 g (quantitative) of a viscous oil.
[0665] Elementary analysis: Cld: C, 59.70; H, 8.11; N, 13.26. Fnd:
C, 59.58; H, 8.20; N, 13.18.
d) 2-[4-(3-Oxapropionic
acid)]-phenyl-2-[1,4,7-tris(carboxymethyl)-1,4,7,1-
0-tetraazacyclododecan-10-yl]-acetic acid
[0666] 445.0 g (1053.0 mmol) of the title compound of Example 23c)
and 496.0 g (5270.0 mmol) of chloroacetic acid are dissolved in
4000 ml of water. It is set at a pH of 10 with 30% aqueous sodium
hydroxide solution, and it is stirred for 8 hours at 70.degree. C.
Then, the pH of the reaction solution is set at 13 by mixing with
30% aqueous sodium hydroxide solution, and it is refluxed for 30
minutes. The solution is cooled in an ice bath and set at a pH of 1
by adding concentrated hydrochloric acid. It is evaporated to the
dry state in a vacuum. The residue is taken up in 4000 ml of
methanol and absorptively precipitated for one hour at room
temperature. Precipitated common salt is filtered out, the filtrate
is evaporated to the dry state, and the residue is purified on
RP-18 C (mobile solvent: gradient that consists of
water/ethanol/acetonitrile).
[0667] Yield: 403.0 g (69.0% of theory) of a colorless solid.
[0668] Water content: 10.2%
[0669] Elementary analysis (relative to anhydrous substance): Cld:
C, 51.98; H, 6.18; N, 10.10. Fnd: C, 51.80; H, 6.31; N, 10.01.
e) 2-[4-(3-Oxapropionic
acid)]-phenyl-2-[1,4,7-tris(carboxylatomethyl)-1,4-
,7,10-tetraazacyclododecan-10-yl]-acetic acid, Gd complex
[0670] 130.73 g (360.65 mmol) of gadolinium oxide is added to 400 g
(721.3 mmol) of the title compound of Example 23d) in 2000 ml of
water, and it is stirred for 5 hours at 80.degree. C. The solution
is filtered, and the filtrate is freeze-dried.
[0671] Yield: 511 g (quantitative) of an amorphous solid.
[0672] Water content: 11.0%.
[0673] Elementary analysis (relative to anhydrous substance): Cld:
C, 40.67; H, 4.41; N, 7.98; Gd, 22.19. Fnd: C, 40.51; H, 4.52; N,
8.03; Gd, 22.05.
f)
6-N-[2-[4-(3-Oxapropionyl)-phenyl]-2-[1,4,7-tris(carboxylatomethyl)-1,4-
,7,10-tetraazacyclododecan-10-yl]-acetic
acid)]-2-N-(1-O-.alpha.-D-carbony-
lmethyl-mannopyranose)-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]--
amide, Gd complex, sodium salt
[0674] 50.0 g (54.55 mmol) of the title compound of Example 21 e),
6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of
lithium chloride and 38.66 g (54.55 mmol) of the title compound of
Example 23e) are dissolved in 400 ml of dimethyl sulfoxide while
being heated slightly. At 10.degree. C., 16.88 g (81.8 mmol) of
N,N-dicyclohexylcarbodiimide is added, and it is then stirred
overnight at room temperature. The solution is poured into 3000 ml
of acetone and stirred for 10 minutes. The precipitated solid is
filtered off and then purified by chromatography (RP-18; mobile
solvent: gradient that consists of water/ethanol/acetonitrile). The
product that is obtained is dissolved in a little water, and the pH
of the solution is set at 7.4 with aqueous sodium hydroxide
solution. Then, the product solution is freeze-dried.
[0675] Yield: 79.1 g (89% of theory) of a colorless solid.
[0676] Water content: 10.3%.
[0677] Elementary analysis (relative to anhydrous substance): Cld:
C, 36.86; H, 3.77; N, 6.88; S, 1.97; F, 19.82; Gd, 9.65. Fnd: C,
36.75; H, 3.8; N, 6.80; S, 2.03; F, 19.75; Gd, 9.57.
EXAMPLE 24
a) 6-N-[1,4,7-Tris(t
butyloxycarbonylmethyl)-10-carboxymethyl-1,4,7,10-tet-
raazacyclododecane-10-carbonylmethyl]-2-N-(1-O-.alpha.-D-carbonylmethyl-ma-
nnopyranose)-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide
[0678] 15.0 g (26.19 mmol) of
1,4,7-tris(t-butyloxycarbonylmethyl)-10-carb-
oxymethyl-1,4,7,10-tetraazacyclododecane, 24.0 g (26.19 mmol) of
the title compound of Example 21e), and 3.01 g (26.19 mmol) of
N-hydroxysuccinimide are dissolved in 150 ml of dimethylformamide,
and 8.25 g (40.0 mmol) of N,N-dicyclohexylcarbodiimide is added at
0.degree. C. It is stirred overnight at room temperature. The
precipitated urea is filtered off, and the filtrate is evaporated
to the dry state in a vacuum. The residue is chromatographed on
silica gel. (Mobile solvent: dichloromethane/methanol=- 20:1).
[0679] Yield: 35.45 g (92.0% of theory) of a colorless solid.
[0680] Elementary analysis: Cld: C, 44.08; H, 5.69; N, 7.62; F,
21.95; S, 2.18. Fnd: C, 44.01; H, 5.81; N, 7.53; F, 21.87; S,
2.03.
b)
6-N-[1,4,7-Tris(carboxylatomethyl]-1,4,7,10-tetraazacyclododecane-10-ca-
rbonyl-methyl-]-2-N-[1-O-.alpha.-D-carbonylmethyl-mannopyranose]-L-lysine--
[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex
[0681] 30.0 g (20.39 mmol) of the title compound of Example 24a) is
dissolved in 50 ml of chloroform, and 300 ml of trifluoroacetic
acid is added. It is stirred for 10 minutes at room temperature. It
is evaporated to the dry state in a vacuum, and the residue is
dissolved in 300 ml of water. 3.69 g (10.19 mmol) of gadolinium
oxide is added, and it is stirred for 5 hours at 80.degree. C. The
solution is evaporated to the dry state in a vacuum and purified on
silica gel (RP-18; mobile solvent: gradient that consists of
water/ethanol/acetonitrile).
[0682] Yield: 11.0 g (37.0% of theory) of a colorless and amorphous
solid.
[0683] Water content: 11.3%.
[0684] Elementary analysis (relative to anhydrous substance): Cld:
C, 34.62; H, 3.87; N, 7.69; F, 22.16; S, 2.20; Gd, 10.97. Fnd: C,
34.57; H, 3.95; N, 7.60; F, 22.05; S, 2.13; Gd, 10.90.
EXAMPLE 25
a) 6-N-[3,6,9-Tris(carboxymethyl)-3,6,9-triazaundecanedioic
acid-1-carboxy-11-oyl]-2-N-[1-O-.alpha.-D-carbonylmethyl-mannopyranose]-L-
-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide
[0685] 12.10 g (30.0 mmol) of
3-N-(2,6-dioxomorpholinoethyl)-6-N-(ethoxyca-
rbonylmethyl)-3,6-diazaoctanedioic acid is added to 24.0 g (26.19
mmol) of the title compound of Example 21e), dissolved in 100 ml of
dimethylformamide/30 ml of pyridine, and it is stirred for 5 hours
at 50.degree. C. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 200 ml of water, and the pH of the
resulting solution is set at 13 by adding 20% aqueous sodium
hydroxide solution. It is stirred for 8 hours at 22.degree. C. and
a pH of 13. The solution is brought to a pH of 7.2 by adding
concentrated hydrochloric acid, and then it is evaporated to the
dry state in a vacuum. The residue is chromatographed on silica gel
RP-18 (mobile solvent: gradient that consists of
water/ethanol/acetonitrile).
[0686] Yield: 17.26 g (51.0% of theory) of a colorless solid.
[0687] Water content: 9.3%.
[0688] Elementary analysis (relative to anhydrous substance): Cld:
C, 37.19; H, 4.21; N, 7.59; F, 25.00; S, 2.48. Fnd: C, 37.10; H,
4.30; N, 7.48; F, 25.07; S, 2.42.
b) 6-N-[3,6,9-Tris(carboxylatomethyl)-3,6,9-triazaundecanedioic
acid-1-carboxy-11-oyl]-2-N-[1-O-.alpha.-D-carbonylmethyl-mannopyranose]-L-
-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd
complex, sodium salt
[0689] 1.40 g (3.87 mmol) of gadolinium oxide is added to 10.0 g
(7.74 mmol) of the title compound of Example 25a) in 100 ml of
water, and it is stirred for 2 hours at 70.degree. C. The solution
is filtered. The filtrate is set at a pH of 7.4 with 2N sodium
hydroxide solution, and it is freeze-dried.
[0690] Yield: 11.36 g (quantitative) of an amorphous solid.
[0691] Water content: 10.5%.
[0692] Elementary analysis (relative to anhydrous substance): Cld:
C, 32.72; H, 3.43; N, 6.68; S, 2.18; Gd, 10.71; Na, 1.57; F, 22.00.
Fnd: C, 32.65; H, 3.51; N, 6.71; S, 2.08 Gd, 10.61; Na, 1.68; F,
21.87.
EXAMPLE 26
a)
6-N-Benzyloxycarbonyl-2-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetra-
azacyclododecane]-10-(pentanoyl-3aza-4-oxo-5-methyl-5yl)]-L-lysine-[1-(4-p-
erfluorooctylsulfonyl)-piperazine]-amide, Gd complex
[0693] 50.0 g (60.20 mmol) of the title compound of Example 21c),
6.93 g (60.20 mmol) of N-hydroxysuccinimide, 5.09 g (120.0 mmol) of
lithium chloride and 37.91 g (60.20 mmol) of
1,4,7-tris[carboxylatomethyl)-1,4,7,-
10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl),
Gd complex are dissolved in 400 ml of dimethyl sulfoxide while
being heated slightly. At 10.degree. C., 20.63 g (100.0 mmol) of
N,N-dicyclohexylcarbodiimide is added, and it is then stirred
overnight at room temperature. The solution is poured into 3000 ml
of acetone, and it is stirred for 10 minutes. The precipitated
solid is filtered off and then purified by chromatography (silica
gel RP-18; mobile solvent: gradient that consists of
water/ethanol/acetonitrile).
[0694] Yield: 75.53 g (87.0% of theory) of a colorless solid.
[0695] Water content: 10.1%.
[0696] Elementary analysis (relative to anhydrous substance): Cld:
C, 37.48; H, 3.84; N, 8.74; S, 2.22; F, 22.39; Gd, 10.90. Fnd: C,
37.39; H, 4.02; N, 8.70; S, 2.16; F, 22.29; Gd, 10.75.
b)
2-N-[1,4,7-Tris(carboxylatomethyl]-1,4,7,10-tetraazacyclododecane-Gd
complex,
10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)-L-lysine-[1-(4-perfluor-
ooctylsulfonyl)-piperazine]-amide
[0697] 70.0 g (48.53 mmol) of the title compound of Example 21d) is
dissolved in 500 ml of water/100 ml of ethanol, mixed with 5.0 g of
palladium catalyst (10% Pd/C) and hydrogenated at room temperature
under a hydrogen atmosphere (1 atm) until no more hydrogen
absorption can be observed. Then, catalyst is suctioned out, it is
thoroughly rewashed with ethanol (twice with 75 ml each) and
evaporated to the dry state in a vacuum. The title compound is
obtained as a strongly viscous and colorless oil.
[0698] Yield: 63.5 g (quantitative).
[0699] Water content: 9.8%.
[0700] Elementary analysis (relative to anhydrous substance): Cld:
C, 37.48; H, 3.84; N, 8.74; S, 2.22; F, 22.39; Gd, 10.90. Fnd: C,
37.39; H, 4.03; N, 8.65; S, 2.20; F, 22.31; Gd, 10.78.
c)
6-N-(1-O-.alpha.-D-Carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)-
-2-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane,
Gd-complex-10-(pentanoyl-3-aza-4oxo-5-methyl-5yl)]-L-lysine-[1-(4-perfluo-
rooctylsulfonyl)-piperazine]-amide
[0701] 50.0 g (38.22 mmol) of the title compound of Example 26b),
4.40 g (38.22 mmol) of N-hydroxysuccinimide, 3.39 g (80.0 mmol) of
lithium chloride and 22.88 g (38.22 mmol) of
1-O-.alpha.-D-carboxymethyl-2,3,4,6-- tetra-O-benzyl-mannopyranose
are dissolved in 400 ml of dimethyl sulfoxide while being heated
slightly (30 to 40.degree. C.). At 10.degree. C., 10.32 g (50.0
mmol) of N,N-dicyclohexylcarbodiimide is added, and it is then
stirred overnight at room temperature. The solution is poured into
3000 ml of acetone and stirred for 10 minutes. The precipitated
solid is filtered off and then purified by chromatography (silica
gel RP-18, mobile solvent: gradient that consists of
water/ethanol/acetonitrile).
[0702] Yield: 64.25 g (89.0% of theory) of a colorless solid.
[0703] Water content: 10.9%.
[0704] Elementary analysis (relative to anhydrous substance): Cld:
C, 46.42; H, 4.54; N, 6.67; S, 1.70; F, 17.10; Gd, 8.33. Fnd: C,
46.36; H, 4.71; N, 6.60; S, 1.61; F, 17.19; Gd, 8.21.
d)
6-N-(1-O-.alpha.-D-Carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)-
-2-N-[1,4,7-tris(carboxylatomethyl)-1,4,8,10-tetraazacyclododecane-10-(pen-
tanoyl-3-aza-4oxo-5-methyl-5yl)]-L-lysine-[1-(4-perfluorooctylsulfonyl)-pi-
perazine]-amide, Gd complex
[0705] 60.0 g (31.77 mmol) of the title compound of Example 26c) is
dissolved in 500 ml of ethanol and mixed with 6.0 g of palladium
catalyst (10% Pd/C). It is hydrogenated at room temperature under a
hydrogen atmosphere (1 atm) until no more hydrogen absorption can
be observed. Then, catalyst is suctioned out, it is rewashed
thoroughly with ethanol (twice with 150 ml each) and evaporated to
the dry state in a vacuum.
[0706] Yield: 48.55 g (quantitative) of a colorless solid.
[0707] Water content: 3.9%.
[0708] Elementary analysis (relative to anhydrous substance): Cld:
C, 35.37; H, 4.02; N, 8.25; S, 2.10; F, 21.13; Gd, 10.29. Fnd: C,
35.28; H, 4.13; N, 8.17; S, 2.03; F, 21.05; Gd, 10.20.
a)
1,7-Bis-(benzyloxycarbonyl)-4-[2-(N-ethyl-N-perfluorooctylsulfonyl]-ami-
no]-acetyl]-1,4,7,10-tetraazacyclododecane)
[0709] 49.46 g (200.0 mmol) of EEDQ
(2-ethoxy-1,2-dihydroquinoline-1-carbo- xylic acid ethyl ester) is
added at 0.degree. C. to 50.0 g (113.5 mmol) of
1,7-bis(benzyloxycarbonyl)-1,4,7,10-tetraazacyclododecane and 66.42
g (113.5 mmol) of 2-(N-ethyl-N-perfluorooctylsulfonyl)-aminoacetic
acid (produced according to DE 196 03 033) in 300 ml of
tetrahydrofuran, and it is stirred overnight at room temperature.
It is evaporated to the dry state in a vacuum and chromatographed
on silica gel (mobile solvent: dichloromethane/methanol=20:1).
[0710] Yield: 65.2 g (57% of theory) of a colorless solid.
[0711] Elementary analysis: Cld: C, 42.91; H, 3.80; N, 6.95; F,
32.05; S, 3.18. Fnd: C, 42.85; H, 3.90; N, 6.87; F, 31.98; S,
3.15.
b)
1,7-Bis-(benzyloxy)-4-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acet-
yl-10-[1-O-.alpha.-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose]--
1,4,7,10-tetraazacyclododecane
[0712] 24.73 g (100 mmol of EEDQ
(2-ethoxy-1,2-dihydroquinoline-1-carboxyl- ic acid ethyl ester) is
added at 0.degree. C. to 60.0 g (59.53 mmol) of the title compound
of Example 27a) and 35.64 g (59.53 mmol) of
1-O-.alpha.-D-carboxymethyl-2,3,4,6-tetra-O-benzyl-mannopyranose,
produced according to DE 19728954, in 300 ml of tetrahydrofuran,
and it is stirred overnight at room temperature. It is evaporated
to the dry state in a vacuum and chromatographed on silica gel
(mobile solvent: dichloromethane/methanol=20:1).
[0713] Yield: 76.6 g (81.0% of theory) of a colorless solid.
[0714] Elementary analysis: Cld: C, 54.44; H, 4.70; N, 4.41; F,
20.33; S, 2.02. Fnd: C, 54.37; H, 4.81; N, 4.35; F, 20.27; S,
1.96.
c)
1-[2-(N-Ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-7-(1-O-.alpha.-D--
carbonylmethyl-mannopyranose)-1,4,7,10-tetraazacyclododecane
[0715] 70 g (44.07 mmol) of the title compound of Example 27b is
dissolved in 800 ml of ethanol, and 8 g of palladium catalyst (10%
Pd/C) is added. It is hydrogenated at room temperature. Catalyst is
filtered out, and the filtrate is evaporated to the dry state in a
vacuum.
[0716] Yield: 42.3 g (quantitative) of a colorless solid.
[0717] Elementary analysis: Cld: C, 35.04; H, 3.99; N, 7.30; F,
33.65; S, 3.34. Fnd: C, 35.15; H, 4.13; N, 7.13; F, 33.48; S,
3.26.
d)
1,7-Bis-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-G-
d-complex-10-(pentanoyl-3-aza-4-oxo-5-methyl-5yl)-4-[2-(N-ethyl-N-perfluor-
ooctylsulfonyl)-amino]-acetyl-10-(1-O-.alpha.-D-carbonylmethyl-mannopyrano-
se)-1,4,7,10-tetraazacyclododecane
[0718] 20 g (20.84 mmol) of the title compound of Example 27c),
5.09 g (120 mmol) of lithium chloride and 37.78 g (60 mmol) of
1,4,7-tris(carboxylatomethyl)-10-pentanoyl-3-aza-4-oxo-5-methyl-5yl)-1,4,-
7,10-tetraazacyclododecane, Gd complex, are dissolved in 400 ml of
dimethyl sulfoxide while being heated slightly. At 10.degree. C.,
29.67 g (120 mmol) of EEDQ is added, and it is then stirred
overnight at room temperature. The solution is poured into 3000 ml
of acetone, and it is stirred for 10 minutes. The precipitated
solid is filtered off and then purified by chromatography (silica
gel RP-18, mobile solvent: gradient that consists of
water/ethanol/acetonitrile).
[0719] Yield: 13.2 g (29.0% of theory) of a colorless solid.
[0720] Water content: 11.8%.
[0721] Elementary analysis (relative to anhydrous substance): Cld:
C, 36.31; H, 4.34; N, 9.62; S, 1.47; F, 14.79; Gd, 14.41. Fnd: C,
36.24; H, 4.27; N, 9.58; S, 1.51; F, 14.85; Gd, 14.25.
EXAMPLE 28
a)
1,7-Bis(benzyloxycarbonyl)-4-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amin-
o]-acetyl-10-[pentanoyl-3-aza-4-oxo-5-methyl-5yl-[1,4,7-tris(carboxylatome-
thyl)-Gd complex,
1,4,7,10-tetraazacyclododecan-10-yl]-1,4,7,10-tetraazacy-
clododecane.
[0722] 50.0 g (49.61 mmol) of the title compound of Example 27a),
5.71 g (49.61 mmol) of N-hydroxysuccinimide, 4.24 g (100 mmol) of
lithium chloride and 31.24 g (49.61 mmol) and
1,4,7-tris(carboxylatomethyl)-10-(p-
entanoyl-3-aza-oxo-5-methyl-5-yl)-1,4,7,10-tetraazacyclododecane,
Gd-complex, are dissolved in 350 ml of dimethyl sulfoxide while
being heated slightly. At 10.degree. C., 15.47 g (75 mmol) of
N,N-dicyclohexylcarbodiimide is added, and it is then stirred
overnight at room temperature. The solution is poured into 2000 ml
of acetone, and it is stirred for 10 minutes. The precipitated
solid is filtered off and then purified by chromatography (silica
gel RP-18, mobile solvent: gradient that consists of
water/ethanol/acetonitrile).
[0723] Yield: 65.1 g (81.0% of theory) of a colorless solid.
[0724] Water content: 7.9%.
[0725] Elementary analysis (relative to anhydrous substance): Cld:
C, 40.79; H, 4.11; N, 8.65; S, 1.98; F, 19.94 Gd, 9.72. Fnd: C,
40.71; H, 4.20; N, 8.58; S, 2.03; F, 19.87 Gd, 9.68.
b)
1-[2-(N-Ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-7{(-pentanoyl-3-a-
za-4-oxo-5-methyl-5yl)-10-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraaza-
cyclododecane, Gd-complex]}-1,4,7,10-tetraazacyclododecane.
[0726] 60.0 g (37.05 mmol) of the title compound of Example 28a) is
dissolved in 600 ml of ethanol, and 6.0 g of palladium catalyst
(10% Pd/C) is added. It is hydrogenated at room temperature.
Catalyst is filtered out, and the filtrate is evaporated to the dry
state in a vacuum.
[0727] Yield: 50.06 g (quantitative) of a colorless solid.
[0728] Water content: 3.9%.
[0729] Elementary analysis (relative to anhydrous substance): Cld:
C, 34.67; H, 4.03; N, 10.37; S, 2.37; F, 23.90; Gd, 11.64. Fnd: C,
34.58; H, 4.15; N, 10.28; S, 2.30; F, 23.84; Gd, 11.57.
c)
1-[2-(N-Ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-4,10-bis[1-O-.alp-
ha.-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose]-7-{(pentanoyl-3-
-aza-4-oxo-5-methyl-5-yl)-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraaza-
cyclododecan-10-yl]-Gd-complex}-1,4,7,10-tetraazacyclododecane
[0730] 40.0 g (29.60 mmol) of the title compound of Example 28b),
2.54 g (60.0 mmol) of lithium chloride and 44.9 g (75.0 mmol) of
1-O-.alpha.-D-carboxymethyl-2,3,4,6-tetra-O-benzyl-mannopyranose
are dissolved in 300 ml of dimethyl sulfoxide while being heated
slightly. At 10.degree. C., 24.73 g (100.0 mmol) of EEDQ is added,
and it is then stirred overnight at room temperature. The solution
is poured into 3000 ml of acetone and stirred for 10 minutes. The
precipitated solid is filtered off and then purified by
chromatography (silica gel RP-18, mobile solvent: gradient that
consists of water/ethanol/acetonitrile).
[0731] Yield: 31.98 g (43.0% of theory) of a colorless solid.
[0732] Water content: 3.5%.
[0733] Elementary analysis (relative to anhydrous substance): Cld:
C, 53.06; H, 5.05; N, 5.57; S, 1.28; F, 12.85; Gd, 6.26. Fnd: C,
52.95; H, 5.19; N, 5.48; S, 1.23; F, 12.77; Gd, 6.14.
d)
1-[2-(N-Ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-4,10-bis[1-O-.alp-
ha.-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose]-7-{(pentanoyl-3-
-aza-4-oxo-5-methyl-5-yl)-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraaza-
cyclododecan-10-yl]-Gd-complex}-1,4,7,10-tetraazacyclododecane
[0734] 30.0 g (11.94 mmol) of the title compound of Example 28c) is
dissolved in 300 ml of ethanol/30 ml of water, and 4.0 g of
palladium catalyst (10% Pd/C) is added. It is hydrogenated at room
temperature, catalyst is filtered out, and the filtrate is
evaporated to the dry state in a vacuum.
[0735] Yield: 21.39 g (quantitative) of a colorless solid.
[0736] Water content: 3.4%.
[0737] Elementary analysis (relative to anhydrous substance): Cld:
C, 36.87; H, 4.39; N, 7.82; S, 1.79; F, 18.03; Gd, 8.78. Fnd: C,
36.80; H, 4.50; N, 7.85; S, 1.68; F, 17.91; Gd, 8.70.
EXAMPLE 29
a) 6-N-[3,6-Bis(carboxymethyl)-octane-1,8-dicarboxylic
acid-1-carboxy-8-oyl]-2-N-(1-O-.alpha.-D-carboxymethyl-mannopyranose)-lys-
ine-[1-(4perfluorooctylsulfonyl)-piperazine]-amide
[0738] 25.62 g (100.0 mmol) of
ethylenediamine-N,N,N',N'-tetraacetic acid dianhydride is added to
27.5 g (30.0 mmol) of the title compound of Example 21e), dissolved
in 300 ml of dimethylformamide/100 ml of pyridine, and it is
stirred for 5 hours at 50.degree. C. It is evaporated to the dry
state in a vacuum. The residue is dissolved in 300 ml of water, set
at a pH of 10 by adding 20% aqueous sodium hydroxide solution, and
then the basic product solution is brought to a pH of 3 by adding
concentrated hydrochloric acid, and it is evaporated to the dry
state in a vacuum. The residue is chromatographed on silica gel
RP-18 (mobile solvent: gradient that consists of
water/ethanol/acetonitrile).
[0739] Yield: 18.22 g (51.0% of theory) of a colorless solid.
[0740] Water content: 7.9%.
[0741] Elementary analysis (relative to anhydrous substance): Cld:
C, 36.31; H, 3.98; N, 7.06; F, 27.12; S, 2.69. Fnd: C, 36.23; H,
4.07; N, 6.98; F, 27.05; S, 2.62.
b) 6-N-[3,6-Bis(carboxylatomethyl)-octane-1,8-dicarboxylic
acid-1-carboxylato-8-oyl-]-2-N-(1-O-.alpha.-D-carboxymethyl-mannopyranose-
)-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Mn
complex, sodium salt
[0742] 10 g (8.397 mmol) of the title compound of Example 29a) is
dissolved in 200 ml of water. 965 mg (8.397 mmol) of manganese(II)
carbonate is added, and it is stirred for 3 hours to 60.degree. C.
The solution is set at a pH of 7.4 with 5% aqueous sodium hydroxide
solution, filtered, and then freeze-dried.
[0743] Yield: 10.52 g (99.0% of theory) of a colorless solid.
[0744] Water content: 7.8%.
[0745] Elementary analysis (relative to anhydrous substance): Cld:
C, 34.16; H, 3.50; N, 6.64; S, 2.53; F, 25.52; Mn, 4.34; Na, 1.82.
Fnd: C, 34.06; H, 3.61; N, 6.58; S, 2.47; F, 25.47; Mn, 4.30; Na,
1.97.
EXAMPLE 30
a) 1,2,3,4,6-Penta-O-acetyl-.alpha.,.beta.-D-mannopyranose
[0746] Analogously, as described in the literature [M. L. Wolfrom
and A. Thompson in Methods in Carbohydrate Chemistry (R. L.
Whistler, M. L. Wolfrom and J. N. BeMiller, Eds.), Academic Press,
New York, Vol. II, 53, pp. 211-215, (1963)], the reaction of 150 g
(832.5 mmol) of .alpha.,.beta.-D-mannopyranose with a mixture that
consists of 1500 ml of absolute pyridine and 1500 ml of acetic acid
anhydride after working-up yields 315 g (96.7%) of the
above-mentioned title compound as crude product in the form of a
viscous and colorless oil. By .sup.1H-NMR-spectroscopic study of
the thus obtained title compound, it was possible to determine the
.alpha. to .beta. ratio of both anomers at 4:1. A separation of the
.alpha.,.beta.-anomers of the above-mentioned title compound can
thus be eliminated in performing the subsequent reaction steps.
[0747] Elementary analysis: Cld: C, 49.21; H, 5.68. Fnd: C, 49.12;
H, 5.78.
b)
1-O-.alpha.-D-(5-Ethoxycarbonyl)-pentyl-2,3,4,6-tetra-O-acetyl-mannopyr-
anose
[0748] Analogously, as described in the literature for the
synthesis of aryl glycopyranosides [J. Conchie and G. A. Levvy in
Methods in Carbohydrate Chemistry (R. L. Whistler, M. L. Wolfrom
and J. N. BeMiller, Eds.), Academic Press, New York, Vol. II, 90,
pp. 345-347, (1963)], the reaction of 156.2 g (400 mmol) of the
title compound of Example 2 la) as an .alpha.,.beta.-anomer mixture
with 67 ml (400 mmol) of 6-hydroxy-hexanoic acid ethyl ester and
60.8 ml (520 mmol) of tin(IV) chloride results in a total of 600 ml
of 1,2-dichloroethane after purification by column chromatography
(eluant: hexane/ethyl acetate 2:1) for the formation of 100.05 g
(51% of theory) of the above-mentioned title compound as a
colorless and viscous oil. By .sup.1H-NMR-spectroscop- ic study of
the thus obtained title compound, it was possible to show that the
above-mentioned title compound is exclusively the pure
.alpha.-anomer.
[0749] Elementary analysis: Cld: C, 52.94; H, 6.77. Fnd: C, 52.80;
H, 6.78.
c)
1-O-.alpha.-D-(5-Carboxy)-pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose
[0750] A stirred suspension of 141.0 g (289 mmol) of the title
compound of Example 30b) in 200 ml of dioxane is mixed at room
temperature and with simultaneous vigorous stirring in portions
with a total of 238.5 g (4.26 mmol) of fine-powder potassium
hydroxide powder. To make it easier to stir, the reaction mixture
is mixed with another 200 ml of dioxane, and the thus obtained
suspension is subsequently heated to boiling and mixed drop by drop
at this temperature with a total of 372 ml (3.128 mol) of benzyl
bromide over a period of two hours. After a reaction time of 4
hours at 110.degree. C. followed by 12 hours at room temperature,
the reaction mixture is slowly poured into a total of 2.5 liters of
ice water for the purpose of working-up, and the aqueous phase is
subsequently completely extracted with diethyl ether. After the
thus obtained ether phase is washed and after the subsequent drying
of the same on sodium sulfate, salt is suctioned out, and the
diethyl ether is removed in a vacuum. Excess benzyl bromide is then
distilled off from the reaction mixture in an oil pump vacuum
quantitatively at an oil bath temperature of 180.degree. C. The
thus obtained, resinous-oily residue is purified on silica gel with
use of ethyl acetate/hexane (1:10) as an eluant.
[0751] Yield: 172.2 g (91.0% of theory) of the above-mentioned
title compound in the form of a colorless and extremely viscous
oil.
[0752] Elementary analysis: Cld: C, 75.68; H, 7.16. Fnd: C, 75.79;
H, 7.04.
d)
6-N-Benzyloxycarbonyl-2-N-[1-O-.alpha.-D-(5-carbonyl)-pentyl-2,3,4,6-te-
tra-O-benzyl-mannopyranose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperaz-
ine]-amide
[0753] 100.0 g (134.0 mmol) of the carboxylic acid that is produced
under Example 30c) and 32.4 g (281.4 mmol) of N-hydroxysuccinimide
are dissolved in 500 ml of dimethylformamide and mixed in portions
at 0.degree. C. with a total of 58.0 g (281.4 mmol) of
N,N'-dicyclohexylcarbodiimide, and it is stirred for 3 more hours
at this temperature. A solution of 111.3 g (134.0 mmol) of the
title compound of Example 21c) that is cooled to 0.degree. C. and
dissolved in 300 ml of dimethylformamide is added drop by drop to
the thus produced active ester solution, and it is stirred for 2
hours at 0.degree. C. and for 12 hours at room temperature. For
working-up, precipitated dicyclohexylurea is filtered out, and the
solution is drawn off until a dry state is reached. The thus
obtained residue is then chromatographed on silica gel (mobile
solvent: dichloromethane/ethanol 20:1; the chromatography is
carried out with use of a solvent gradient with continuous increase
of the proportion of ethanol).
[0754] Yield: 132.5 g (67.4% of theory) of the title compound in
the form of a colorless and strongly viscous oil.
[0755] Elementary analysis: Cld: C, 54.02; H, 4.88; N, 3.82; F,
22.01; S, 2.19. Fnd; C, 53.87; H, 4.85; N, 4.02; F, 22.55; S,
2.06.
e)
2-N-[1-O-.alpha.-D-(5-Carbonyl)pentyl-mannopyranose]-L-lysine-[1-(4-per-
fluorooctylsulfonyl)-piperazine]-amide
[0756] 120.0 g (81.77 mmol) of the compound that is produced under
30d) is dissolved in 800 ml of ethanol, mixed with 4.5 g of
Pearlman's catalyst (Pd 20%, C) and hydrogenated at room
temperature under a hydrogen atmosphere (1 atm) until no more
hydrogen absorption can be observed (about 8 hours). Catalyst is
suctioned out, it is thoroughly rewashed with ethanol (about 200
ml) and evaporated to the dry state in a vacuum. The title compound
is obtained as a strongly viscous and colorless oil.
[0757] Yield: 78.5 g (98.7% of theory).
[0758] Elementary analysis: Cld: C, 37.04; H, 4.25; N, 5.76; F,
33.20; S, 3.30. Fnd: C, 36.96; H, 4.85; N, 5.41; F, 34.13; S,
3.22.
f)
2-N-[1-O-.alpha.-D-(5-Carbonyl)pentyl-mannopyranose]-6-N-[1,4,7-tris-(c-
arboxylatomethyl)-10-(-3-aza-4-oxo-5-methyl-5-yl-pentanoyl)-1,4,7,10-tetra-
azacyclododecane]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide-
, Gd complex
[0759] 99.8 g (158.4 mmol; 2.2 molar equivalents relative to the
amine components of Example 30e) that are used) of the Gd complex,
described in Patent Application DE 197 28 954 C1 under Example 31
h), of
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1-
,4,7-triacetic acid and 6.7 g of anhydrous lithium chloride (158.4
mmol) are dissolved at 40.degree. C. in 800 ml of absolute dimethyl
sulfoxide while being stirred. At this temperature, it is
subsequently mixed with a total of 18.2 g (158.4 mmol) of
N-hydroxysuccinimide and 70.0 g (71.96 mmol) of the title compound
of Example 30e), dissolved in 250 ml of absolute dimethyl
sulfoxide. After cooling to room temperature, the reaction solution
is mixed with 32.7 g (158.4 mmol) of N,N'-dicyclohexylcarbodiimide
and stirred for 12 hours at room temperature. The suspension that
is obtained is then mixed with sufficient acetone until the
above-mentioned title compound is completely precipitated, the
precipitate is suctioned off, dried, taken up in water, insoluble
dicyclohexylurea is filtered off, and the filtrate is desalinated
with an AMICON.RTM. YM-3 ultrafiltration membrane (cut-off: 3,000
Da), and low-molecular components are removed. The retentate is
then freeze-dried.
[0760] Yield: 93.0 g (81.6% of theory) as a colorless
lyophilizate.
[0761] H.sub.2O content (Karl-Fischer): 9.53%.
[0762] Elementary analysis (relative to anhydrous substance): Cld:
C, 37.15; H, 4.39; N, 7.96; F, 20.38; S, 2.02; Gd, 9.92. Fnd: C,
36.92; H, 4.50; N, 7.68; F, 19.77; S, 1.91; Gd, 10.08.
EXAMPLE 31
a)
2-N-[1-O-.alpha.-D-(5-Carbonyl)pentyl-mannopyranose]-6-N-{2-[4-(3-oxapr-
opionyl)-phenyl]-2-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclodo-
decan-10-yl]-acetic
acid}-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazin- e]-amide,
Gd complex, sodium salt
[0763] A stirred suspension of 5.0 g (9.06 mmol) of the title
compound of Example 23e) in 15 ml of absolute dimethyl sulfoxide is
mixed at 70.degree. C. with 0.68 g (15.9 mmol) of lithium chloride.
After 30 minutes of stirring at 70.degree. C., the now clear
reaction solution is mixed in portions with a total of 1.83 g (15.9
mmol) of N-hydroxysuccinimide, and the reaction mixture is kept at
this temperature for 1 more hour. After cooling to 0.degree. C., it
is mixed with 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide, and
the reaction solution is stirred for 1 more hour at 0.degree. C.,
followed by 12 hours at 22.degree. C. The thus obtained reaction
solution of the N-hydroxysuccinimide ester of the title compound of
Example 3e) is now mixed at 22.degree. C. drop by drop with a
solution of 4.0 g (4.12 mmol) of the title compound of Example
10Ae) in 15 ml of absolute dimethyl sulfoxide, and it is stirred
for another 12 hours at room temperature. For working-up, the
reaction solution is added in drops at 22.degree. C. into 900 ml of
acetone, whereby the title compound precipitates as a colorless
precipitate. The precipitate is suctioned off, dissolved in 200 ml
of distilled water, and then the pH of this solution is set
precisely at 7.2 with 1 molar sodium hydroxide solution. The thus
obtained aqueous product solution is ultrafiltered three times with
a YM3-ultrafiltration membrane (AMICON.RTM.: cut-off: 3,000 Da) for
the purposes of desalination and separation of low-molecular
components. The thus obtained retentate is then freeze-dried.
[0764] Yield: 6.33 g (92.4% of theory, relative to the amine
component used) as a colorless lyophilizate with a water content of
7.38%.
[0765] Elementary analysis (relative to anhydrous substance): Cld:
C, 38.48; H, 4.13; N, 6.65; F, 19.16; S, 1.90; Gd, 9.33; Na, 1.36.
Fnd: C, 39.52; H, 4.12; N, 6.67; F, 19.70; S, 1.89; Gd, 9.30; Na,
1.41.
EXAMPLE 32
a) 3,5-Bis-benzyloxycarbonylamino-benzoic
acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,-
5H,5H-perfluorotridecyl)-amide
[0766] 20 g (47.5 mmol) of 3,5-bisbenzyloxycarbonylamino-benzoic
acid (synthesis according to the subsequent bibliographic
reference: Skulnick, Harvey I.; Johnson, Paul D.; Aristoff, Paul
A.; Morris, Jeanette K.; Lovasz, Kristine D.; et al.; J. Med.
Chem.; 40; 7; 1997; 1149-1164) and 4.78 g (47.5 mmol) of
triethylamine are dissolved in a solvent mixture that consists of
125 ml of dry tetrahydrofuran and 125 ml of dry dioxane. After
cooling to -15.degree. C., a solution of 6.56 g (48 mmol) of
isobutyl chloroformate in 30 ml of dry tetrahydrofuran is slowly
added in drops while being stirred, whereby the internal
temperature is to be kept below -10.degree. C. After a reaction
time of 15 minutes at 15.degree. C., a solution of 58.6 g (47.5
mmol) of 1-amino-1H,1H,2H,2H,4H,4H,5H,5H-3- -oxo-perfluorotridecane
and 4.78 g (47.5 mmol) of triethylamine in 100 ml of dry
tetrahydrofuran is added in drops at -20.degree. C. After a
reaction time of one hour at -15.degree. C. and two hours at room
temperature, the reaction solution is evaporated to the dry state
in a vacuum. The remaining residue is taken up in 300 ml of ethyl
acetate and washed twice with 200 ml each of saturated sodium
bicarbonate solution and once with 300 ml of water. After the
organic phase is dried on sodium sulfate, salt is suctioned out,
and the ethyl acetate is removed in a vacuum. The remaining oily
residue is purified on silica gel with use of
dichloromethane/hexane/2-propanol (10:5:1) as an eluant.
[0767] Yield: 36.2 g (82.5% of theory) of the title compound as a
colorless oil.
[0768] Elementary analysis: Cld: C, 46.82; H, 3.27; N, 4.55; F,
34.97. Fnd: C, 47.21; H, 3.31; N, 4.61; F, 34.48.
b) 3,5-Di-amino-benzoic
acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfluorotri-
decyl)]-amide
[0769] 30.0 g (32.4 mmol) of the amide that is produced under 32a)
is dissolved in 300 ml of ethanol and mixed with 1.2 g of
Pearlman's catalyst (Pd 20%, C). It is hydrogenated at room
temperature under a hydrogen atmosphere (1 atm) until no more
hydrogen absorption can be observed. Catalyst is suctioned out, it
is thoroughly rewashed with ethanol (about 300 ml), and it is
evaporated to the dry state in a vacuum. The title compound is
obtained as a strongly viscous, yellowish oil.
[0770] Yield: 20.12 g (94.8% of theory).
[0771] Elementary analysis: Cld: C, 36.66; H, 2.77; N, 6.41; F,
49.28. Fnd: C, 36.07; H, 2.87; N, 6.23; F, 49.43.
c)
3-N-[-(1-O-.alpha.-D-Carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranos-
e)-5-amino-benzoic
acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl-
)-amide
[0772] 10.95 g (18.30 mmol) of
1-carboxymethyloxy-2,3,4-tetra-O-benzyl-.al- pha.-D-mannopyranoside
[Production as described in Patent DE 197 28 954 C1] is dissolved
in 150 ml of dimethylformamide and mixed with a total of 2.09 g
(18.3 mmol) of N-hydroxysuccinimide. It is cooled to 0.degree. C.,
and 3.78 g (18.3 mmol) of dicyclohexylcarbodiimide is added. It is
stirred for one hour at 0.degree. C. and then for 4 hours at room
temperature. It is cooled to 0.degree. C., and a solution that
consists of 24.0 g (36.6 mmol, 2 molar equivalents relative to the
carboxylic acid used) of the diamino compound that is described
under Example 32b), dissolved in 350 ml of dimethylformamide, is
slowly added in drops within 3 hours. Then, it is stirred for one
more hour at 0.degree. C., then overnight at room temperature. It
is evaporated to the dry state in a vacuum, and the residue is
taken up in 300 ml of ethyl acetate. Precipitated urea is filtered
out, and the filtrate is washed twice with 100 ml each of 5%
aqueous soda solution. The organic phase is dried on magnesium
sulfate and evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent: n-hexane/isopropanol
13:1). 16.8 g (74.3% of theory, relative to the carboxylic acid
used) of the title compound is obtained in the form of a colorless
oil. By increasing the polarity of the eluant composition in
n-hexane/isopropanol to 5:1, a total of 10.15 g of unreacted
diamino compound 32b) is recovered in the subsequent chromatography
fractions, which can be reacted again according to the
above-mentioned reaction instructions.
[0773] Elementary analysis: Cld: C, 54.42; H, 4.40; N, 3.40; F,
26.13. Fnd: C, 54.32; H, 4.49; N, 3.48; F, 25.94.
d)
3-N-[-(1-O-.alpha.-D-Carbonylmethyl-mannopyranose)]-5-amino-benzoic
acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide
[0774] Similar to what is described for the synthesis of the title
compound of Example 32b), the hydrogenolysis of 12.0 g (9.70 mmol)
of the title compound of Example 32c), with use of 0.5 g of
Pearlman's catalyst (Pd 20%, C) in an ethanol/water (9:1) mixture
after working-up yields 8.08 g (96.7% of theory) of the
above-mentioned title compound in the form of a yellowish-colored
and viscous oil.
[0775] Elementary analysis: Cld: C, 37.64; H, 3.28; N, 4.88; F,
37.49. Fnd: C, 37.32; H, 3.17; N, 4.97; F, 37.55.
e)
3-N-(1-O-.alpha.-D-Carbonylmethyl-mannopyranose)-5-N-{2-[4-(3-oxapropio-
nyl)-phenyl]-2-[1,4,7-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododec-
an-10-yl]-acetic acid}-benzoic
acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfl- uorotridecyl)-amide,
Gd complex, sodium salt
[0776] 13.6 g (19.2 mmol; 2.2 molar equivalents relative to the
amine component of Example 32d) that is used) of the Gd complex
that is described under Example 23Ae) and 0.81 g of anhydrous
lithium chloride (19.2 mmol) are dissolved at 40.degree. C. in 100
ml of absolute dimethyl sulfoxide while being stirred and mixed at
this temperature with a total of 2.2 g (19.2 mmol) of
N-hydroxysuccinimide and 7.5 g (8.7 mmol) of the title compound of
Example 32d), dissolved in 50 ml of absolute dimethyl sulfoxide.
After cooling to room temperature, the reaction solution is mixed
with 3.96 g (19.2 mmol) of N,N'-dicyclohexylcarbodiimide and
stirred for 12 hours at room temperature. The suspension that is
obtained is then mixed with sufficient acetone until the
above-mentioned title compound is completely precipitated, the
precipitate is suctioned off, dried, taken up in water, insoluble
dicyclohexylurea is filtered off, and the filtrate is desalinated
with an AMICON.RTM. YM-3 ultrafiltration membrane (cut-off: 3,000
Da), and low-molecular components are removed. The retentate is
then freeze-dried.
[0777] Yield: 11.51 g (84.5% of theory) as a colorless
lyophilizate.
[0778] H.sub.2O content (Karl-Fischer): 6.77%.
[0779] Elementary analysis (relative to anhydrous substance): Cld:
C, 40.05; H, 3.94; N, 6.29; F, 20.71; Gd, 10.08; Na, 1.47. Fnd: C,
39.98; H, 4.00; N, 6.31; F, 20.73; Gd, 10.11; Na, 1.42.
EXAMPLE 33
a)
3,5-Bis-(benzyloxycarbonylamino)-1-{N-[1-(4-perfluorooctylsulfonyl)-pip-
erazine]}-benzamide
[0780] 10 g (23.75 mmol) of 3,5-bis-benzyloxycarbonylamino-benzoic
acid (synthesis according to the subsequent bibliographic
reference: Skulnick, Harvey I.; Johnson, Paul D.; Aristoff, Paul
A.; Morris, Jeanette K.; Lovasz, Kristine D.; et al.; J. Med.
Chem.; 40; 7; 1997; 1149-1164) and 2.39 g (23.75 mmol) of
triethylamine are dissolved in a solvent mixture that consists of
60 ml of dry tetrahydrofuran and 70 ml of dry dioxane. After
cooling to -15.degree. C., a solution of 3.28 g (24 mmol) of
isobutyl chloroformate in 20 ml of dry tetrahydrofuran is slowly
added in drops while being stirred, whereby the internal
temperature does not exceed -10.degree. C. After a reaction time of
15 minutes at -15.degree. C., a solution of 23.0 g (23.75 mmol) of
perfluorooctylsulfonyl-piperazin- e and 2.39 g (23.75 mmol) of
triethylamine in 50 ml of dry tetrahydrofuran is added in drops at
-20.degree. C. After a reaction time of one hour at -15.degree. C.
and two hours at room temperature, the reaction solution is
evaporated to the dry state in a vacuum. The remaining residue is
taken up in 200 ml of ethyl acetate and washed twice with 100 ml
each of saturated sodium bicarbonate solution and once with 300 ml
of water. After the organic phase is dried on sodium sulfate, salt
is suctioned out, and the ethyl acetate is removed in a vacuum. The
remaining oily residue is purified on silica gel with use of
dichloromethane/hexane/2-pr- opanol (15:5:1) as an eluant.
[0781] Yield: 18.35 g (79.6% of theory) of the title compound as a
colorless oil.
[0782] Elementary analysis: Cld: C, 43.31; H, 2.80; N, 5.77; F,
33.27; S, 3.30. Fnd: C, 43.21; H, 2.75; N, 5.61; F, 33.38; S,
3.22.
b)
3,5-Di-amino-1-{N-[1-(4-perfluorooctylsulfonyl)-piperazine]}-benzamide
[0783] 9.70 g (10.0 mmol) of the amide that is produced under 33a)
is dissolved in 100 ml of ethanol and mixed with 0.4 g of
Pearlman's catalyst (Pd 20%, C). It is hydrogenated at room
temperature under a hydrogen atmosphere (1 atm) until no more
hydrogen absorption can be observed. Catalyst is suctioned out, it
is thoroughly rewashed with ethanol (about 150 ml) and evaporated
to the dry state in a vacuum. The title compound is obtained as a
strongly viscous, yellowish oil.
[0784] Yield: 6.9 g (98.2% of theory).
[0785] Elementary analysis: Cld: C, 32.49; H, 2.15; N, 7.98; F,
45.98; S, 4.56. Fnd: C, 32.56; H, 2.17; N, 8.09; F, 45.63; S,
4.61.
c)
5-Amino-3-N-(1-O-.alpha.-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannop-
yranose)-benzoic
acid-N-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide
[0786] 5.48 g (9.15 mmol) of
1-carboxymethyloxy-2,3,4,-tetra-O-benzyl-.alp-
ha.-D-mannopyranoside [production as described in Patent DE 197 28
954 C1] is dissolved in 100 ml of dimethylformamide and mixed with
a total of 1.04 g (9.15 mmol) of N-hydroxysuccinimide. It is cooled
to 0.degree. C., and 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide
is added. It is stirred for one hour at 0.degree. C. and then for 4
hours at room temperature. After renewed cooling to 0.degree. C., a
solution that consists of 12.85 g (18.30 mmol, 2 molar equivalents
relative to the carboxylic acid used) of the diamino compound that
is described under Example 33b) and that is dissolved in 250 ml of
dimethylformamide is slowly added in drops within 3 hours. Then, it
is stirred for one more hour at 0.degree. C., and then overnight at
room temperature. It is evaporated to the dry state in a vacuum,
and the residue is taken up in 100 ml of ethyl acetate.
Precipitated urea is filtered out, and the filtrate is washed twice
with 100 ml each of 5% aqueous soda solution. The organic phase is
dried on magnesium sulfate and evaporated to the dry state in a
vacuum. The residue is chromatographed on silica gel (mobile
solvent: n-hexane/isopropanol 13:1). 8.14 g (69.4% of theory,
relative to the carboxylic acid used) of the title compound is
obtained in the form of a colorless oil. By increasing the polarity
of the eluant composition during the chromatography to 6:1
(n-hexane/isopropanol), a total of 4.36 g of unreacted diamino
compound 33b) is recovered in the subsequent chromatography
fractions, and the compound can be reacted again according to
above-mentioned reaction instructions.
[0787] Elementary analysis: Cld: C, 51.49; H, 4.01; N, 4.37; F,
25.17; S, 2.50. Fnd: C, 51.60; H, 4.19; N, 4.28; F, 25.14; S,
2.44.
d) 5-Amino-3-N-(1-O-.alpha.-D-carbonylmethyl-mannopyranose)-benzoic
acid-N-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide
[0788] Similar to what is described for the synthesis of the title
compound of Example 33b), the hydrogenolysis of 6.4 g (5.0 mmol) of
the title compound of Example 33c), with use of 0.3 g of Pearlman's
catalyst (Pd 20%, C), in an ethanol/water (8:1) mixture after
working-up yields 4.43 g (96.2% of theory) of the above-mentioned
title compound in the form of a yellowish-colored and viscous
oil.
[0789] Elementary analysis: Cld: C, 35.15; H, 2.95; N, 6.07; F,
35.01; S, 3.48. Fnd: C, 35.32; H, 3.02; N, 5.89; F, 35.05; S,
3.58.
e)
3-N-(1-O-.alpha.-D-Carbonylmethyl-mannopyranose)-5-N-[1,4,7-tris(carbox-
ylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)-1,4,7,10-tetraazacyc-
lododecane]-benzoic
acid-N-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide- , Gd
complex
[0790] 5.54 g (8.8 mmol; 2.2 molar equivalents relative to the
amine components of Example 33d) that are used) of the Gd complex,
described in Patent Application DE 197 28 954 C1 under Example 31
h), of
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1-
,4,7-triacetic acid and 0.37 g of anhydrous lithium chloride (8.8
mmol) are dissolved at 40.degree. C. in 60 ml of absolute dimethyl
sulfoxide while being stirred and mixed at this temperature with a
total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.7 g (4.0
mmol) of the title compound of Example 13Ad), dissolved in 40 ml of
absolute dimethyl sulfoxide. After cooling to room temperature, the
reaction solution is mixed with 1.82 g (8.8 mmol) of
N,N'-dicyclohexylcarbodiimide, and it is stirred for 12 hours at
room temperature. The suspension that is obtained is then mixed
with sufficient acetone until the above-mentioned title compound is
completely precipitated, the precipitate is suctioned off, dried,
taken up in water, insoluble dicyclohexylurea is filtered out, and
the filtrate is desalinated with an AMICON.RTM. YM-3
ultrafiltration membrane (cut-off, 3,000 Da), and low-molecular
components are removed. The retentate is then freeze-dried.
[0791] Yield: 5.36 g (87.4% of theory) as a colorless
lyophilizate.
[0792] H.sub.2O-content (Karl-Fischer): 6.77%.
[0793] Elementary analysis (relative to anhydrous substance): Cld:
C, 36.01; H, 3.61; N, 8.22; F, 21.05; Gd, 10.25; S, 2.09. Fnd: C,
35.87; H, 3.70; N, 8.22; F, 20.91; Gd, 10.18; S, 2.16.
EXAMPLE 34
a)
1,4,7-Triazaheptane-1,7-bis-(2-N-trifluoroacetyl-6-N-benzyloxycarbonyl--
L-lysine)-diamide
[0794] 100 g (107.9 mmol) of the carboxylic acid that is produced
under Example 21a) and 26.1 g (226.59 mmol) of N-hydroxysuccinimide
are dissolved in 500 ml of dimethylformamide and mixed in portions
at 0.degree. C. with a total of 46.7 g (226.59 mmol) of
N,N'-dicyclohexylcarbodiimide, and it is stirred for 3 more hours
at this temperature. A solution of 5.57 g (53.95 mmol) of
diethylenetriamine that is cooled to 0.degree. C. and dissolved in
60 ml of dimethylformamide is added drop by drop to the thus
produced active ester solution, and it is stirred for 2 hours at
0.degree. C. and for 12 hours at room temperature. For working-up,
precipitated dicyclohexylurea is filtered out, and the solvent is
drawn off until a dry state is reached. The thus obtained residue
is then chromatographed on silica gel (mobile solvent:
dichloromethane/ethanol 15:1; chromatography is carried out with
use of a solvent gradient with continuous increase of the
proportion of ethanol).
[0795] Yield: 26.0 g (58.8% of theory, relative to the amine
component that is used) of the title compound in the form of a
colorless and strongly viscous oil.
[0796] Elementary analysis: Cld: C, 52.74; H, 5.78; N, 11.96; F,
13.90. Fnd: C, 52.66; H, 5.89; N, 11.88; F, 14.02.
b)
1,4,7-Triazaheptane-1,7-bis-(2-N-trifluoroacetyl-6-N-benzyloxycarbonyl--
L-lysine)-diamide-4-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl
[0797] 16.18 g (27.0 mmol) of
2-[N-ethyl-N-perfluorooctylsulfonyl)-aminoac- etic acid (production
according to: DE 196 03 033), dissolved in 50 ml of
tetrahydrofuran, is added at 0.degree. C. and under nitrogen
atmosphere to a solution that consists of 20 g (24.4 mmol) of the
diamide that is produced under 34a) and that is dissolved in a
mixture that consists of 150 ml of tetrahydrofuran and 15 ml of
chloroform. Then, a total of 18.0 g (36.6 mmol) of EEDQ
[2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is added in
portions at 0.degree. C. and allowed to stir overnight at room
temperature, and it is then concentrated by evaporation in a
vacuum. The remaining oil is chromatographed on silica gel (mobile
solvent: n-hexane/isopropanol 15:1). 24.74 g (72.4% of theory,
relative to the sec-amine that is used) of the title compound is
obtained in the form of a colorless oil.
[0798] Elementary analysis: Cld: C, 42.01; H, 3.96; F, 31.19; N,
8.00; S, 2.29. Fnd: C, 41.92; H, 4.07; F, 31.22; N, 7.87; S,
2.34.
c)
1,7-Bis-(6-N-benzyloxycarbonyl-L-lysine)-diamide-4-[2-(N-ethyl-N-perflu-
orooctylsulfonyl)-amino]-acetyl-1,4,7-triazaheptane
[0799] 22.0 g (15.7 mmol) of the title compound that is produced
under Example 34b) is dissolved in 100 ml of ethanol, and ammonia
gas is introduced at 0.degree. C. in this solution for 40 minutes.
Then, it is stirred for another 4 hours at 0.degree. C. and for 3
hours at room temperature, and it is evaporated to the dry state in
a vacuum at a bath temperature of 40.degree. C. The remaining oily
residue is purified on silica gel with use of
dichloromethane/hexane/2-propanol (20:10:1) as an eluant.
[0800] Yield: 12.92 g (98.4% of theory) of the above-mentioned
title compound as a colorless and strongly viscous oil.
[0801] Elementary analysis: Cld: C, 44.22; H, 4.64; N, 9.38; S,
2.68; F, 27.03. Fnd: C, 44.31; H, 4.72; N, 9.30; S, 2.74; F,
26.99.
d)
1,7-Bis-[6-N-benzyloxycarbonyl-2-N-(1-O-.alpha.-D-carbonylmethyl-2,3,4,-
6-tetra-O-benzyl-mannopyranose)-L-lysine]-diamide-4-[2-(N-ethyl-N-perfluor-
ooctylsulfonyl)-amino]-acetyl-1,4,7-triazaheptane
[0802] 5.47 g (9.15 mmol) of
1-carboxymethyloxy-2,3,4,-tetra-O-benzyl-.alp-
ha.-D-mannopyranoside [production as described in Patent DE 197 28
954 C1] is dissolved in 80 ml of dimethylformamide and mixed with a
total of 1.05 g (9.15 mmol) of N-hydroxysuccinimide. It is cooled
to 0.degree. C., and 1.9 g (9.15 mmol) of dicyclohexylcarbodiimide
is added. It is stirred for one hour at 0.degree. C. and then for 4
hours at room temperature. It is cooled to 0.degree. C., and a
solution that consists of 7.65 g (9.15 mmol) of the amino compound
that is described under Example 34e) and that is dissolved in 50 ml
of dimethylformamide is slowly added in drops within 3 hours. Then,
it is stirred for one more hour at 0.degree. C., then overnight at
room temperature. It is evaporated to the dry state in a vacuum,
and the residue is taken up in 100 ml of ethyl acetate.
Precipitated urea is filtered out, and the filtrate is washed twice
with 50 ml each of 5% aqueous soda solution. The organic phase is
dried on magnesium sulfate and evaporated to the dry state in a
vacuum. The residue is chromatographed on silica gel (mobile
solvent: n-hexane/isopropanol 20:1). 17.01 g (78.9% of theory,
relative to the carboxylic acid used) of the title compound is
obtained in the form of a colorless oil.
[0803] Elementary analysis: Cld: C, 59.13; H, 5.43; N, 4.76; F,
13.71; S, 1.36. Fnd: C, 59.22; H, 5.39; N, 4.85; F, 13.70; S,
1.40.
e)
1,7-Bis-[2-N-(1-O-.alpha.-D-carbonylmethyl-mannopyranose)-L-lysine]-dia-
mide-4-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1,4,7-triazahep-
tane
[0804] 15.0 g (6.36 mmol) of the amide that is produced under 34d)
is dissolved in 150 ml of ethanol and mixed with 0.5 g of
Pearlman's catalyst (Pd 20%, C). It is hydrogenated at room
temperature under a hydrogen atmosphere (1 atm) until no more
hydrogen absorption can be observed. Catalyst is suctioned out, it
is thoroughly rewashed with ethanol (about 100 ml) and evaporated
to the dry state in a vacuum. The title compound is obtained as a
strongly viscous, yellowish oil.
[0805] Yield: 8.54 g (97.2% of theory).
[0806] Elementary analysis: Cld: C, 39.13; H, 5.04; N, 8.11; F,
23.38; S, 2.32. Fnd: C, 39.07; H, 4.98; N, 8.18; F, 23.40; S,
2.30.
f)
1,7-Bis-[2-N-(1-O-.alpha.-D-carbonylmethyl-mannopyranose)-6-N-[1,4,7-tr-
is(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)-1,4,7,10-te-
traazacyclododecane]-L-lysine]-diamide-4-[2-(N-ethyl-N-perfluorooctylsulfo-
nyl)-amino]-acetyl-1,4,7-triazaheptane, digadolinium complex
[0807] A stirred suspension of 5.7 g (9.06 mmol) of the Gd complex,
described in Patent Application DE 197 28 954 C1 under Example
31h), of
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1-
,4,7-triacetic acid in 75 ml of absolute dimethyl sulfoxide is
mixed at 70.degree. C. with 0.68 g (15.9 mmol) of lithium chloride.
After 30 minutes of stirring at 70.degree. C., the now clear
reaction solution is mixed in portions with a total of 1.83 g (15.9
mmol) of N-hydroxysuccinimide, and the reaction mixture is kept at
this temperature for 1 more hour. After cooling to 0.degree. C., it
is mixed with 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide, and
the reaction solution is stirred for another hour at 0.degree. C.,
followed by 12 hours at 22.degree. C. The thus obtained reaction
solution of N-hydroxysuccinimide ester of the Gd complex of
10-(4-carboxy-1-methyl-2--
oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid
is now mixed at 22.degree. C. drop by drop with a solution of 2.84
g (2.06 mmol) of the title compound of Example 34e) in 15 ml of
absolute dimethyl sulfoxide, and it is stirred for another 12 hours
at room temperature. For working-up, the reaction solution is added
in drops at 22.degree. C. into 500 ml of acetone, whereby the title
compound precipitates as a colorless precipitate. The precipitate
is suctioned off, dissolved in 200 ml of distilled water and
ultrafiltered three times with a YM3-ultrafiltration membrane
(AMICON.RTM.: cut-off: 3,000 Da) for the purpose of desalination
and separation of low-molecular components. The thus obtained
retentate is then freeze-dried.
[0808] Yield: 4.80 g (89.6% of theory, relative to the amine
component that is used) as a colorless lyophilizate with a water
content of 8.98%.
[0809] Elementary analysis (relative to anhydrous substance): Cld:
C, 38.28; H, 4.84; N, 9.68; F, 12.40; S, 1.23; Gd, 12.07. Fnd: C,
38.20 H, 4.91; N, 9.77; F, 12.45; S, 1.19; Gd, 12.10.
EXAMPLE 35
a) 1,7-Bis(benzyloxycarbonyl)-4-{3-oxa-pentane-1,5-dicarboxylic
acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-1,4,7,10-te-
traazacyclododecane
[0810] 16.56 g (24.4 mmol) of the title compound of Example 35e),
dissolved in 150 ml of tetrahydrofuran, is added at 0.degree. C.
and under nitrogen atmosphere to a solution of 10.75 g (24.4 mmol)
of 1,7-bis-[benzyloxycarbonyl]-1,4,7,10-tetraazacyclododecane,
dissolved in a mixture that consists of 150 ml of tetrahydrofuran
and 15 ml of chloroform. Then, a total of 18.0 g (36.6 mmol) of
EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is added in
portions at 0.degree. C., and it is allowed to stir overnight at
room temperature and then concentrated by evaporation in a vacuum.
The remaining oil is chromatographed on silica gel (mobile solvent:
n-hexane/isopropanol 12:1). 17.22 g (64.3% of theory relative to
the sec-amine that is used) of the monoamide and 3.8 g (8.8% of
theory) of the diamide are obtained as a by-product. The title
compound is isolated in the form of a colorless oil.
[0811] Elementary analysis: Cld: C, 43.41; H, 3.92; F, 29.18; N,
7.59; S, 2.60. Fnd: C, 43.52; H, 4.07; F, 29.24; N, 7.67; S,
2.55.
b) 1,7-Bis(benzyloxycarbonyl)-4-{3-oxa-pentane-1,5-dicarboxylic
acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-10-[1-O-.al-
pha.-D-(5-carbonyl)-pentyl-2,3,4,6-tetra-O-benzyl-mannopyranose]-1,4,7,10--
tetraazacyclododecane
[0812] 10.0 g (13.4 mmol) of the carboxylic acid that is produced
under Example 30c) and 3.24 g (28.1 mmol) of N-hydroxysuccinimide
are dissolved in 100 ml of dimethylformamide and mixed in portions
at 0.degree. C. with a total of 5.8 g (28.1 mmol) of
N,N'-dicyclohexylcarbodiimide, and it is stirred for 3 more hours
at this temperature. A solution of 14.83 g (13.4 mmol) of the title
compound of Example 35a) that is cooled to 0.degree. C. and that is
dissolved in 100 ml of dimethylformamide is added drop by drop to
the thus produced active ester solution, and it is stirred for 2
hours at 0.degree. C. and for 12 hours at room temperature. For
working-up, precipitated dicyclohexylurea is filtered out, and the
solvent is then drawn off until a dry state is reached. The thus
obtained residue is then chromatographed on silica gel (mobile
solvent: dichloromethane/ethyl acetate 20:1; chromatography was
carried out with use of a solvent gradient with continuous increase
of the proportion of ethyl acetate).
[0813] Yield: 18.3 g (78.2% of theory) of the title compound in the
form of a colorless and strongly viscous oil.
[0814] Elementary analysis: Cld: C, 55.11; H, 5.03; N, 4.82; F,
18.52; S, 1.84. Fnd: C, 54.87; H, 4.85; N, 4.92; F, 18.55; S,
1.86.
c) 1-{3-Oxa-pentane-1,5-dicarboxylic
acid-1-oyl-5-[1-(4-perfluorooctylsulf-
onyl)-piperazine]-amide}-7-[1-O-.alpha.-D-(5-carbonyl)-pentyl-mannopyranos-
e]-1,4,7,10-tetraazacyclododecane
[0815] 17.0 g (9.75 mmol) of the compound that is produced under
34b) is dissolved in 150 ml of ethanol, mixed with 1.0 g of
Pearlman's catalyst (Pd 20%, C) and hydrogenated at room
temperature under a hydrogen atmosphere (1 atm) until no more
hydrogen absorption can be observed. Catalyst is suctioned out, it
is thoroughly rewashed with ethanol (twice with 75 ml each) and
evaporated to the dry state in a vacuum. The title compound is
obtained as a strongly viscous and colorless oil.
[0816] Yield: 10.76 g (99.0% of theory).
[0817] Elementary analysis: Cld: C, 38.78; H, 4.61; N, 7.54; F,
8.97; S, 2.88. Fnd: C, 38.86; H, 4.65; N, 7.41; F, 29.02; S,
2.92.
d)
1,7-Bis-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-G-
d-complex-10-(pentanoyl-3-aza-4-oxo-5-methyl-5yl)-4-[2-(N-ethyl-N-perfluor-
ooctylsulfonyl]-amino]-acetyl-2-oxa-acetyl]-10-[1-O-.alpha.-D-6-carbonylpe-
ntyl-mannopyranose]-1,4,7,10tetraazacyclododecane
[0818] 24.86 g (39.46 mmol; 4.4 molar equivalents relative to the
amine component 35c) that is used) of the Gd complex, described in
Patent Application DE 197 28 954 C1 under Example 31h), of
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1-
,4,7-triacetic acid and 1.67 g of anhydrous lithium chloride (39.46
mmol) are dissolved at 40.degree. C. in 200 ml of absolute dimethyl
sulfoxide while being stirred and mixed at this temperature with a
total of 4.53 g (39.46 mmol) of N-hydroxysuccinimide and 10.0 g
(8.97 mmol) of the title compound of Example 34c), dissolved in 100
ml of absolute dimethyl sulfoxide. After cooling to room
temperature, the reaction solution is mixed with 8.14 g (39.46
mmol) of N,N'-dicyclohexylcarbodiimide and stirred for 12 hours at
room temperature. The suspension that is obtained is then mixed
with sufficient acetone until the above-mentioned title compound is
completely precipitated, the precipitate is suctioned off, dried,
taken up in water, insoluble dicyclohexylurea is filtered out, and
the filtrate is desalinated with an AMICON.RTM. YM-3
ultrafiltration membrane (cut-off, 3,000 Da), and low-molecular
components are removed. The retentate is then freeze-dried.
[0819] Yield: 16.37 g (79.3% of theory) as a colorless
lyophilizate.
[0820] H.sub.2O content (Karl-Fischer): 7.65%.
[0821] Elementary analysis (relative to anhydrous substance): Cld:
C, 38.01; H, 4.61; N, 9.58; F, 13.81; S, 1.37; Gd, 13.45. Fnd: C,
37.92; H, 4.55; N, 9.58; F, 13.77; S, 1.31; Gd, 13.48.
e) 3-Oxa-pentane-1,5-dicarboxylic
acid-mono-[1-(4-perfluorooctylsulfonyl)-- piperazine]-amide
[0822] 25 g (44.0 mmol) of 1-perfluorooctylsulfonylpiperazine is
dissolved in 150 ml of tetrahydrofuran and mixed at room
temperature with a total of 5.1 g (44.0 mmol) of diglycolic acid
anhydride, and the thus obtained reaction solution is refluxed for
12 hours. After cooling to room temperature, it is evaporated to
the dry state, and the remaining oily residue is purified on silica
gel with use of dichloromethane/2-propanol (16:1) as an eluant.
[0823] Yield: 27.94 g (92.8% of theory) of the above-mentioned
title compound in the form of a colorless and viscous oil.
[0824] Elementary analysis: Cld: C, 58.52; H, 4.27; N, 1.98; S,
2.26; F, 22.80. Fnd: C, 58.42; H, 4.41; N, 1.80; S, 2.28; F,
23.02.
EXAMPLE 36
a) 1,7-Bis(benzyloxycarbonyl)-4-{3-(oxa-pentane-1,5-dicarboxylic
acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-10-[1-O-.be-
ta.-D-6-carbonylpentyl-2,3,4,6-tetra-O-benzyl-glucopyranose]-1,4,7,10-tetr-
aazacyclododecane)
[0825] 68.5 g (91.79 mmol) of
1-carboxymethyloxy-2,3,4,-tetra-O-benzyl-.al-
pha.-D-mannopyranoside [production as described in Patent DE 197 28
954 C1] is dissolved in 750 ml of dry tetrahydrofuran, and then
9.25 g (91.79 mmol) of triethylamine is added. After the reaction
solution is cooled to -15.degree. C. to -20.degree. C., a solution
of 12.64 g (92.5 mmol) of isobutyl chloroformate in 150 ml of dry
tetrahydrofuran is slowly added in drops at this temperature while
being stirred, whereby the rate of addition by drops can be
selected so that an internal temperature of -10.degree. C. is not
exceeded. After a reaction time of 15 minutes at -15.degree. C., a
solution of 101.6 g (91.79 mmol) of the title compound of Example
35a) and 9.25 g (91.79 mmol) of triethylamine are then slowly added
in drops as a solution in 500 ml of dry tetrahydrofuran at
-20.degree. C. After a reaction time of one hour at -15.degree. C.
and two hours at room temperature, the reaction solution is
evaporated to the dry state in a vacuum. The remaining residue is
taken up in 450 ml of ethyl acetate and washed twice with 300 ml
each of saturated sodium bicarbonate solution and once with 400 ml
of water. After the organic phase is dried on sodium sulfate, salt
is suctioned out, and the ethyl acetate is drawn off in a vacuum.
The remaining oily residue is purified on silica gel with use of
dichloromethane/hexane/2-propanol (10:20:1) as an eluant.
[0826] Yield: 130.6 g (81.6% of theory) of the above-mentioned
title compound as a colorless and strongly viscous oil.
[0827] Elementary analysis: Cld: C, 55.11; H, 5.03; N, 4.82; F,
18.52; S, 1.84. Fnd: C, 55.20; H, 5.09; N, 4.91; F, 18.48; S,
1.80.
b) 1-{3-Oxa-pentane-1,5-dicarboxylic
acid-1-oyl-5-[1-(4-perfluorooctylsulf-
onyl)-piperazine]-amide}-7-[1-O-.alpha.-D-(5-carbonyl)-pentyl-mannopyranos-
e]-1,4,7,10-tetraazacyclododecane
[0828] 110.0 g (63.08 mmol) of the compound that is produced under
36a) is dissolved in 1000 ml of ethanol, mixed with 5.0 g of
Pearlman's catalyst (Pd 20%, C) and hydrogenated until quantitative
hydrogen uptake is reached. Catalyst is suctioned out, it is
rewashed with ethanol and evaporated to the dry state in a vacuum.
The title compound is obtained as a viscous and colorless oil.
[0829] Yield: 92.61 g (99.5% of theory)
[0830] Elementary analysis: Cld: C, 52.10; H, 5.12; N, 5.70; F,
21.89; S, 2.17. Fnd: C, 52.20; H, 5.09; N, 5.71; F, 21.87; S,
2.20.
c)
1,7-Bis-[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pe-
ntanoyl)-4-{3-oxa-pentane-1,5-dicarboxylic
acid-1-oyl-5-[1-(4-perfluorooct-
ylsulfonyl)-piperazine]-amide}-10-[1-O-.alpha.-D-(5-carbonyl)-pentyl-manno-
pyranose]-1,4,7,10-tetraazacyclododecane, digadolinium complex
[0831] 55.4 g [88.0 mmol; 4.4 molar equivalents relative to the
diamine component of Example 33d) that is used] of the Gd complex,
described in Patent Application DE 197 28 954 C1 under Example
31h), of
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1-
,4,7-triacetic acid and 3.7 g of anhydrous lithium chloride (88.0
mmol) are dissolved at 40.degree. C. in 500 ml of absolute dimethyl
sulfoxide while being stirred and mixed at this temperature with a
total of 10.1 g (88.0 mmol) of N-hydroxysuccinimide and 29.5 g
(20.0 mmol) of the title compound of Example 36b), dissolved in 200
ml of absolute dimethyl sulfoxide. After cooling to room
temperature, the reaction solution is mixed with 18.2 g (88.0 mmol)
of N,N'-dicyclohexylcarbodiimide and stirred for 12 hours at room
temperature. The suspension that is obtained is then mixed with
sufficient acetone until the above-mentioned title compound is
completely precipitated, the precipitate is suctioned off, dried,
taken up in water, insoluble dicyclohexylurea is filtered out, and
the filtrate is desalinated with an AMICON.RTM. YM-3
ultrafiltration membrane (cut-off 3,000 Da), and low-molecular
components are removed. The retentate is then freeze-dried.
[0832] Yield: 35.96 g (76.9% of theory) as a colorless
lyophilizate.
[0833] H.sub.2O content (Karl-Fischer): 5.98%
[0834] Elementary analysis (relative to anhydrous substance): Cld:
C, 38.01; H, 4.61; N, 8.22; F, 13.81; Gd, 13.45; S, 1.37. Fnd: C,
37.87; H, 4.70; N, 8.22; F, 13.90; Gd, 13.48; S, 1.36.
EXAMPLE 37
a)
5-(Ethoxycarbonyl)pentyl-2,3,4,6-tetra-O-acetyl-.alpha.-D-mannopyranosi-
de
[0835] Similar to what is described in the literature for the
synthesis of arylglycopyranosides [J. Conchie and G. A. Levvy in
Methods in Carbohydrate Chemistry (R. L. Whistler, M. L. Wolfrom
and J. N. BeMiller, Eds.), Academic Press, New York, Vol. II, 90,
pp. 345-347, (1963)], the reaction of 156.2 g (400 mmol) of
D-mannose pentaacetate as an
.alpha.,.beta.-(.alpha.,.beta.-ratio=4:1)-anomer mixture [for
synthesis of
1,2,3,4,6-penta-O-acetyl-.alpha.,.beta.-D-mannopyranose cf.: M. L.
Wolfrom and A. Thompson in Methods in Carbohydrate Chemistry (R. L.
Whistler, M. L. Wolfrom and J. N. BeMiller, Eds.), Academic Press,
New York, Vol. II, 53, pp. 211-215, (1963)] with 67 ml (400 mmol)
of 6-hydroxy-hexanoic acid ethyl ester and 60.8 ml (520 mmol) of
tin(IV) chloride results in a total of 600 ml of 1,2-dichloroethane
after purification by column chromatography (eluant: hexane/ethyl
acetate 2:1) for the formation of 100.05 g (51% of theory) of the
above-mentioned title compound as a colorless and viscous oil. By
.sup.1H-NMR-spectroscop- ic study of the thus obtained title
compound, it was possible to show that the above-mentioned title
compound is only the pure .alpha.-anomer.
[0836] Elementary analysis: Cld: C, 52.94; H, 6.77. Fnd: C, 52.80;
H, 6.78.
b)
5-(Carboxy)pentyl-2,3,4,6-tetra-O-benzyl-.alpha.-D-mannopyranoside
[0837] A stirred suspension of 141.0 g (289 mmol) of the title
compound of Example 37a) in 200 ml of dioxane is mixed in portions
at room temperature and with simultaneous vigorous stirring with a
total of 238.5 g (4.26 mol) of fine-powder potassium hydroxide
powder. To make it easier to stir, the reaction mixture is mixed
with another 200 ml of dioxane, and the thus obtained suspension is
subsequently heated to boiling heat and mixed drop by drop at this
temperature with a total of 372 ml (3.128 mol) of benzyl bromide
over a period of two hours. After a reaction time of 4 hours at
110.degree. C., followed by 12 hours at room temperature, the
reaction mixture is slowly poured into a total of 2.5 liters of ice
water for the purpose of working-up, and the aqueous phase is
subsequently completely extracted with diethyl ether. After the
thus obtained ether phase is washed and the ether phase is
subsequently dried on sodium sulfate, salt is suctioned out, and
the diethyl ether is drawn off in a vacuum. Excess benzyl bromide
is then distilled off quantitatively in an oil pump vacuum at an
oil bath temperature of 180.degree. C. from the reaction mixture.
The thus obtained, resinous-oily residue is purified on silica gel
with use of ethyl acetate/hexane (1:10) as an eluant.
[0838] Yield: 172.2 g (91.0% of theory) of the above-mentioned
title compound in the form of a colorless and extremely viscous
oil.
[0839] Elementary analysis: Cld: C, 75.68; H, 7.16. Fnd: C, 75.79;
H, 7.04.
c)
5-[(Carboxy)-pentyl-2,3,4,6-tetra-O-benzyl-.alpha.-D-mannopyranoside-]N-
-hydroxysuccinimide ester
[0840] 60.0 g (91.5 mmol) of the title compound of Example 37b) is
dissolved in 750 ml of dimethylformamide and mixed with a total of
10.4 g (91.5 mmol) of N-hydroxysuccinimide. It is cooled to
0.degree. C., and 18.9 g (91.5 mmol) of dicyclohexylcarbodiimide is
added. It is stirred for one hour at 0.degree. C. and then for 4
hours at room temperature. The solvent is drawn off in a vacuum,
and the remaining residue is mixed with 100 ml of ethyl acetate and
cooled to 0.degree. C. Precipitated urea is filtered out, and the
filtrate that is obtained is evaporated to the dry state in a
vacuum. The thus obtained, resinous-oily residue is purified on
silica gel with use of ethyl acetate/hexane (1:20) as an
eluant.
[0841] Yield: 61.23 g (89.0% of theory) of the above-mentioned
title compound in the form of a colorless and viscous oil.
[0842] Elementary analysis: Cld: C, 70.29; H, 6.57; N, 1.86. Fnd:
C, 70.39; H, 5.64; N, 1.91.
d)
2,6-Bis-{6-N.sub..alpha.-2-N.sub..alpha.-[-[1-O-.alpha.-D-6-carbonyl-pe-
ntyl-(2,3,4,6-tetra-O-benzyl)-mannopyranose}-L-lysine}-methyl
ester
[0843] A solution of 27.51 g (36.6 mmol) of the title compound of
Example 37c) in 150 ml of dimethylformamide is added in drops to a
solution, cooled to 0.degree. C., that consists of 4.26 g (18.30
mmol; 0.5 molar equivalent relative to the carboxylic acid that is
used) of L-lysine methyl ester-dihydrochloride (commercially
available from the Bachem Company) and 4.05 g (40.26 mmol) of
triethylamine in 100 ml of dimethylformamide. After the addition is
completed, it is stirred for one more hour at 0.degree. C. and then
overnight at room temperature. It is evaporated to the dry state in
a vacuum, and the residue is taken up in 300 ml of ethyl acetate.
Precipitated urea is filtered out, and the filtrate is washed twice
with 100 ml each of 5% aqueous soda solution. The organic phase is
dried on magnesium sulfate and evaporated to the dry state in a
vacuum. The residue is chromatographed on silica gel (mobile
solvent: n-hexane/isopropanol 25:1). 39.56 g (75.4% of theory) of
the title compound is obtained in the form of a colorless oil.
[0844] Elementary analysis: Cld: C, 72.88; H, 7.31; N, 1.95. Fnd:
C, 72.90; H, 7.29; N, 2.02.
e)
2,6-Bis-[6-N.sub..epsilon.-2-N.sub..alpha.-[1-O-.alpha.-D-6-carbonyl-pe-
ntyl-(2,3,4,6-tetra-O-benzyl)-mannopyranose]]-L-lysine
[0845] 30.0 g (20.92 mmol) of the compound that is produced under
Example 37d) is dissolved in 150 ml of ethanol. The solution of4 g
(100.0 mmol) of sodium hydroxide in 10 ml of distilled water is
then added to it, and it is stirred for 3 hours at 50.degree. C.
According to the thin-layer chromatogram, saponification is
quantitative. It is evaporated to the dry state in a vacuum, the
remaining residue is taken up in 300 ml of ethyl acetate, and the
organic phase is extracted twice with 100 ml each of dilute,
aqueous citric acid solution. After drying on sodium sulfate, it is
filtered, and evaporated to the dry state in a vacuum. The residue
is chromatographed on silica gel (mobile solvent:
n-hexane/isopropanol 13:1). 25.56 g (88.5% of theory) of the title
compound is obtained in the form of a colorless oil.
[0846] Elementary analysis: Cld: C, 72.88; H, 7.31; N, 1.95. Fnd:
C, 72.78; H, 7.33; N, 1.96.
f)
2,6-Bis-[6-N.sub..epsilon.-2-N.sub..alpha.-[1-O-.alpha.-D-6-carbonyl-pe-
ntyl-(2,3,4,6-tetra-O-benzyl)-mannopyranose]-L-lysine]-N-hydroxysuccinimid-
e ester
[0847] 14.0 g (9.15 mmol) of the title compound of Example 37e) is
dissolved in 100 ml of dimethylformamide and mixed with a total of
1.04 g (9.15 mmol) of N-hydroxysuccinimide. It is cooled to
0.degree. C., and 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide is
added. It is stirred for one hour at 0.degree. C. and then for 4
hours at room temperature. The solvent is then drawn off in a
vacuum, and the remaining residue is mixed with 100 ml of ethyl
acetate and cooled to 0.degree. C. Precipitated urea is filtered
out, and the filtrate that is obtained is evaporated to the dry
state in a vacuum. The thus obtained, resinous-oily residue is
purified on silica gel with use of ethyl acetate/n-hexane (1:20) as
an eluant.
[0848] Yield: 12.94 g (92.4% of theory) of the above-mentioned
title compound in the form of a colorless and viscous oil.
[0849] Elementary analysis: Cld: C, 71.40; H, 7.05; N, 2.74. Fnd:
C, 71.39; H, 7.14; N, 2.81.
g) 2,6-N,N'-Bis
[1-O-.alpha.-D-(6-carbonyl)-pentyl-2,3,4,6-tetra-O-benzyl--
mannopyranose]-L-lysine-1,7-(1,4,7-triazaheptane)-diamide
[0850] A solution that consists of 14.0 g (9.15 mmol; 2 molar
equivalents relative to the amine that is used) of the title
compound of Example 37f) in 100 ml of dimethylformamide is slowly
added in drops to a solution, cooled to 0.degree. C., of 0.47 g
(4.57 mmol) of diethylenetriamine in 25 ml of dimethylformamide.
After the addition is completed, it is stirred for one more hour at
0.degree. C. and then overnight at room temperature. It is
evaporated to the dry state in a vacuum, and the residue is taken
up in 200 ml of ethyl acetate. Precipitated urea is filtered out,
and the filtrate is washed twice with 50 ml each of 5% aqueous soda
solution. The organic phase is dried on magnesium sulfate and
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent: n-hexane/isopropanol
25:1). 9.53 g (71.4% of theory) of the title compound is obtained
in the form of a colorless oil.
[0851] Elementary analysis: Cld: C, 72.79; H, 7.42; N, 3.36. Fnd:
C, 72.90; H, 7.39; N, 3.32.
h)
2-N-[2-(N-Ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-6-N-(benzyloxyc-
arbonyl)-L-lysine-methyl ester
[0852] 20.8 g (35.6 mmol) of the
2-[N-ethyl-N-perfluorooctylsulfonyl)-amin- oacetic acid and 3.60 g
(35.6 mmol) of triethylamine are dissolved in 200 ml of
dimethylformamide, and 4.09 g (35.6 mol) of N-hydroxysuccinimide is
added. It is cooled to 0.degree. C., and 7.34 g (35.6 mmol) of
dicyclohexylcarbodiimide is added. It is stirred for one hour at
0.degree. C. and then for 4 hours at room temperature. It is cooled
to 0.degree. C., and a solution that consists of 11.77 g (35.6
mmol) of 6-N-benzyloxycarbonyl-L-lysine-methyl ester-hydrochloride
and 4.0 g (40.0 mmol) of triethylamine in 100 ml of
dimethylformamide is added in drops within 10 minutes. It is
stirred for one hour at 0.degree. C., then overnight at room
temperature. It is evaporated to the dry state in a vacuum, and the
residue is taken up in 100 ml of ethyl acetate. Precipitated urea
is filtered out, and the filtrate is washed twice with 100 ml each
of 5% aqueous soda solution. The organic phase is dried on
magnesium sulfate and evaporated to the dry state in a vacuum. The
residue is chromatographed on silica gel (mobile solvent:
n-hexane/ethyl acetate 20:1). 27.43 g (88.0% of theory) of a
colorless oil is obtained.
[0853] Elementary analysis: Cld: C, 38.41; H, 3.45; N, 4.80; F,
36.89; S, 3.66. Fnd: C, 38.45; H, 3.38; N, 4.88; F, 37.02; S,
3.71.
i)
2-N.alpha.-{[2-(N-Ethyl-N-perfluorooctylsulfonyl]-amino-acetyl}-6-N.sub-
..epsilon.-(benzyloxycarbonyl)-L-lysine
[0854] 25.0 g (28.55 mmol) of the compound that is produced under
Example 37h) is dissolved in 150 ml of ethanol. The solution of 4 g
(100.0 mmol) of sodium hydroxide in 10 ml of distilled water is
then added to it, and it is stirred for 3 hours at 50.degree. C.
According to the thin-layer chromatogram, saponification is
quantitative. It is evaporated to the dry state in a vacuum, and
the remaining residue is taken up in 300 ml of ethyl acetate, and
the organic phase is extracted twice with 100 ml each of dilute,
aqueous citric acid solution. After drying on sodium sulfate, it is
filtered and evaporated to the dry state in a vacuum. The residue
is chromatographed on silica gel (mobile solvent:
n-hexane/isopropanol 10:1). 22.73 g (92.4% of theory) of the title
compound is obtained in the form of a colorless oil.
[0855] Elementary analysis: Cld: C, 37.64; H, 3.28; N, 4.88; F,
37.49; S, 3.72. Fnd: C, 37.65; H, 3.38; N, 4.88; F, 37.52; S,
3.73.
j)
1,4,7-Triazaheptane-4-{2-N-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-
-acetyl-6-N-benzyloxycarbonyl}-L-lysine-amide-1,7-bis
{2,6-N,N'-bis[1-O-.alpha.-D-(5-carbonyl)-pentyl-2,3,4,6-tetra-O-benzylman-
nopyranose]-L-lysine-diamide}
[0856] 15.33 g (17.8 mmol) of the title compound of Example 37i)
and 1.80 g (17.8 mmol) of triethylamine are dissolved in 250 ml of
dry tetrahydrofuran. After the reaction solution is cooled to
-15.degree. C. to -20.degree. C., a solution of 4.92 g (35.6 mmol)
of isobutyl chloroformate, dissolved in 50 ml of dry
tetrahydrofuran, is slowly added in drops at this temperature while
being stirred, whereby the rate of addition by drops can be
selected so that an internal temperature of -10.degree. C. is not
exceeded. After a reaction time of 15 minutes at -15.degree. C., a
solution of 52.0 g (17.8 mmol) of the title compound of Example
37g) and 1.80 g (17.8 mmol) of triethylamine in 300 ml of dry
tetrahydrofuran is then slowly added in drops at -20.degree. C.
After a reaction time of one hour at -15.degree. C. and two hours
at room temperature, the reaction solution is evaporated to the dry
state in a vacuum. The remaining residue is taken up in 500 ml of
ethyl acetate and washed twice with 200 ml each of saturated sodium
bicarbonate solution and once with 200 ml of water. After the
organic phase is dried on sodium sulfate, salt is suctioned out,
and the ethyl acetate is drawn off in a vacuum. The remaining oily
residue is purified on silica gel with use of ethyl
acetate/n-hexane (1:20) as an eluant.
[0857] Yield: 54.6 g (81.6% of theory) of the above-mentioned title
compound as a colorless and strongly viscous oil.
[0858] Elementary analysis: Cld: C, 65.09; H, 6.45; N, 3.72; F,
8.58; S, 0.85. Fnd: C, 65.13; H, 4.41; N, 3.69; F, 8.52; S,
0.90.
k)
1,4,7-Triazaheptane-4-{2-N-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-
-acetyl}-L-lysine-amide-1,7-bis{2,6-N,N'-bis[1-O-.alpha.-D-(5-carbonyl)-pe-
ntyl-mannopyranose]-L-lysine-diamide}
[0859] 50.0 g (13.28 mmol) of the compound that is produced under
37j) is dissolved in 500 ml of ethanol, mixed with 4.0 g of
Pearlman's catalyst (Pd 20%, C) and hydrogenated at room
temperature under a hydrogen atmosphere (1 atm) until no more
hydrogen absorption can be observed. Catalyst is suctioned out, it
is thoroughly rewashed with ethanol (about 400 ml) and evaporated
to the dry state in a vacuum. The title compound is obtained as a
strongly viscous and colorless oil.
[0860] Yield: 26.85 g (93.0% of theory)
[0861] Elementary analysis: Cld: C, 45.85; H, 6.35; N, 6.44; F,
14.86; S, 1.47. Fnd: C, 45.76; H, 6.35; N, 6.41; F, 14.92; S,
1.39.
l)
1,4,7-Triazaheptane-4-{2-N-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-
-acetyl-6-N-[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-p-
entanoyl)-1,4,7,10-tetraazacyclododecane}-L-lysine-amide-1,7-bis{2,6-N,N'--
bis[1-O-.alpha.-D-(5-carbonyl)-pentyl-mannopyranose]-L-lysine-diamide},
gadolinium complex
[0862] 5.54 g (8.8 mmol; 2.2 molar equivalents relative to the
amine component of Example 37k) that is used) of the Gd complex,
described in Patent Application DE 197 28 954 C1 under Example
31h), of
10-(4-carboxy-1-methyl-2-oxo-3-aza-butyl)-1,4,7,10-tetraazacyclododecane--
1,4,7-triacetic acid and 0.37 g of anhydrous lithium chloride (8.8
mmol) are dissolved at 40.degree. C. in 60 ml of absolute dimethyl
sulfoxide while being stirred and mixed at this temperature with a
total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 1.84 g (4.0
mmol) of the title compound of Example 37k), dissolved in 40 ml of
absolute dimethyl sulfoxide. After cooling to room temperature, the
reaction solution is mixed with 1.82 g (8.8 mmol) of
N,N'-dicyclohexylcarbodiimide and stirred for 12 hours at room
temperature. The suspension that is obtained is then mixed with
sufficient acetone until the above-mentioned title compound is
completely precipitated, the precipitate is suctioned off, dried,
taken up in water, insoluble dicyclohexylurea is filtered out, and
the filtrate is desalinated with an AMICON.RTM. YM-3
ultrafiltration membrane (cut-off 3,000 Da), and low-molecular
components are removed. The retentate is then freeze-dried.
[0863] Yield: 8.77 g (78.7% of theory) as a colorless
lyophilizate.
[0864] H.sub.2O content (Karl-Fischer): 4.43%.
[0865] Elementary analysis (relative to anhydrous substance): Cld:
C, 43.98; H, 5.97; N, 7.54; F, 11.59; Gd, 5.64; S, 1.15. Fnd: C,
43.97; H, 6.02; N, 7.62; F, 11.61; Gd, 10.18; S, 1.15.
EXAMPLE 38
a)
2-N.alpha.-6-N.epsilon.-Bis-[1-O-.alpha.-D-carbonylmethyl-2,3,4,6-tetra-
-O-benzyl-mannopyranose]-L-lysine]-methyl ester
[0866] 10.95 g (18.30 mmol) of
1-carboxymethyloxy-2,3,4,-tetra-O-benzyl-.a-
lpha.-D-mannopyranoside [production as described in Patent DE 197
28 954 C1] is dissolved in 150 ml of dimethylformamide and mixed
with a total of 2.09 g (18.3 mmol) of N-hydroxysuccinimide. It is
cooled to 0.degree. C., and 3.78 g (18.3 mmol) of
dicyclohexyl-carbodiimide is added. It is stirred for one hour at
0.degree. C. and then for 4 hours at room temperature. It is cooled
to 0.degree. C., and a solution that consists of 2.13 g (9.15 mmol;
0.5 molar equivalent relative to the carboxylic acid that is used)
of L-lysine methyl ester-dihydrochloride (commercially available
from the Bachem Company) and 2.02 g (20.13 mmol) of triethylamine
in 70 ml of dimethylformamide is added in drops within one hour.
After the addition is completed, it is stirred for one more hour at
0.degree. C. and then overnight at room temperature. It is
evaporated to the dry state in a vacuum, and the residue is taken
up in 300 ml of ethyl acetate. Precipitated urea is filtered out,
and the filtrate is washed twice with 100 ml each of 5% aqueous
soda solution. The organic phase is dried on magnesium sulfate and
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent: n-hexane/isopropanol
25:1). 10.05 g (82.3% of theory) of the title compound is obtained
in the form of a colorless oil.
[0867] Elementary analysis: Cld: C, 71.94; H, 6.79; N, 2.10. Fnd:
C, 71.90; H, 6.79; N, 2.09.
b)
2-N.alpha.-6-N.epsilon.-Bis-[1-O-.alpha.-D-carbonylmethyl-2,3,4,6-tetra-
-O-benzyl-mannopyranose]-L-lysine
[0868] Similar to what is described in Example 37e) for the
synthesis of the title compound that is relevant there, the methyl
ester saponification of 15 g (11.23 mmol) of the title compound of
Example 38a) results in the formation of 13.89 g (93.6% of theory)
of the above-mentioned title compound in the form of a colorless
and viscous oil.
[0869] Elementary analysis: Cld: C, 71.80; H, 6.71; N, 2.12. Fnd:
C, 71.84; H, 6.69; N, 2.15.
c)
2-N.alpha.-6-N.epsilon.-Bis-[1-O-.alpha.-D-carbonylmethyl-2,3,4,6-tetra-
-O-benzyl-mannopyranose]-L-lysine-N-hydroxysuccinimide ester
[0870] 12.09 g (9.15 mmol) of the title compound of Example 38b) is
dissolved in 100 ml of dimethylformamide and mixed with a total of
1.04 g (9.15 mmol) of N-hydroxysuccinimide. It is cooled to
0.degree. C., and 1.89 g (9.15 mmol) of dicyclohexylcarbodiimide is
added. It is stirred for one hour at 0.degree. C. and then for 4
hours at room temperature. The solvent is then drawn off in a
vacuum, and the remaining residue is mixed with 100 ml of ethyl
acetate and cooled to 0.degree. C. Precipitated urea is filtered
out, and the filtrate that is obtained is evaporated to the dry
state in a vacuum. The thus obtained, resinous-oily filtrate is
purified on silica gel with use of ethyl acetate/n-hexane (1:20) as
an eluant.
[0871] Yield: 12.24 g (94.4% of theory) of the above-mentioned
title compound in the form of a colorless and viscous oil.
[0872] Elementary analysis: Cld: C, 70.27; H, 6.47; N, 2.96. Fnd:
C, 70.31; H, 6.44; N, 3.01.
d)
6-N-Benzyloxycarbonyl-2-N-{[2,6-N,N'-bis(1-O-.alpha.-D-carbonylmethyl-2-
,3,4,6-tetra-O-benzyl-mannopyranose)]-L-lysyl-}-L-lysine-[1-(4-perfluorooc-
tylsulfonyl)-piperazine]-amide
[0873] 19.0 g (13.4 mmol) of the carboxylic
acid-N-hydroxysuccinimide ester that is produced under Example 38c)
is dissolved in 75 ml of dimethylformamide and mixed drop by drop
at 0.degree. C. with a solution, cooled to 0.degree. C., of 11.13 g
(13.4 mmol) of the title compound of Example 21c), dissolved in
50.0 ml of dimethylformamide. The resulting reaction solution is
stirred for 2 more hours at 0.degree. C. and for 12 hours at room
temperature. For working-up, precipitated dicyclohexylurea is
filtered out, and the solvent is then drawn off until a dry state
is reached in a vacuum. The thus obtained residue is
chromatographed on silica gel [mobile solvent:
dichloromethane/ethanol 28:1; and chromatography is performed here
with use of a solvent gradient with a proportion of the polar
eluant component that is used (here:ethanol) that rises
continuously in the course of the chromatography].
[0874] Yield: 25.28 g (88.4% of theory) of the title compound in
the form of a colorless and strongly viscous oil.
[0875] Elementary analysis: Cld: C, 59.10; H, 5.34; N, 3.94; F,
15.13; S, 1.50. Fnd: C, 59.18; H, 5.35; N, 4.02; F, 15.15; S,
1.56.
e)
2-N-{[2,6-N,N'-Bis(1-O-.alpha.-D-carbonylmethyl-mannopyranose)]-L-lysyl-
-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide
[0876] 20.0 g (9.37 mmol) of the compound that is produced under
38d) is dissolved in 200 ml of ethanol, mixed with 1.5 g of
Pearlman's catalyst (Pd 20%, C) and hydrogenated at room
temperature under a hydrogen atmosphere (1 atm) until no more
hydrogen absorption can be observed. Catalyst is suctioned out, it
is thoroughly rewashed with ethanol (twice with about 100 ml each)
and evaporated to the dry state in a vacuum. The title compound is
obtained as a strongly viscous and colorless oil.
[0877] Yield: 11.62 g (97.0% of theory).
[0878] Elementary analysis: Cld: C, 38.50; H, 4.65; N, 6.57; F,
25.25; S, 2.51. Fnd: C, 38.46; H, 4.65; N, 6.51; F, 25.23; S,
2.52.
f)
6-N-[1,4,7-Tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pentan-
oyl)-1,4,7,10-tetraazacyclododecane)-2-N-{[2,6-N,N'-bis(1-O-.alpha.-D-carb-
onylmethyl-mannopyranose)]-L-lysyl}-L-lysine-[1-(4-perfluorooctylsulfonyl)-
-piperazine]-amide, Gd complex
[0879] 9.98 g (15.84 mmol; 2.2 molar equivalents relative to the
amine component of Example 38e) that is used) of the Gd complex,
described in Patent Application DE 197 28 954 C1 under Example
31h), of
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1-
,4,7-triacetic acid and 0.67 g of anhydrous lithium chloride (15.84
mmol) are dissolved at 40.degree. C. in 100 ml of absolute dimethyl
sulfoxide while being stirred and mixed at this temperature with a
total of 1.82 g (15.84 mmol) of N-hydroxysuccinimide and 9.19 g
(7.19 mmol) of the title compound of Example 38e), dissolved in 50
ml of absolute dimethyl sulfoxide. After cooling to room
temperature, the reaction solution is mixed with 3.27 g (15.84
mmol) of N,N'-dicyclohexylcarbodiimide and stirred for 12 hours at
room temperature. The suspension that is obtained is then mixed
with sufficient acetone until the above-mentioned title compound is
completely precipitated, the precipitate is suctioned off, dried,
taken up in water, insoluble dicyclohexylurea is filtered off, and
the filtrate is desalinated with an AMICON.RTM. YM-3
ultrafiltration membrane (cut-off 3,000 Da), and in this case
possible, still present low-molecular components are simultaneously
removed. The retentate is then freeze-dried.
[0880] Yield: 11.85 g (87.2% of theory) as a colorless
lyophilizate.
[0881] H.sub.2O content (Karl-Fischer): 5.54%
[0882] Elementary analysis (relative to anhydrous substance): Cld:
C, 38.12; H, 4.64; N, 8.15; F, 20.38; S, 1.70; Gd, 8.32. Fnd: C,
38.16; H, 4.59; N, 8.18; F, 20.37; S, 1.68; Gd, 8.28.
EXAMPLE 39
a)
1,7-Bis(benzyloxycarbonyl)-4-(3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecan-
oyl)-1,4,7,10-tetraazacyclododecane
[0883] At 0.degree. C. and under nitrogen atmosphere, 12.74 g (24.4
mmol) of the title compound of Example 39g), dissolved in 150 ml of
tetrahydrofuran, is added to a solution of 10.75 g (24.4 mmol) of
1,7-bis-[benzyloxycarbonyl]-1,4,7,10-tetraazacyclododecane,
dissolved in a mixture that consists of 150 ml of tetrahydrofuran
and 15 ml of chloroform. Then, a total of 18.0 g (36.6 mmol) of
EEDQ [2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is added in
portions at 0.degree. C., allowed to stir overnight at room
temperature, and then concentrated by evaporation in a vacuum. The
remaining oil is chromatographed on silica gel (mobile solvent:
n-hexane/isopropanol 16:1). 15.89 g (69.0% of theory, relative to
the sec-amine that is used) of the monoamide and 3.8 g (8.8% of
theory) of the diamide are obtained as by-products. The title
compound is isolated in the form of a colorless oil.
[0884] Elementary analysis: Cld: C, 45.77; H, 3.95; F, 34.19; N,
5.93. Fnd: C, 45.72; H, 4.01; F, 34.22, N, 5.88.
b)
1,7-Bis(benzyloxycarbonyl)-4-(3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecan-
oyl)-10-[1-S-.alpha.-D-(2-carbonyl)-ethyl-2,3,4,6-tetra-O-acetyl-mannopyra-
nose]-1,4,7,10-tetraazacyclododecane
[0885] 7.09 g (13.4 mmol) of
3-(2,3,4,6-tetra-O-acetyl-1-thio-a-D-mannopyr- anosyl)-propionic
acid-N-hydroxysuccinimide ester (production according to: J.
Haensler et al., Bioconjugate Chem. 4, 85, (1993); Chipowsky, S.,
and Lee, Y. C. (1973), Synthesis of 1-Thio-Aldosides; Carbohydrate
Research 31, 339-346) is dissolved in 100 ml of dimethylformamide
and mixed drop by drop at 0.degree. C. with a solution, precooled
to 0.degree. C., of 12.65 g (13.4 mmol) of the title compound of
Example 39a), dissolved in 100 ml of dimethylformamide. It is
stirred for 2 hours at 0.degree. C. and for 12 hours at room
temperature. For working-up, the solvent is drawn off in a vacuum
until a dry state is reached, and the thus obtained residue is then
chromatographed on silica gel (mobile solvent:
dichloromethane/ethyl acetate 20:1; the chromatography was
performed with use of a solvent gradient with continuous increase
of the proportion of ethyl acetate).
[0886] Yield: 16.23 g (88.9% of theory) of the title compound in
the form of a colorless and strongly viscous oil.
[0887] Elementary analysis: Cld: C, 46.70; H, 4.36; N, 4.11; F,
23.69; S, 2.35. Fnd: C, 46.66; H, 4.35; N, 4.12; F, 23.65; S,
2.30.
c)
1-(3-Oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoyl)-7-[1-S-.alpha.-D-(2-ca-
rbonyl)-ethyl-2,3,4,6-tetra-O-acetyl-mannopyranose]-1,4,7,10-tetraazacyclo-
dodecane
[0888] 15.0 g (11.0 mmol) of the compound that is produced under
39b) is dissolved in 150 ml of ethanol, mixed with 1.0 g of
Pearlman's catalyst (Pd 20%, C) and hydrogenated at room
temperature under a hydrogen atmosphere (1 atm) until no more
hydrogen absorption can be observed. Catalyst is suctioned out, it
is thoroughly rewashed with ethanol (twice with 75 ml each) and
evaporated to the dry state in a vacuum. The title compound is
obtained as a strongly viscous and colorless oil.
[0889] Yield: 11.56 g (96.0% of theory).
[0890] Elementary analysis: Cld: C, 40.59; H, 4.33; N, 5.12; F,
29.50; S, 2.93. Fnd: C, 40.63; H, 4.35; N, 5.11; F, 29.52; S,
2.92.
d)
1-(3-Oxa-2H,.sup.2H,4H,4H,5H,5H-perfluorotridecanoyl)-7-[1-S-.alpha.-D--
(2-carbonyl)-ethyl-mannopyranose]-1,4,7,10-tetraazacyclododecane
[0891] 10.0 g (9.13 mmol) of the title compound of Example 39c) is
suspended in 100 ml of absolute methanol and mixed at 5.degree. C.
with a catalytic amount of sodium methanolate. After a reaction
time of 3 hours at room temperature, even thin-layer
chromatographic checking (eluant:chloroform/methanol 4:1) of the
course of the reaction indicates a quantitative reaction. For the
purpose of working-up, the now clear reaction solution is
neutralized by mixing with Amberlite IR 120 (H.sup.+
form)-cation-exchange resin, exchanger is suctioned out, rewashed
with methanol, and the thus obtained methanolic filtrate is drawn
off in a vacuum until a dry state is reached. The oily residue that
is obtained is purified by column chromatography on silica gel
(mobile solvent: dichloromethane/n-hexane/ethyl acetate 15:20:1;
and chromatography is performed with use of a solvent gradient with
continuous increase of the proportion of ethyl acetate). After
.sup.1H-NMR spectroscopic study of the title compound, the presence
of the .alpha.-configuration at the anomeric center of the
D-mannopyranose was definitively established based on the size of
the coupling constant of J.sub.1,2=0.9 Hz. This a-configuration is
the existing configuration that is exclusive to the anomeric
center, i.e., the amount of the .beta.-configured anomer of the
title compound that can possibly be formed thus lies below the
.sup.1H-NMR-spectroscopic detection limit. The above-mentioned
title compound was accordingly shown only in the form of the pure
.alpha.-configured anomer.
[0892] Yield: 8.28 g (98.0% of theory) of the title compound in the
form of a colorless and strongly viscous oil.
[0893] Elementary analysis: Cld: C, 37.59; H, 4.24; N, 6.05; F,
34.85; S, 3.46. Fnd: C, 37.57; H, 4.28; N, 6.02; F, 34.85; S,
3.44.
e)
1-(3-Oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoyl)-7-[1-S-.alpha.-D-(2-ca-
rbonyl)-ethyl-mannopyranose]-4,10-bis[1,4,7-tris(carboxylatomethyl)-10-(3--
aza-4-oxo-5-methyl-5-yl-pentanoyl)]-1,4,7,10-tetraazacyclododecane,
digadolinium complex
[0894] Amide conjugate of the 1,4,7,10-tetraazacyclododecane with
[1,7-bis-[gadolinium complex of
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)--
1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid];
3-(2,3,4,6-tetra-O-acetyl-1-thio-.alpha.-D-mannopyranosyl)-propionic
acid
[0895] 2.48 g [(3.94 mmol); 4.4 molar equivalents relative to the
diamine component 39d) that is used] of the Gd complex, described
in Patent Application DE 197 28 954 C1 under Example 31h), of
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1-
,4,7-troacetic acid and 167 mg of anhydrous lithium chloride (3.94
mmol) are dissolved at 40.degree. C. in 40 ml of absolute dimethyl
sulfoxide while being stirred and mixed at this temperature with a
total of 453 mg (3.94 mmol) of N-hydroxysuccinimide and 980 mg
(0.895 mmol) of the title compound of Example 19Ad), dissolved in
10 ml of absolute dimethyl sulfoxide. After cooling to room
temperature, the reaction solution is mixed with 814 mg (3.946
mmol) of N,N'-dicyclohexylcarbodiimide and stirred for 12 hours at
room temperature. The suspension that is obtained is then mixed
with sufficient acetone until the above-mentioned title compound is
completely precipitated, the precipitate is suctioned off, dried,
taken up in water, insoluble dicyclohexylurea is filtered out, and
the filtrate is desalinated with an AMICON.RTM. YM-3
ultrafiltration membrane (cut-off 3,000 Da), and low-molecular
components are removed. The retentate is then freeze-dried.
[0896] Yield: 1.32 g (69.1% of theory) as a colorless
lyophilizate.
[0897] H.sub.2O content (Karl-Fischer): 7.65%
[0898] Elementary analysis (relative to anhydrous substance): Cld:
C, 37.43; H, 4.45; N, 9.12; F, 15.02; S, 1.49; Gd, 14.63. Fnd: C,
37.42; H, 4.50; N, 9.18; F, 15.07; S, 1.51; Gd, 14.58.
f) 3-Oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid-t-butyl
ester
[0899] 25.0 g (53.8 mmol) of 1H,1H,2H,2H-perfluoro-1-decanol
[commercially available from the Lancaster Company] is dissolved in
250 ml of absolute toluene and mixed at room temperature with a
catalytic amount (about 0.75 g) of tetra-n-butyl-ammonium hydrogen
sulfate. Then, a total of 7.55 g (134.6 mmol; 2.5 equivalents
relative to the alcohol component that is used) of fine-powder
potassium hydroxide powder is added at 0.degree. C., followed by
15.73 g (80.7 mmol; 1.5 equivalents relative to the alcohol
component that is used) of bromoacetic acid-tert-butylester, and it
is allowed to stir for 2 more hours at 0.degree. C. The thus
obtained reaction solution is stirred for 12 hours at room
temperature, and for the purpose of working-up, it is mixed with a
total of 500 ml of ethyl acetate and 250 ml of water. The organic
phase is separated and washed twice with water. After the organic
phase is dried on sodium sulfate, salt is suctioned out, and the
solvent is drawn off in a vacuum. The remaining oily residue is
purified on silica gel with use of ethyl acetate/hexane (1:10) as
an eluant.
[0900] Yield: 26.3 g (84.6% of theory) of the above-mentioned title
compound as a colorless and strongly viscous oil.
[0901] Elementary analysis: Cld: C, 33.23; H, 2.61; F, 55.85. Fnd:
C, 33.29; H, 2.61; F, 55.90.
g) 3-Oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanecarboxylic acid
[0902] 20.0 g (34.58 mmol) of the title compound of Example 39f) is
suspended in 200 ml of a mixture that consists of methanol and 0.5
molar sodium hydroxide solution at a ratio of 2:1 while being
stirred at room temperature, and then it is heated to 60.degree. C.
After a reaction time of 12 hours at 60.degree. C., the now clear
reaction mixture is neutralized for working-up by mixing with
Amberlite IR 120 (H.sup.+ form)-cation-exchange resin, exchanger is
suctioned out, and the thus obtained methanolic-aqueous filtrate is
drawn off in a vacuum until a dry state is reached. The
amorphous-oily residue that is obtained is purified on silica gel
with use of ethyl acetate/n-hexane (1:3) as an eluant.
[0903] Yield: 16.0 g (88.6% of theory) of the above-mentioned title
compound as a colorless and strongly viscous oil.
[0904] Elementary analysis: Cld: C, 27.60; H, 1.35; F, 61.85. Fnd:
C, 27.58; H, 1.36; F, 61.90.
EXAMPLE 40
a)
6-Benzyloxycarbonyl-2-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acet-
yl-L-lysine-methyl ester
[0905] 16.18 g (27.0 mmol) of
2-[N-ethyl-N-perfluorooctylsulfonyl)-aminoac- etic acid (production
according to: DE 196 03 033), dissolved in 50 ml of
tetrahydrofuran, is added drop by drop at 0.degree. C. and under
nitrogen atmosphere to 8.0 g (24.4 mmol) of
.epsilon.-carbonyloxybenzyl-L-lysineme- thyl ester hydrochloride
(commercially available from the Bachem Company), dissolved in a
mixture that consists of 150 ml of tetrahydrofuran, 15 ml of
chloroform and 2.62 g (26.0 mmol) of triethylamine. Then, a total
of 18.0 g (36.6 mmol) of EEDQ
[2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinolin- e] is added in
portions at 0.degree. C. and allowed to stir overnight at room
temperature. It is then concentrated by evaporation in a vacuum,
and the remaining oil is chromatographed on silica gel (mobile
solvent: n-hexane/isopropanol 15:1). 17.0 g (79.6% of theory,
relative to the primary amine used) of the title compound is
obtained in the form of a colorless oil.
[0906] Elementary analysis: Cld: C, 38.41; H, 3.45; F, 36.89; N,
4.80; S, 3.66. Fnd: C, 38.42; H, 3.47; F, 36.92; N, 4.87; S,
3.64.
b)
2-[2-(N-Ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-L-lysine-methyl
ester
[0907] 15.0 g (20.23 mmol) of the compound that is produced under
Example 40a) is dissolved in 200 ml of ethanol, mixed with 800 mg
of Pearlman's catalyst (Pd 20% on activated carbon) and
hydrogenated until the calculated amount of hydrogen is taken up.
Catalyst is suctioned out, thoroughly rewashed with ethanol and
evaporated to the dry state in a vacuum. The title compound is
obtained as a colorless oil.
[0908] Yield: 14.68 g (97.9% of theory)
[0909] Elementary analysis: Cld: C, 32.40; H, 3.26; F, 43.56; N,
5.67; S, 4.32. Fnd: C, 32.42; H, 3.27; F, 43.60; N, 5.67; S,
4.34.
c)
6-(1-O-.alpha.-D-Carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)
2-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-L-lysine-methyl
ester
[0910] 21.31 g (35.6 mmol) of
1-carboxymethyloxy-2,3,4,-tetra-O-benzyl-.al-
pha.-D-mannopyranoside [production as described in Patent DE 197 28
954 C1] and 3.60 g (35.6 mmol) of triethylamine are dissolved in
500 ml of dry tetrahydrofuran. After the reaction solution is
cooled to -15.degree. C. to -20.degree. C., a solution of 4.92 g
(35.6 mmol) of isobutyl chloroformate in 75 ml of dry
tetrahydrofuran is slowly added at this temperature while being
stirred, whereby the rate of addition by drops can be selected so
that an internal temperature of -10.degree. C. is not exceeded.
After a reaction time of 15 minutes at -15.degree. C., a solution
of 26.39 g (35.6 mmol) of the title compound of Example 40b) and
3.60 g (35.6 mmol) of triethylamine in 100 ml of dry
tetrahydrofuran is then slowly added in drops at -20.degree. C.
After a reaction time of one hour at -15.degree. C. and two hours
at room temperature, the reaction solution is evaporated to the dry
state in a vacuum. The remaining residue is taken up in 250 ml of
ethyl acetate and washed twice with 100 ml each of saturated sodium
bicarbonate solution and once with 200 ml of water. After the
organic phase is dried on sodium sulfate, salt is suctioned out,
and the ethyl acetate is drawn off in a vacuum. The remaining oily
residue is purified on silica gel with use of ethyl
acetate/n-hexane (1:10) as an eluant.
[0911] Yield: 38.12 g (81.0% of theory) of the above-mentioned
title compound as a colorless and strongly viscous oil.
[0912] Elementary analysis: Cld: C, 49.92; H, 3.92; N, 2.53; F,
29.18; S, 2.90. Fnd: C, 49.99; H, 4.11; N, 2.69; F, 29.22; S,
3.01.
d)
6-(1-O-.alpha.-D-Carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)
2-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-L-lysine
[0913] 27.65 g (20.92 mmol) of the compound that is produced under
Example 40c) is dissolved in 250 ml of methanol. The solution of
4.0 g (100.0 mmol) of sodium hydroxide in 10 ml of distilled water
is then added, and it is stirred for 3 hours at 50.degree. C. After
the course of the reaction is checked by means of thin-layer
chromatography, methyl ester saponification has already taken place
quantitatively. It is evaporated to the dry state in a vacuum, the
remaining residue is taken up in 300 ml of ethyl acetate, and the
organic phase is extracted twice with 100 ml each of dilute,
aqueous citric acid solution. After drying on sodium sulfate, it is
filtered and evaporated to the dry state in a vacuum. The residue
that is obtained is chromatographed on silica gel (mobile solvent:
n-hexane/chloroform/isopropanol 15:10:1). 24.31 g (88.9% of theory)
of the title compound is obtained in the form of a colorless and
viscous oil.
[0914] Elementary analysis: Cld: C, 51.46; H, 4.70; N, 3.21; F,
24.71; S, 2.45. Fnd: C, 51.49; H, 4.71; N, 3.19; F, 24.72; S,
2.41.
e) 6-(1-O-.alpha.-D-Carbonylmethyl-mannopyranose)
2-[2-(N-ethyl-N-perfluor-
ooctylsulfonyl)-amino]-acetyl-L-lysine
[0915] 20.0 g (15.30 mmol) of the title compound of Example 40d) is
dissolved in a mixture that consists of 250 ml of 2-propanol and 25
ml of water, and it is mixed with 1.0 g of palladium catalyst (10%
Pd on activated carbon). It is hydrogenated for 12 hours at room
temperature and a hydrogen pressure of one atmosphere. Catalyst is
filtered out, and the filtrate is evaporated to the dry state in a
vacuum. The residue is dissolved in 200 ml of methanol, and the
reaction product is precipitated by mixing with a total of 800 ml
of diethyl ether. After the thus obtained solid is suctioned off,
the latter is dried in a vacuum at 50.degree. C.
[0916] Yield: 14.32 g (99.0% of theory) of an amorphous solid.
[0917] Elementary analysis: Cld: C, 35.56; H, 3.84; N, 4.44; S,
3.39; F, 34.15. Fnd: C, 35.58; H, 3.81; N, 4.45; S, 3.40; F,
34.17.
f) 6-(1-O-.alpha.-D-Carbonylmethyl-mannopyranose)
2-[2-(N-ethyl-N-perfluor-
ooctylsulfonyl)-amino]-acetyl-L-lysine-N-{2-hydroxyprop-3-yl-[1,4,7-tris(c-
arboxylatomethyl)-1,4,7,10-tetraazacyclododecan-10-yl]}-amide, Gd
complex
[0918] 7.48 g (7.91 mmol) of the title compound of Example 40e) is
dissolved in 50 ml of dimethyl sulfoxide at 40.degree. C., and 1.00
g (8.70 mol) of N-hydroxysuccinimide is added. It is cooled to
20.degree. C., and 1.795 g (8.7 mmol) of dicyclohexylcarbodiimide
is added. It is stirred for one hour at 20.degree. C. and then for
4 hours at 40.degree. C. Then, a solution that consists of 4.53 g
(7.91 mmol) of the gadolinium complex of
10-(2-hydroxy-3-aminopropyl)-4,7,10-tris(carboxymethyl)-1,4,7,-
10-tetraazacyclododecanine [for production, cf.: WO 97/02051] in 20
ml of dimethyl sulfoxide is added in drops at this temperature
within 10 minutes. It is stirred for one hour at 40.degree. C.,
then overnight at room temperature. The thus obtained suspension is
then mixed with sufficient acetone until the above-mentioned title
compound is completely precipitated, the precipitate is suctioned
off, dried, taken up in water, insoluble dicyclohexylurea is
filtered out, and the filtrate is desalinated with an AMICON.RTM.
YM-3 ultrafiltration membrane (cut-off 3,000 Da), and low-molecular
components are removed. The retentate is then freeze-dried.
[0919] Yield: 9.71 g (81.7% of theory) as a colorless
lyophilizate.
[0920] H.sub.2O content (Karl-Fischer): 3.97%
[0921] Elementary analysis (relative to anhydrous substance): Cld:
C, 35.16; H, 4.16; N, 7.45; F, 21.48; Gd, 10.46; S, 2.13. Fnd: C,
35.17; H, 4.20; N, 7.42; F, 21.49; Gd, 10.48; S, 2.09.
EXAMPLE 41
a)
6-N-[1-O-.alpha.-D-(5-Carbonyl)-pentyl-2,3,4,6-tetra-O-benzyl-mannopyra-
nose]-2N-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-L-lysine-meth-
yl ester
[0922] 5.23 g (8.0 mmol) of the
5-(carboxy)pentyl-2,3,4,6-tetra-O-benzyl-.-
alpha.-D-mannopyranoside described in Example 30c), 1.3 g (8.0
mmol) of 1-hydroxybenzotriazole and 2.6 g (8.0 mmol) of
2-(1H-benzotriazol-1-yl)-1- ,1,3,3-tetramethyluronium
tetrafluoroborate (TBTU; Peboc Limited, UK) are dissolved in 75 ml
of DMF and stirred for 15 minutes. This solution is then mixed with
5.16 ml (30 mmol) of N-ethyldiisopropylamine and with 5.93 g (8.0
mmol) of the amine that is described under Example 40b), and it is
stirred for 1.5 days at room temperature. For working-up, the
solvent is drawn off in a vacuum until a dry state is reached, and
the thus obtained residue is then chromatographed on silica gel
(mobile solvent: dichloromethane/ethyl acetate 30:1; chromatography
was carried out with use of a solvent gradient with a proportion of
ethyl acetate that rises continuously).
[0923] Yield: 9.70 g (88.0% of theory) of the title compound in the
form of a colorless and strongly viscous oil.
[0924] Elementary analysis: Cld: C, 52.29; H, 4.97; N, 3.05; F,
23.43; S, 2.33. Fnd: C, 52.33; H, 4.95; N, 3.12; F, 23.50; S,
2.30.
b)
6-N-[1-O-.alpha.-D-(5-Carbonyl)-pentyl-2,3,4,6-tetra-O-benzyl-mannopyra-
nose]-2N-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-L-lysine
[0925] 9.0 g (12.40 mmol) of the compound that is produced under
Example 41a) is dissolved in 150 ml of methanol. The solution of
2.48 g (62.0 mmol) of sodium hydroxide in 15 ml of distilled water
is then added to it, and it is stirred for 3 hours at 50.degree. C.
After the course of the reaction is checked by means of thin-layer
chromatography, methyl ester saponification has already taken place
quantitatively according to the above-mentioned reaction time. It
is evaporated to the dry state in a vacuum, and the remaining
residue is taken up in 300 ml of ethyl acetate, and the organic
phase is extracted twice with 100 ml each of dilute, aqueous citric
acid solution. After drying on sodium sulfate, it is filtered and
evaporated to the dry state in a vacuum. The residue that is
obtained is chromatographed on silica gel (mobile solvent:
n-hexane/chloroform/isopropanol 25:10:1). 15.88 g (93.9% of theory)
of the title compound is obtained in the form of a colorless and
strongly viscous oil.
[0926] Elementary analysis: Cld: C, 51.95; H, 4.88; N, 3.08; F,
23.67; S, 2.35. Fnd: C, 51.99; H, 4.91; N, 3.09; F, 23.70; S,
2.33.
c)
6-N-[1-O-.alpha.-D-(5-Carbonyl)-pentyl-mannopyranose]-2N-[2-(N-ethyl-N--
perfluorooctylsulfonyl)-amino]-acetyl-L-lysine
[0927] 13.0 g (9.52 mmol) of the title compound of Example 41b) is
dissolved in a mixture that consists of 150 ml of 2-propanol and 25
ml of water, and 1.0 g of the palladium catalyst (10% Pd on
activated carbon) is added. It is hydrogenated for 12 hours at I
atmosphere of hydrogen pressure and room temperature. Catalyst is
filtered out, and the filtrate is evaporated to the dry state in a
vacuum. The residue that is obtained is chromatographed on silica
gel (mobile solvent: n-hexane/chloroform/iso- propanol 15:10:1).
9.09 g (95.1% of theory) of the title compound is obtained in the
form of a colorless and strongly viscous oil.
[0928] Elementary analysis: Cld: C, 37.10; H, 4.22; N, 4.19; F,
32.18; S, 3.10. Fnd: C, 37.09; H, 4.21; N, 4.19; F, 32.20; S,
3.13.
d)
6-N-[1-O-.alpha.-D-(5-Carbonyl)-pentyl-mannopyranose]-2N-[2-(N-ethyl-N--
perfluorooctylsulfonyl)-amino]-acetyl-L-lysine-N-{2-hydroxy-prop-3-yl-[1,4-
,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-10-yl]}-amide,
Gd complex
[0929] 7.93 g (7.91 mmol) of the title compound of Example 41c) is
dissolved at 40.degree. C. in 75 ml of dimethyl sulfoxide, and it
is mixed with 1.00 g (8.70 mol) of N-hydroxysuccinimide. It is
cooled to room temperature, and a total of 1.795 g (8.7 mmol) of
dicyclohexylcarbodiimide is added. It is stirred for one hour at
20.degree. C. and then for 4 hours at 40.degree. C. Then, a
solution that consists of 4.53 g (7.91 mmol) of the gadolinium
complex of
10-(2-hydroxy-3-aminopropyl)-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraaza-
cyclododecanine [for production, cf.: WO 97/02051] in 20 ml of
dimethyl sulfoxide is added in drops at 40.degree. C. within 10
minutes to this solution of the active ester of the title compound
of Example 41c). It is stirred for one hour at 40.degree. C., then
overnight at room temperature. The thus obtained suspension is then
mixed with a sufficient amount of a mixture that consists of
acetone/2-propanol (2:1) until the above-mentioned title compound
is completely precipitated, the precipitate is suctioned off,
rewashed with ethyl acetate, dried, taken up in water, insoluble
dicyclohexylurea is filtered out, and the filtrate is desalinated
with an AMICON.RTM. YM-3 ultrafiltration membrane (cut-off 3,000
Da), and low-molecular components are removed. The retentate is
then freeze-dried.
[0930] Yield: 9.71 g (78.8% of theory) as a colorless
lyophilizate.
[0931] H.sub.2O content (Karl-Fischer): 6.65%
[0932] Elementary analysis (relative to anhydrous substance): Cld:
C, 36.97; H, 4.52; N, 7.19; F, 20.71; Gd, 10.08; S, 2.06. Fnd: C,
37.02; H, 4.50; N, 7.22; F, 20.69; Gd, 10.08; S, 2.09.
EXAMPLE 42
a)
6-N-{4-[2,3-Bis-(N,N-bis(t-butyloxycarbonylmethyl)-amino)-propyl]-pheny-
l}-3-oxa-propionyl-2-N-(1-.alpha.-D-carbonylmethyl-mannopyranose)
L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide
[0933] 5.25 g (7.72 mmol) of the tetra-t.bu-ester of
"Tyr-EDTA-carboxylic acid" and 781 mg (7.72 mmol) of triethylamine
are dissolved in 50 ml of methylene chloride. At -15.degree. C., a
solution that consists of 1.16 g (8.5 mmol) of isobutyl
chloroformate in 10 ml of methylene chloride is added in drops
within 5 minutes, and it is stirred for another 20 minutes at
-15.degree. C. Then, the solution is cooled to -25.degree. C., and
a solution that consists of 7.07 g (7.72 mmol) of the title
compound of Example 30e) and 2.12 g (21.0 mmol) of triethylamine,
in 70 ml of tetrahydrofuran, is added in drops within 30 minutes,
and subsequently stirred for 30 more minutes at -15.degree. C., and
then stirring is continued overnight at room temperature. For
working-up, the solvent is drawn off in a vacuum, and the remaining
oily residue is taken up in 250 ml of chloroform. The chloroform
phase is extracted twice with 100 ml each of a 10% aqueous ammonium
chloride solution, the organic phase is dried on magnesium sulfate
and evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:methylene
chloride/ethanol=20:1).
[0934] Yield: 9.60 g (79.0% of theory) of a colorless and very
viscous oil.
[0935] Elementary analysis: Cld: C, 46.39; H, 5.55; N, 5.32; F,
20.45; S, 2.03. Fnd: C, 46.42; H, 5.51; N, 5.29; F, 20.49; S,
2.09.
b)
6-N-{4-[2,3-Bis-(N,N-bis(carboxymethyl)-amino)-propyl]-phenyl}-3-oxa-pr-
opionyl-2-N-(1-.alpha.-D-carbonylmethyl-mannopyranose)
L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide
[0936] 9.0 g (5.70 mmol) of the compound produced under Example
42a) is dissolved in 150 ml of methanol. The solution of 4.0 g
(100.0 mmol) of sodium hydroxide in 25 ml of distilled water is
then added to it, and it is stirred for 6 hours at 60.degree. C.
After the course of the reaction is checked by means of thin-layer
chromatography, saponification of the tetra-t-butyl ester has
already taken place quantitatively according to the above-mentioned
reaction time. It is evaporated to the dry state in a vacuum, and
the remaining residue is taken up in 50 ml of dimethyl sulfoxide in
the heat, and then it is mixed with a sufficient amount of a
mixture that consists of acetone/ethyl acetate (1:1) until the
above-mentioned title compound is completely precipitated, the thus
obtained precipitate is suctioned off, thoroughly rewashed with
ethyl acetate, dried, taken up in water, the pH of the product
solution is set at 3.5 with 1 molar hydrochloric acid, possibly
present insoluble components are filtered out, and the filtrate is
desalinated with an AMICON.RTM. YM-3 ultrafiltration membrane
(cut-off 3,000 Da), and low-molecular components are removed. The
retentate is then freeze-dried.
[0937] Yield: 6.76 g (87.6% of theory) as a colorless
lyophilizate.
[0938] H.sub.2O content (Karl-Fischer): 3.30%.
[0939] Elementary analysis (relative to anhydrous substance): Cld:
C, 39.89; H, 4.09; N, 6.20; F, 23.84; S, 2.37. Fnd: C, 39.92; H,
4.15; N, 6.22; F, 23.92; S, 2.29.
c)
6-N-{4-[2,3-Bis-(N,N-bis(carboxylatomethyl)-amino)-propyl]-phenyl}-3-ox-
a-propionyl-2-N-(1-.alpha.-D-carbonylmethyl-mannopyranose)
L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Mn
complex, disodium salt
[0940] 3.0 g (2.22 mmol) of the title compound of Example 42b) is
dissolved in 150 ml of a water/ethanol (3:1) mixture at boiling
heat, and it is mixed in portions with 0.25 g (2.22 mmol) of
manganese(II) carbonate at 80.degree. C. Then, the thus obtained
reaction solution is refluxed for 5 hours. After cooling to room
temperature, the solvent mixture is completely drawn off in a
vacuum, and the remaining residue is dissolved in a mixture that
consists of 200 ml of distilled water/n-butanol (1:1). A pH of 7.2
is set by mixing with 1N sodium hydroxide solution while being
stirred vigorously. After the n-butanol is completely drawn off in
a vacuum, the remaining aqueous phase is desalinated with an
AMICON.RTM. YM-3 ultrafiltration membrane (cut-off 3,000 Da), and
low-molecular components are removed. The retentate is then
freeze-dried.
[0941] Yield: 3.19 g (99.0% of theory) as a colorless
lyophilizate.
[0942] H.sub.2O content (Karl-Fischer): 5.08%.
[0943] Elementary analysis (relative to anhydrous substance): Cld:
C, 37.23; H, 3.54; F, 22.25; Mn, 3.78; N, 5.79; Na, 3.17; S, 2.21.
Fnd: C, 37.30; H, 3.49; F, 22.29; Mn, 3.81; N, 5.76; Na, 3.19; S,
2.18.
EXAMPLE 43
a) 3-Benzyloxycarbonylamino-glutaric
acid-[1-(4-perfluorooctylsulfonyl)-pi- perazine]-monoamide
[0944] A stirred solution of 25.0 g (94.96 mmol) of
3-N-(benzyloxycarbonyl)-glutaric acid-anhydride [synthesis
according to: Hatanaka, Minoru; Yamamoto, Yu-ichi; Nitta, Hajime;
Ishimaru, Toshiyasu; TELEAY; Tetrahedron Lett.: EN; 22; 39; 1981;
3883-3886;] in 150 ml of absolute tetrahydrofuran is mixed drop by
drop while being stirred with a solution of 53.97 g (95.0 mmol) of
1-perfluorooctylsulfonylpiperazine in 150 ml of tetrahydrofuran,
and the thus obtained reaction solution is refluxed for 12 hours.
After cooling to room temperature, it is concentrated by
evaporation to the dry state, and the remaining oily residue is
purified on silica gel with use of dichloromethane/2-propanol
(20:1) as an eluant.
[0945] Yield: 75.80 g (96.0% of theory) of the above-mentioned
title compound in the form of a colorless and viscous oil.
[0946] Elementary analysis: Cld: C, 36.11; H, 2.67; N, 5.05; S,
3.86; F, 38.84. Fnd: C, 36.12; H, 2.61; N, 5.08; S, 3.88; F,
38.82.
b) 3-Amino-glutaric
acid-[1-(4-perfluorooctylsulfonyl)-piperazine]-monoami- de
[0947] 31.50 g (37.88 mmol) of the compound that is produced under
43b) is dissolved in 300 ml of ethanol, it is mixed with 2.5 g of
Pearlman's catalyst (Pd 20%, C) and hydrogenated until quantitative
hydrogen uptake is reached at 1 atmosphere of hydrogen pressure.
Catalyst is suctioned out, it is rewashed with ethanol and
evaporated to the dry state in a vacuum. The title compound is
obtained as a whitish-yellow, viscous oil.
[0948] Yield: 25.22 g (95.5% of theory)
[0949] Elementary analysis: Cld: C, 29.28; H, 2.31; N, 6.03; S,
4.06; F, 46.31. Fnd: C, 29.32; H, 2.29; N, 6.08; S, 4.08; F,
46.28.
c)
3-N-(1-.alpha.-D-Carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)-g-
lutaric
acid-[1-(4-perfluorooctylsulfonyl)-piperazine]-monoamide
[0950] 21.52 g (18.96 mmol) of
1-carboxymethyloxy-2,3,4,-tetra-O-benzyl-.a-
lpha.-D-mannopyranoside [production as described in Patent DE 197
28 954 C1] is dissolved at room temperature in 100 ml of absolute
dimethylformamide, and it is mixed at 0.degree. C. with 2.56 g
(22.2 mmol) of N-hydroxysuccinimide, followed by 4.55 g (22.2 mmol)
of dicyclohexylcarbodiimide. After a reaction time of 60 minutes at
0.degree. C. and 3 hours at 22.degree. C., insoluble
dicyclohexylurea is filtered out, and the thus obtained clear
active ester solution of the above-mentioned title compound is
slowly added in drops at 0.degree. C. to a stirred solution of
13.22 g (18.96 mmol) of the compound of Example 43b), dissolved in
100 ml of dimethylformamide. After a reaction time of 12 hours at
room temperature, the solvent is drawn off in a vacuum, and the
remaining residue is taken up in 300 ml of ethyl acetate, urea is
filtered out, and the organic filtrate is washed twice with 100 ml
each of saturated sodium bicarbonate solution and once with 100 ml
of 10% aqueous citric acid solution and once with 200 ml of water.
After the organic phase is dried on sodium sulfate, salt is
suctioned out, and the ethyl acetate is drawn off in a vacuum. The
remaining oily residue is purified on silica gel with use of ethyl
acetate/n-hexane (1:15) as an eluant.
[0951] Yield: 21.39 g (88.3% of theory) of the above-mentioned
title compound as a colorless and strongly viscous oil.
[0952] Elementary analysis: Cld: C, 49.81; H, 4.10; N, 3.29; F,
25.27; S, 2.51. Fnd: C, 49.89; H, 4.11; N, 3.32; F, 25.22; S,
2.51.
d) 3-N-(1-.alpha.-D-Carbonylmethyl-mannopyranose)-glutaric
acid-[1-(4-perfluorooctylsulfonyl)-piperazine]-monoamide
[0953] 19.55 g (15.30 mmol) of the title compound of Example 43c)
is dissolved in a mixture that consists of 250 ml of 2-propanol and
25 ml of water and mixed with 1.5 g of palladium catalyst (10% Pd
on activated carbon). It is hydrogenated for 12 hours at room
temperature and a hydrogen pressure of one atmosphere. Catalyst is
filtered out, and the filtrate is evaporated to the dry state in a
vacuum. The residue is dissolved in 200 ml of methanol, and the
reaction product is precipitated by mixing with a total of 800 ml
of diethyl ether. After the thus obtained solid is suctioned off,
the latter is dried in a vacuum at 40.degree. C.
[0954] Yield: 17.49 g (97.5% of theory) of an amorphous solid.
[0955] Elementary analysis: Cld: C, 32.73; H, 3.08; N, 4.58; S,
3.49; F, 35.20. Fnd: C, 32.68; H, 3.15; N, 4.55; S, 3.50; F,
35.17.
e) 3-N-(1-.alpha.-D-Carbonylmethyl-mannopyranose)-glutaric
acid-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide-5-N-{2-hydroxy-prop--
3-yl-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-10-yl]}--
amide, Gd complex
[0956] 14.43 g (15.84 mmol) of the title compound of Example 43d)
and 0.67 g of anhydrous lithium chloride (15.84 mmol) are dissolved
at 40.degree. C. in 100 ml of absolute dimethyl sulfoxide while
being stirred, and it is mixed at this temperature with a total of
1.82 g (15.84 mmol) of N-hydroxysuccinimide and a solution of 9.08
g (15.84 mmol) of the gadolinium complex of
10-(2-hydroxy-3-aminopropyl)-4,7,10-tris(carboxymet-
hyl)-1,4,7,10-tetraazacyclododecanine [for production, cf.: WO
97/02051], in 50 ml of dimethyl sulfoxide. After cooling to room
temperature, the reaction solution is mixed with 3.27 g (15.84
mmol) of N,N'-dicyclohexylcarbodiimide, and it is stirred for 12
hours at room temperature. The suspension that is obtained is then
mixed with sufficient acetone until the above-mentioned title
compound is completely precipitated, the precipitate is suctioned
off, dried, taken up in water, insoluble dicyclohexylurea is
filtered out, and the filtrate is desalinated with an AMICON.RTM.
YM-3 ultrafiltration membrane (cut-off 3,000 Da) and in this case
possible, still present low-molecular components are simultaneously
removed. The retentate is then freeze-dried.
[0957] Yield: 18.71 g (80.2% of theory) as a colorless
lyophilizate.
[0958] H.sub.2O content (Karl-Fischer): 4.87%.
[0959] Elementary analysis (relative to anhydrous substance): Cld:
C, 34.24; H, 3.83; N, 7.61; F, 21.92; S, 2.18; Gd, 10.67. Fnd: C,
34.26; H, 3.79; N, 7.58; F, 21.87; S, 2.18; Gd, 10.68.
EXAMPLE 44
a) 1,7-Bis(benzyloxycarbonyl)-4-{3-oxa-pentane-1,5-dicarboxylic
acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-10-[2,6-N,N-
'-bis(1-O-.alpha.-D-carbonylmethyl-2,3,4,6-tetra-O-benzyl-mannopyranose)]--
L-lysyl-1,4,7,10-tetraazacyclododecane
[0960] 33.04 g (25.0 mmol) of the title compound of Example 18c),
dissolved in 250 ml of tetrahydrofuran, is added at 0.degree. C.
and under nitrogen atmosphere to a solution that consists of 27.0 g
(24.4 mmol) of the sec-amine that is produced under Example 35a),
in a mixture that consists of 150 ml of tetrahydrofuran and 15 ml
of chloroform. Then, a total of 18.0 g (36.6 mmol) of EEDQ
[2-ethoxy-1-ethoxycarbonyl-1,2-dihy- droquinoline] is added in
portions at 0.degree. C. and allowed to stir overnight at room
temperature. It is then evaporated to the dry state in a vacuum,
and the remaining oil is chromatographed on silica gel (mobile
solvent: n-hexane/isopropanol 25:1). 45.87 g (78.0% of theory,
relative to the sec-amine that is used) of the title compound is
obtained in the form of a colorless oil.
[0961] Elementary analysis: Cld: C, 59.30; H, 5.39; F, 13.40; N,
4.65; S, 1.33. Fnd: C, 59.32; H, 5.37; F, 13.37; N, 4.70; S,
1.34.
b) 1-{3-Oxa-pentane-1,5-dicarboxylic
acid-1-oyl-5-[1-(4-perfluorooctylsulf-
onyl)-piperazine]-amide}-7-[2,6-N,N'-bis(1-O-.alpha.-D-carbonylmethyl-mann-
opyranose)]-L-lysyl-1,4,7,10-tetraazacyclododecane
[0962] 24.1 g (10.0 mmol) of the title compound that is produced
under Example 44a) is dissolved in 250 ml of ethanol, and it is
mixed with 1.4 g of Pearlman's catalyst (Pd 20%, C). It is
hydrogenated until quantitative hydrogen uptake is reached, then
catalyst is suctioned out, it is thoroughly rewashed with ethanol
and evaporated to the dry state in a vacuum. The product is
yellowish in color, and extremely viscous oil is obtained.
[0963] Yield: 12.80 g (90.1% of theory)
[0964] Elementary analysis: Cld: C, 39.72; H, 4.89; F, 22.73; N,
7.88; S, 2.26. Fnd: C, 39.72; H, 4.87; F, 22.77; N, 7.90; S,
2.24.
c) 1-{3-Oxa-pentane-1,5-dicarboxylic
acid-1-oyl-5-[1-(4-perfluorooctylsulf-
onyl)-piperazine]-amide}-7-[2,6-N,N'-bis(1-O-.alpha.-D-carbonylmethyl-mann-
opyranose)]-L-lysyl-4,10-bis[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-
-5-methyl-5-yl-pentanoyl)]-1,4,7,10-tetraazacyclododecane,
digadolinium complex
[0965] 5.54 g [8.8 mmol; 2.2 molar equivalents relative to the
amine component of Example 44b) that is used] of the Gd-complex,
described in Patent Application DE 197 28 954 C1 under Example 31
h), of
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1-
,4,7-triacetic acid and anhydrous lithium chloride (0.37 g, 8.8
mmol) is dissolved at 40.degree. C. in 60 ml of absolute dimethyl
sulfoxide while being stirred, and a total of 1.01 g (8.8 mmol) of
N-hydroxysuccinimide and 5.68 g (4.0 mmol) of the title compound of
Example 44b), dissolved in 40 ml of absolute dimethyl sulfoxide, is
mixed at this temperature. After cooling to room temperature, the
reaction solution is mixed with 1.82 g (8.8 mmol) of
N,N'-dicyclohexylcarbodiimide and stirred for 12 hours at room
temperature. The suspension that is obtained is then mixed with
sufficient acetone until the above-mentioned title compound is
completely precipitated, the precipitate is suctioned off, dried,
taken up in water, insoluble dicyclohexylurea is filtered out, and
the filtrate is desalinated with an AMICON.RTM. YM-3
ultrafiltration membrane (cut-off 3,000 Da), and low-molecular
components are removed. The retentate is then freeze-dried.
[0966] Yield: 8.52 g (80.6% of theory; relative to the diamine
component that is used) as a colorless lyophilizate.
[0967] H.sub.2O content (Karl-Fischer): 6.09%
[0968] Elementary analysis (relative to anhydrous substance): Cld:
C, 38.61; H, 4.76; N, 9.53; F, 12.21; Gd, 11.89; S, 1.12. Fnd: C,
38.57; H, 4.82; N, 9.52; F, 12.21; Gd, 11.93; S, 1.15.
EXAMPLE 45
a) 1,7-Bis(benzyloxycarbonyl)-4-{3-oxa-pentane-1,5-dicarboxylic
acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-10-{2,6-N,N-
'-bis(1-O-.alpha.-D-(5-carbonyl)-pentyl-2,3,4,6-tetra-O-benzyl-mannopyrano-
se)}-L-lysyl-1,4,7,10-tetraazacyclododecane
[0969] 35.80 g (25.0 mmol) of the title compound of Example 37e),
dissolved in 250 ml of tetrahydrofuran, is added at 0.degree. C.
and under nitrogen atmosphere to a solution that consists of 27.0 g
(24.4 mmol) of the sec-amine that is produced under Example 35a),
in a mixture that consists of 150 ml of tetrahydrofuran and 15 ml
of chloroform. Then, a total of 18.0 g (36.6 mmol) of EEDQ
[2-ethoxy-1-ethoxycarbonyl-1,2-dihy- droquinoline] is added in
portions at 0.degree. C., and it is allowed to stir overnight at
room temperature. It is then evaporated to the dry state in a
vacuum, and the remaining oil is chromatographed on silica gel
(mobile solvent:n-hexane/isopropanol 20:1). 49.48 g (80.4% of
theory, relative to the sec-amine that is used) of the title
compound is obtained in the form of a colorless oil.
[0970] Elementary analysis: Cld: C, 60.47; H, 5.79; F, 12.80; N,
4.44; S, 1.27.
[0971] Fnd: C, 60.52; H, 5.77; F, 12.77; N, 4.50; S, 1.30.
b) 1-{3-Oxa-pentane-1,5-dicarboxylic
acid-1-oyl-5-[1-(4-perfluorooctylsulf-
onyl)-piperazine]-amide}-7-[2,6-N,N'-bis(1-O-.alpha.-D-(5-carbonyl)-pentyl-
-mannopyranose)]-L-lysyl-1,4,7,10-tetraazacyclododecane
[0972] 25.2 g (10.0 mmol) of the title compound that is produced
under Example 45a) is dissolved in 250 ml of ethanol and mixed with
1.8 g of Pearlman's catalyst (Pd 20%, C). It is hydrogenated until
quantitative hydrogen uptake is reached, then catalyst is suctioned
out, it is thoroughly rewashed with ethanol and evaporated to the
dry state in a vacuum. The product is yellowish in color, and
extremely viscous oil is obtained.
[0973] Yield: 14.11 g (92.5% of theory)
[0974] Elementary analysis: Cld: C, 49.60; H, 7.20; F, 21.17; N,
7.34; S, 2.10. Fnd: C, 49.62; H, 7.17; F, 21.20; N, 7.30; S,
2.14.
c) 1-{3-Oxa-pentane-1,5-dicarboxylic
acid-1-oyl-5-[1-(4-perfluorooctylsulf-
onyl)-piperazine]-amide}-7-[2,6-N,N'-bis(1-O-.alpha.-D-(5-carbonyl)-pentyl-
-mannopyranose)]-L-lysyl-4,10-bis[1,4,7-tris(carboxylatomethyl)-10-(3-aza--
4-oxo-5-methyl-5-yl-pentanoyl)]-1,4,7,10-tetraazacyclododecane,
digadolinium complex
[0975] 5.54 g [8.8 mmol; 2.2 molar equivalents relative to the
amine component of Example 45b) that is used] of the Gd complex,
described in Patent Application DE 197 28 954 C1 under Example
31h), of the
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1-
,4,7-triacetic acid and anhydrous lithium chloride (0.37 g, 8.8
mmol) are dissolved at 40.degree. C. in 60 ml of absolute dimethyl
sulfoxide while being stirred, and it is mixed at this temperature
with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 6.10
g (4.0 mmol) of the title compound of Example 45b), dissolved in 40
ml of absolute dimethyl sulfoxide. After cooling to room
temperature, the reaction solution is mixed with 1.82 g (8.8 mmol)
of N,N'-dicyclohexylcarbodiimide, and it is stirred for 12 hours at
room temperature. The suspension that is obtained is then mixed
with sufficient acetone until the above-mentioned title compound is
completely precipitated, the precipitate is suctioned off, dried,
taken up in water, insoluble dicyclohexylurea is filtered out, and
the filtrate is desalinated with an AMICON.RTM. YM-3
ultrafiltration membrane (cut-off 3,000 Da), and low-molecular
components are removed. The retentate is then freeze-dried.
[0976] Yield: 9.26 g (84.0% of theory; relative to the diamine
component that is used) as a colorless lyophilizate.
[0977] H.sub.2O content (Karl-Fischer): 5.89%.
[0978] Elementary analysis (relative to anhydrous substance): Cld:
C, 40.52; H, 5.16; N, 9.15; F, 11.72; Gd, 11.41; S, 1.16. Fnd: C,
40.57; H, 5.20; N, 9.12; F, 11.69; Gd, 11.43; S, 1.18.
EXAMPLE 46
a)
6-N-t-Butyloxycarbonyl-2-N-benzyloxycarbonyl-L-lysine-[1-(4-perfluorooc-
tylsulfonyl)-piperazine]-amide
[0979] 19.02 g (50.0 mmol) of
.alpha.-N-(benzyloxycarbonyl)-.epsilon.-N'-(-
tert-butyloxycarbonyl)-L-lysine (commercially available from the
Bachem Company) is dissolved in 150 ml of absolute tetrahydrofuran.
8.31 g (50.0 mmol) of carbonyl diimidazole and 5.03 g (50.0 mmol)
of triethylamine, dissolved in 75 ml of dry tetrahydrofuran, are
added drop by drop at 0.degree. C., and stirring is allowed to
continue for 10 minutes at this temperature. Then, a solution of
48.42 g (50.0 mmol) of perfluorooctylsulfonyl-piperazine and 5.03 g
(50.0 mmol) of triethylamine in 250 ml of dry tetrahydrofuran is
added in drops at 0.degree. C. After stirring overnight, the
tetrahydrofuran is drawn off in a vacuum, and the remaining oil is
chromatographed on silica gel (mobile solvent: n-hexane/isopropanol
15:1). 49.48 g (80.4% of theory, relative to the sec-amine that is
used) of the title compound is obtained in the form of a colorless
oil.
[0980] Elementary analysis (relative to anhydrous substance): Cld:
C, 40.01; H, 3.79; N, 6.02; F, 34.70; S, 3.45. Fnd: C, 40.07; H,
3.82; N, 6.02; F, 34.67; S, 3.48.
b)
6-N-t-Butyloxycarbonyl-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazin-
e]-amide
[0981] 30.0 g (32.2 mmol) of the title compound of Example 46a) is
dissolved in 300 ml of isopropanol and mixed with 1.5 g of
Pearlman's catalyst (20% palladium hydroxide on carbon). It is
hydrogenated for 10 hours at room temperature, whereby after the
course of the reaction is checked by means of thin-layer
chromatography, hydrogenolytic cleavage of the benzyloxycarbonyl
protective group has already taken place quantitatively according
to the above-mentioned reaction time. Catalyst is filtered out, and
the filtrate is evaporated to the dry state in a vacuum. The
remaining residue is chromatographed on silica gel (mobile solvent:
n-hexane/isopropanol 25:1). 25.13 g (98.0% of theory) of the title
compound is obtained in the form of a colorless oil.
[0982] Elementary analysis: Cld: C, 34.68; H, 3.67; F, 40.55; N,
7.03; S, 4.03. Fnd: C, 34.72; H, 3.70; F, 40.60; N, 7.01; S,
3.98.
c)
6-N-t-Butyloxycarbonyl-2-N-[1-S-.alpha.-D-(2-carbonyl)-ethyl-2,3,4,6-te-
tra-O-acetyl-mannopyranose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperaz-
ine]-amide
[0983] 15.53 g (35.60 mmol) of
3-(2,3,4,6-tetra-O-acetyl-1-thio-.alpha.-D--
mannopyranosyl)-propionic acid (production according to: J.
Haensler et al., Bioconjugate Chem. 4, 85, (1993); Chipowsky, S.
and Lee, Y. C. (1973), Synthesis of 1-Thio-aldosides; Carbohydrate
Research 31, 339-346) and 3.60 g (35.60 mmol) of triethylamine are
dissolved in 300 ml of dry tetrahydrofuran. After the reaction
solution is cooled to -15.degree. C. to -20.degree. C., a solution
of 4.92 g (35.60 mmol) of isobutyl chloroformate in 75 ml of dry
tetrahydrofuran is slowly added in drops at this temperature while
being stirred, whereby the rate of addition by drops can be
selected in such a way that an internal temperature of -10.degree.
C. is not exceeded. After a reaction time of 15 minutes at
-15.degree. C., a solution of 28.35 g (35.60 mmol) of the title
compound of Example 42b) and 3.60 g (35.60 mmol) of triethylamine
is then slowly added in drops to 200 ml of dry tetrahydrofuran at
20.degree. C. After a reaction time of one hour at -15.degree. C.
and two hours at room temperature, the reaction solution is
evaporated to the dry state in a vacuum. The remaining residue is
taken up in 250 ml of ethyl acetate and washed twice with 100 ml
each of saturated sodium bicarbonate solution and once with 200 ml
of water. After the organic phase is dried on sodium sulfate, salt
is suctioned out, and the ethyl acetate is drawn off in a vacuum.
The remaining oily residue is purified on silica gel with use of
ethyl acetate/n-hexane (1:25) as an eluant.
[0984] Yield: 34.21 g (79.1% of theory) of the above-mentioned
title compound as a colorless and strongly viscous oil.
[0985] Elementary analysis: Cld: C, 39.54; H, 4.23; N, 4.61; F,
26.58; S, 5.28. Fnd: C, 39.49; H, 4.21; N, 4.59; F, 26.52;
d)
6-N-t-Butyloxycarbonyl-2-N-[1-S-.alpha.-D-(2-carbonyl)-ethyl-mannopyran-
ose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide
[0986] 29.93 g (24.64 mmol) of the title compound of Example 46c)
is suspended in 400 ml of absolute methanol, and it is mixed at
5.degree. C. with a catalytic amount of sodium methanolate. After a
reaction time of 3 hours at room temperature, even thin-layer
chromatographic checking (eluant:chloroform/methanol=9:1) of the
course of the reaction indicates a quantitative reaction. For the
purpose of working-up, the now clear reaction solution is
neutralized by mixing with Amberlite.RTM. IR 120
(H.sup.+-form)-cation-exchange resin, exchanger is suctioned out,
and the thus obtained methanolic filtrate is evaporated to the dry
state in a vacuum. The amorphous residue that is obtained is
purified by chromatography on silica gel with use of
2-propanol/ethyl acetate/n-hexane (1:1:15) as an eluant.
[0987] Yield: 23.42 g (90.8% of theory) of a colorless and viscous
oil.
[0988] Elementary analysis: Cld: C, 36.72; H, 14.14; N, 5.35; F,
30.85; S, 6.13. Fnd: C, 36.69; H, 14.11; N, 5.35; F, 30.82; S,
6.11.
e)
2-N-[1-S-.alpha.-D-(2-Carbonyl)-ethyl-mannopyranose]-L-lysine-[1-(4-per-
fluorooctylsulfonyl)-piperazine]-amide
[0989] 20.93 g (20.0 mmol) of the title compound of Example 46d) is
dissolved in a mixture that consists of 50 ml of trifluoroacetic
acid and 100 ml of dichloromethane at 0.degree. C. while being
stirred vigorously, and it is stirred for 10 minutes at this
temperature. Then, it is evaporated to the dry state in a vacuum,
and the residue is taken up in 150 ml of water. The pH of this
aqueous product solution is set at 9.5 by adding 2 molar aqueous
sodium hydroxide solution drop by drop. The aqueous product
solution is desalinated with an AMICON.RTM. YM-3 ultrafiltration
membrane (cut-off: 3,000 Da), and in this case, possible, still
present, low-molecular components are simultaneously removed. The
retentate is then freeze-dried.
[0990] Yield: 17.79 g (94.2% of theory) of the free amine as a
colorless lyophilizate.
[0991] H.sub.2O content (Karl-Fischer): 3.09%.
[0992] Elementary analysis (relative to anhydrous substance): Cld:
C, 34.26; H, 3.73; N, 5.92; F, 34.12; S, 6.77. Fnd: C, 34.26; H,
3.79; N, 5.88; F, 34.07; S, 6.80.
f)
2-N-[1-S-.alpha.-D-(2-Carbonyl)-ethyl-mannopyranose]-6-N-[1,4,7-tris(ca-
rboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)-1,4,7,10-tetraaz-
acyclododecane]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide,
gadolinium complex
[0993] 5.54 g [(8.8 mmol, 2.2 molar equivalents relative to the
amine component of Example 46e) that is used] of the Gd complex,
described in Patent Application DE 197 28 954 C1 under Example
31h), of the
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1-
,4,7-triacetic acid and 0.37 g of anhydrous lithium chloride (8.8
mmol) are dissolved at 40.degree. C. in 60 ml of absolute dimethyl
sulfoxide while being stirred, and it is mixed at this temperature
with a total of 1.01 g (8.8 mmol) of N-hydroxysuccinimide and 3.78
g (4.0 mmol) of the title compound of Example 46e), dissolved in 40
ml of absolute dimethyl sulfoxide. After cooling to room
temperature, the reaction solution is mixed with 1.82 g (8.8 mmol)
of N,N'-dicyclohexylcarbodiimide, and it is stirred for 12 hours at
room temperature. The suspension that is obtained is then mixed
with sufficient acetone until the above-mentioned title compound is
completely precipitated, the precipitate is suctioned off, taken up
in water, insoluble dicyclohexylurea is filtered out, and the
filtrate is desalinated with an AMICON.RTM. YM-3 ultrafiltration
membrane (cut-off 3,000 Da), and low-molecular components are
removed. The retentate is then freeze-dried.
[0994] Yield: 5.17 g (83.0% of theory) as a colorless
lyophilizate.
[0995] H.sub.2O content (Karl-Fischer): 4.43%.
[0996] Elementary analysis (relative to anhydrous substance): Cld:
C, 35.45; H, 4.07; N, 8.09; F, 20.72; Gd, 10.09; S, 4.11. Fnd: C,
35.50; H, 4.01; N, 8.12; F, 20.6; Gd, 10.13; S, 4.14.
EXAMPLE 47
a)
6-N-Benzyloxycarbonyl-2-N-(1-O-.beta.-D-carbonylmethyl-2,3,4,6-tetra-O--
benzylglucopyranose)-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-am-
ide
[0997] 8.02 g (13.4 mmol) of the title compound
[1-carboxymethyloxy-2,3,4,-
6-tetra-O-benzyl-.beta.-D-gluocopyranoside], described in Patent
Application DE 197 28 954 C1 under Example 46a), and 3.24 g (28.14
mmol) of N-hydroxysuccinimide are dissolved in 100 ml of
dimethylformamide and mixed in portions at 0.degree. C. with a
total of 5.80 g (28.14 mmol) of N,N'-dicyclohexylcarbodiimide. It
is stirred for 3 more hours at this temperature. A solution, cooled
to 0.degree. C., of 11.13 g (13.4 mmol) of the title compound of
Example 21c), dissolved in 50 ml of dimethylformamide, is added
drop by drop to the thus produced active ester solution, and it is
stirred for 2 hours at 0.degree. C. and for 12 hours at room
temperature. For working-up, precipitated dicyclohexylurea is
filtered out, and the solvent is then drawn off until a dry state
is reached. The thus obtained residue is then chromatographed on
silica gel (mobile solvent:dichloromethane/ethanol, 20:1;
chromatography was carried out with use of a solvent gradient with
continuous increase of the ethanol content).
[0998] Yield: 12.67 g (67.0% of theory) of the title compound in
the form of a colorless and strongly viscous oil.
[0999] Elementary analysis: Cld: C, 52.77; H, 4.50; N, 3.97; F,
22.89; S, 2.27. Fnd: C, 52.75; H, 4.61; N, 3.98; F, 22.94; S,
2.26.
b)
2-N-(1-O-.beta.-D-Carbonylmethyl-glucopyranose)-L-lysine-[1-(4-perfluor-
ooctylsulfonyl)-piperazine]-amide
[1000] 11.52 g (8.17 mmol) of the compound that is produced under
47a) is dissolved in 100 ml of ethanol, mixed with 0.5 g of
Pearlman's catalyst (Pd 20%, C), and hydrogenated at room
temperature under a hydrogen atmosphere (1 atm) until no more
hydrogen absorption can be observed. Catalyst is suctioned out, it
is thoroughly rewashed with ethanol (three times with about 40 ml
in each case), and evaporated to the dry state in a vacuum. The
title compound is obtained as a strongly viscous and colorless
oil.
[1001] Yield: 7.36 g (98.4% of theory).
[1002] Elementary analysis: Cld: C, 34.07; H, 3.63; N, 6.11; F,
35.24; S, 3.50. Fnd: C, 34.11; H, 3.59; N, 6.08; F, 35.23; S,
3.52.
c)
2-N-(1-O-.beta.-D-Carbonylmethyl-glucopyranose)-6-N-[1,4,7-tris(carboxy-
latomethyl)-10-(aza-4-oxo-5-methyl-5-yl-pentanoyl)-1,4,7,10-tetraazacyclod-
odecane]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide,
Gd complex
[1003] 9.98 g [(15.84 mmol; 2.2 molar equivalents relative to the
amine component of Example 47b) that is used] of the Gd complex,
described in Patent Application DE 197 28 954 C1 under Example
31h), of
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1-
,4,7-triacetic acid and 0.67 g (15.84 mmol) of anhydrous lithium
chloride are dissolved at 40.degree. C. in 80 ml of absolute
dimethyl sulfoxide while being stirred, and it is mixed at this
temperature with a total of 1.82 g (15.84 mmol) of
N-hydroxysuccinimide and 7.25 g (7.19 mmol) of the title compound
of Example 47b), dissolved in 30 ml of absolute dimethyl sulfoxide.
After cooling to room temperature, the reaction solution is mixed
with 3.27 g (15.84 mmol) of N,N'-dicyclohexylcarbodiimide, and it
is stirred for 12 hours at room temperature. The suspension that is
obtained is then mixed with sufficient acetone until the
above-mentioned title compound is completely precipitated, the
precipitate is suctioned off, taken up in water, insoluble
dicyclohexylurea is filtered out, and the filtrate is desalinated
with an AMICON.RTM. YM-3 ultrafiltration membrane (cut-off 3,000
Da), and low-molecular components are removed. The retentate is
then freeze-dried.
[1004] Yield: 9.11 g (83.0% of theory) as a colorless
lyophilizate.
[1005] H.sub.2O content (according to Karl-Fischer): 4.02%.
[1006] Elementary analysis (relative to anhydrous substance): Cld:
C, 35.37; H, 4.02; N, 8.25; F, 21.13; S, 2.10; Gd, 10.29. Fnd: C,
35.42; H, 4.07; N, 8.18; F, 21.09; S, 2.06; Gd, 10.34.
EXAMPLE 48
a)
2-N-Trifluoroacetyl-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]--
amide
[1007] 10.0 g (11.46 mmol) of the compound, produced under 21b), is
dissolved in 100 ml of ethanol, mixed with 1.0 g of Pearlman's
catalyst (Pd 20%/C) and hydrogenated until quantitative hydrogen
uptake is reached. Catalyst is suctioned out, it is rewashed with
ethanol and evaporated to the dry state in a vacuum. The title
compound is obtained as a viscous and colorless oil.
[1008] Yield: 8.85 g (97.5% of theory).
[1009] Elementary analysis: Cld: C, 30.31; H, 2.54; N, 7.07; F,
47.95; S, 4.05. Fnd: C, 30.36; H, 2.50; N, 7.11; F, 47.99; S,
4.00.
b)
2-N-Trifluoroacetyl-6-N-[1-O-.alpha.-D-(5-carbonyl)-pentyl-2,3,4,6-tetr-
a-O-benzyl-mannopyranose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazin-
e]-amide
[1010] A solution of 27.51 g (36.6 mmol) of the title compound of
Example 37c) in 150 ml of dimethylformamide is added in drops to a
solution, cooled to 0.degree. C., that consists of 29.0 g (36.6
mmol) of the title compound of Example 48a) and 4.05 g (40.26 mmol)
of triethylamine in 100 ml of dimethylformamide. After addition is
completed, it is stirred for one more hour at 0.degree. C. and then
overnight at room temperature. It is evaporated to the dry state in
a vacuum, and the residue is taken up in 300 ml of ethyl acetate.
Insoluble components are filtered out, and the filtrate is washed
twice with 100 ml each of 5% aqueous soda solution. The organic
phase is dried on magnesium sulfate and evaporated to the dry state
in a vacuum. The residue is chromatographed on silica gel (mobile
solvent: n-hexane/isopropanol 25:1). 42.05 g (80.4% of theory) of
the title compound is obtained in the form of a colorless oil.
[1011] Elementary analysis: Cld: C, 50.42; H, 4.51; N, 7.96; F,
26.59; S, 2.24. Fnd: C, 50.38; H, 4.50; N, 7.91; F, 26.62; S,
2.20.
c)
6-N-[1-O-.alpha.-D-(5-Carbonyl)-pentyl-2,3,4,6-tetra-O-benzyl-mannopyra-
nose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide
[1012] 20.0 g (14.0 mmol) of the compound that is produced under
Example 48b) is dissolved in 150 ml of ethanol. The solution of 2.8
g (70.0 mmol) of sodium hydroxide in 25 ml of distilled water is
then added to it, and it is stirred for 0.5 hour at 50.degree. C.
According to the thin-layer chromatogram, the protective group
cleavage is already carried out quantitatively at this time. It is
evaporated to the dry state in a vacuum, and traces of water are
removed by repeated co-distillation with ethanol. The residue is
chromatographed on silica gel (mobile solvent: n-hexane/isopropanol
20:1). 16.66 g (89.3% of theory) of the title compound is obtained
in the form of a colorless oil.
[1013] Elementary analysis: Cld: C, 52.25; H, 4.91; N, 4.20; F,
24.22; S, 2.41. Fnd: C, 52.30; H, 4.90; N, 4.18; F, 24.22; S,
2.38.
d)
6-N-[1-O-.alpha.-D-(5-Carbonyl)-pentyl-mannopyranose]-L-lysine-[1-(4-pe-
rfluorooctylsulfonyl)-piperazine]-amide
[1014] 15.0 g (11.25 mmol) of the compound that is produced under
48c) is dissolved in 150 ml of a 10:1 mixture that consists of
ethanol and water, and it is mixed with 1.0 g of Pearlman's
catalyst (Pd 20%/C). Then, it is hydrogenated until quantitative
hydrogen uptake is reached at room temperature and under one
atmosphere of hydrogen pressure. Catalyst is suctioned out, it is
rewashed with ethanol/water (10:1) and evaporated to the dry state
in a vacuum. The title compound is obtained as a viscous and
colorless oil.
[1015] Yield: 10.77 g (98.4% of theory).
[1016] Elementary analysis: Cld: C, 37.04; H, 4.25; N, 5.76; F,
33.20; S, 3.30. Fnd: C, 37.06; H, 4.20; N, 5.81; F, 33.19; S,
3.30.
e)
6-N-[1-O-.alpha.-D-(5-Carbonyl)-pentyl-mannopyranose]-2-N-[1,4,7-tris(c-
arboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)-1,4,7,10-tetraa-
zacyclododecane]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide,
Gd complex
[1017] 5.54 g [(8.8 mmol; 2.2 molar equivalents relative to the
amine component of Example 48d) that is used] of the Gd complex,
described in Patent Application DE 197 28 954 C1 under Example
31h), of
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1-
,4,7-triacetic acid and 0.37 g (8.8 mmol) of anhydrous lithium
chloride are dissolved at 40.degree. C. in 60 ml of absolute
dimethyl sulfoxide while being stirred and mixed at this
temperature with a total of 1.01 g (8.8 mmol) of
N-hydroxysuccinimide and 3.89 g (4.0 mmol) of the title compound of
Example 48d), dissolved in 60 ml of absolute dimethyl sulfoxide.
After cooling to room temperature, the reaction solution is mixed
with 1.82 g (8.8 mmol) of N,N'-dicyclohexylcarbodiimide and stirred
for 12 hours at room temperature. The suspension that is obtained
is then mixed with sufficient acetone until the above-mentioned
title compound is completely precipitated, the precipitate is
suctioned off, taken up in water, insoluble dicyclohexylurea is
filtered out, and the filtrate is desalinated with an AMICON.RTM.
YM-3 ultrafiltration membrane (cut-off: 3,000 Da), and
low-molecular components are removed. The retentate is then
freeze-dried.
[1018] Yield: 4.81 g (75.9% of theory) as a colorless
lyophilizate.
[1019] H.sub.2O content (Karl-Fischer): 8.98%.
[1020] Elementary analysis (relative to anhydrous substance): Cld:
C, 37.15; H, 4.39; N, 7.96; F, 20.38; Gd, 9.92; S, 2.02. Fnd: C,
37.27; H, 4.40; N, 8.02; F, 20.31; Gd, 10.00; S, 1.98.
EXAMPLE 49
a)
1,7-Bis(benzyloxycarbonyl)-4-(1-O-.beta.-D-carbonylmethyl-2,3,4,6-tetra-
-O-benzyl-galactopyranose)-10-{3-oxa-pentane-1,5-dicarboxylic
acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide]-1,4,7,10-te-
traazacyclododecane
[1021] 35.80 g (25.0 mmol) of the title compound of Example 37e),
dissolved in 250 ml of tetrahydrofuran, is added at 0.degree. C.
and under nitrogen atmosphere to a solution that consists of 27.0 g
(24.4 mmol) of the sec-amine that is produced under Example 35a),
in a mixture that consists of 150 ml of tetrahydrofuran and 15 ml
of chloroform. Then, a total of 18.0 g (36.6 mmol) of EEDQ
[2-ethoxy-1-ethoxycarbonyl-1,2-dihy- droquinoline] is added in
portions at 0.degree. C., and it is allowed to stir overnight at
room temperature. It is then evaporated to the dry state in a
vacuum, and the remaining oil is chromatographed on silica gel
(mobile solvent: n-hexane/isopropanol 20:1). 32.11 g (78.0% of
theory, relative to the sec-amine that is used) of the title
compound is obtained in the form of a colorless oil.
[1022] Elementary analysis: Cld: C, 54.09; H, 4.72; F, 19.14; N,
4.98; S, 1.90. Fnd: C, 54.12; H, 4.77; F, 19.17; N, 5.03; S,
1.90.
b)
1-(1-O-.beta.-D-Carbonylmethyl-galactopyranose)-7-{3-oxa-pentane-1,5-di-
carboxylic
acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-1-
,4,7,10-tetraazacyclododecane
[1023] In 250 ml of ethanol, 30.0 g (17.77 mmol) of the title
compound that is produced under Example 49a) is dissolved, and it
is mixed with 3.0 g of Pearlman's catalyst (Pd 20%,/C). It is
hydrogenated until quantitative hydrogen uptake is reached,
catalyst is then suctioned out, it is thoroughly rewashed with
ethanol and evaporated to the dry state in a vacuum. The product is
yellowish in color, and extremely viscous oil is obtained.
[1024] Yield: 17.89 g (95.1% oftheory)
[1025] Elementary analysis: Cld: C, 36.30; H, 4.09; F, 30.50; N,
7.94; S, 3.03. Fnd: C, 36.26; H, 4.12; F, 30.46; N, 7.90; S,
3.04.
c)
1-(1-O-.beta.-D-Carbonylmethyl-galactopyranose)-7-{3-oxa-pentane-1,5-di-
carboxylic
acid-1-oyl-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide}-4-
,10-bis[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pentan-
oyl)-1,4,7,10-tetraazacyclododecane]-1,4,7,10-tetraazacyclododecane,
di-gadolinium complex
[1026] 5.54 g [8.8 mmol; 4.4 molar equivalents relative to the
amine component of Example 49b) that is used] of the Gd complex,
described in Patent Application DE 197 28 954 C1 under Example
31h), of
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1-
,4,7-triacetic acid and 0.37 g (8.8 mmol) of anhydrous lithium
chloride are dissolved at 40.degree. C. in 60 ml of absolute
dimethyl sulfoxide while being stirred and mixed at this
temperature with a total of 1.01 g (8.8 mmol) of
N-hydroxysuccinimide and 2.11 g (2.0 mmol) of the title compound of
Example 49b), dissolved in 25 ml of absolute dimethyl sulfoxide.
After cooling to room temperature, the reaction solution is mixed
with 1.82 g (8.8 mmol) of N,N'-dicyclohexylcarbodiimide and stirred
for 12 hours at room temperature. The suspension that is obtained
is then mixed with sufficient acetone until the above-mentioned
title compound is completely precipitated, the precipitate is
suctioned off, dried, taken up in water, insoluble dicyclohexylurea
is filtered out, and the filtrate is desalinated with an
AMICON.RTM. YM-3 ultrafiltration membrane (cut-off 3,000 Da), and
low-molecular components are removed. The retentate is then
freeze-dried.
[1027] Yield: 3.29 g (72.2% of theory; relative to the amine
component that is used) as a colorless lyophilizate.
[1028] H.sub.2O content (Karl-Fischer): 5.99%.
[1029] Elementary analysis (relative to anhydrous substance): Cld:
C, 36.84; H, 4.37; N, 9.82; F, 14.15; Gd, 19.63; S, 1.40. Fnd: C,
36.87; H, 4.40; N, 9.82; F, 14.09; Gd, 19.59; S, 1.38.
EXAMPLE 50
a)
3-(1-O-.alpha.-D-2,3,4,6-Tetra-O-benzyl-mannopyranose)-2-N-benzyloxycar-
bonyl-L-serine-methyl ester
[1030] 21.42 g (39.61 mmol) of
2,3,4,6-tetra-O-benzyl-.alpha.-D-mannopyran- ose (production
according to: F. Kong et al., J. Carbohydr. Chem.; 16; 6; 1997;
877-890) is dissolved in 500 ml of dry acetonitrile. After the
reaction solution is cooled to 5.degree. C., a solution of 13.23 g
(59.52 mmol) of trifluoromethanesulfonic acid trimethyl silyl ester
in 30 ml of acetonitrile, followed by a solution that consists of
20.06 g (79.21 mmol) of N-benzyloxycarbonyl-L-serine methyl ester
(commercially available from the Bachem Company) in 50 ml of
acetonitrile, are slowly added in drops at this temperature while
being stirred, whereby the rate of addition by drops can be
selected in such a way that an internal temperature of 10.degree.
C. is not exceeded. After a reaction time of 15 hours at room
temperature, the reaction solution is evaporated to the dry state
in a vacuum. The remaining residue is taken up in 250 ml of ethyl
acetate and washed twice with 100 ml each of saturated sodium
bicarbonate solution and once with 200 ml of water. After the
organic phase is dried on sodium sulfate, salt is suctioned out,
and the ethyl acetate is drawn off in a vacuum. The remaining oily
residue is purified on silica gel with use of ethyl
acetate/n-hexane (1:5) as an eluant.
[1031] Yield: 23.60 g (76.8% of theory) of the above-mentioned
title compound as a colorless oil.
[1032] Elementary analysis: Cld: C, 71.21; H, 6.37; N, 1.81. Fnd:
C, 71.19; H, 6.41; N, 1.79.
b)
3-(1-O-.alpha.-D-2,3,4,6-Tetra-O-benzyl-mannopyranose)-2-N-benzyloxycar-
bonyl-L-serine
[1033] 10.0 g (12.90 mmol) of the compound that is produced under
Example 50a) is dissolved in a mixture that consists of 20 ml of
methanol, 20 ml of water and 50 ml of tetrahydrofuran. 0.47 g
(19.35 mmol) of lithium hydroxide, dissolved in 25 ml of distilled
water, is then added at room temperature, and it is then stirred
for 6 hours at 60.degree. C. After the course of the reaction is
checked by means of thin-layer chromatography (eluant:methylene
chloride/methanol 10:1), saponification of the methyl ester of
Example 30a) has already taken place quantitatively according to
the above-mentioned reaction time. For the purpose of working-up,
the product solution is evaporated to the dry state in a vacuum,
and the remaining residue is taken up in 250 ml of ethyl acetate in
heat (about 60.degree. C.). Then, the thus obtained ethyl acetate
phase is washed twice with 50 ml each of a 15% aqueous hydrochloric
acid, and once with 100 ml of distilled water. The organic phase is
dried on magnesium sulfate, filtered and evaporated to the dry
state in a vacuum. The residue is chromatographed on silica gel
(mobile solvent:n-hexane/ethyl acetate 5:1). 8.40 g (85.7% of
theory) of the title compound is obtained in the form of a
colorless oil.
[1034] Elementary analysis: Cld: C, 70.94; H, 6.22; N, 1.84. Fnd:
C, 70.97; H, 6.30; N, 1.78.
c)
3-(1-O-.alpha.-D-2,3,4,6-Tetra-O-benzyl-mannopyranose-2-N-benzyloxycarb-
onyl-L-serine-[1-(4-perfluorooctylsulfonyl)piperazine]-amide
[1035] 20.57 g (27.0 mmol) of the carboxylic acid, produced
according to Example 50b) and dissolved in 50 ml of
tetrahydrofuran, is added drop by drop at 0.degree. C. and under
nitrogen atmosphere to 13.86 g (24.40 mmol) of
1-perfluorooctylsulfonyl-piperazine (produced according to DE
19603033), dissolved in a mixture that consists of 150 ml of
tetrahydrofuran and 15 ml of chloroform. Then, a total of 18.0 g
(36.60 mmol) of EEDQ
[2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is added in
portions at 0.degree. C., and it is allowed to stir overnight at
room temperature. For the purpose of working-up, the reaction
solution is concentrated by evaporation in a vacuum, and the
remaining, extremely viscous oil is chromatographed on silica gel
with use of an n-hexane/isopropanol (15:1) mixture as an eluant
system. 17.0 g (79.6% of theory, relative to the primary amine that
is used) of the title compound is obtained in the form of a
colorless and viscous oil.
[1036] Elementary analysis: Cld: C, 51.53; H, 4.23; N, 3.15; F,
25.65; S, 2.41. Fnd: C, 51.48; H, 4.27; N, 3.10; F, 25.71; S,
2.35.
d)
3-(1-O-.alpha.-D-Mannopyranose)-L-serine-[1-(4-perfluorooctylsulfonyl)p-
iperazine]-amide
[1037] 15.0 g (11.41 mmol) of the compound that is produced
according to Example 50c) is dissolved in 200 ml of ethanol, and it
is mixed with 1.5 g of Pearlman's catalyst (Pd 20%, C). Then, the
reaction solution is hydrogenated at room temperature under a
hydrogen atmosphere (1 atm) until no more hydrogen absorption can
be observed (about 8 hours). For the purpose of working-up,
catalyst is suctioned out, it is thoroughly rewashed with ethanol
(twice with about 100 ml each), and the product-containing
ethanolic filtrate is evaporated to the dry state in a vacuum. The
title compound is obtained as a strongly viscous and colorless
oil.
[1038] Yield: 8.79 g (94.0% of theory).
[1039] Elementary analysis: Cld: C, 30.78; H, 3.20; N, 5.13; F,
39.41; S, 3.91. Fnd: C, 30.87; H, 3.14; N, 5.19; F, 39.50; S,
3.88.
e)
3-(1-O-.alpha.-D-Mannopyranose)-2-N-[1,4,7-tris(carboxylatomethyl)-10-(-
3-aza-4-oxo-5-methyl-5-yl-pentanoyl)-1,4,7,10-tetraazacyclododecane]-L-ser-
ine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex
[1040] A stirred suspension of 5.7 g [9.06 mmol; corresponding to
1.5 molar equivalents relative to the title compound (primary
amine) of Example 50d) that is used] of the Gd complex, described
in Patent Application DE 197 28 954 C1 under Example 31h), of
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1-
,4,7-triacetic acid in 75 ml of absolute dimethyl sulfoxide is
mixed at 70.degree. C. with 0.68 g (15.9 mmol) of lithium chloride.
After 30 minutes of stirring at 70.degree. C., the now clear
reaction solution is mixed in portions with a total of 1.83 g (15.9
mmol) of N-hydroxysuccinimide, and the reaction mixture is kept for
1 more hour at 70.degree. C. After the reaction solution is cooled
to 10.degree. C., it is mixed with 4.52 g (23.85 mmol) of
dicyclohexylcarbodiimide, and the reaction solution is stirred for
another hour at 0.degree. C., followed by 12 hours at 22.degree. C.
The thus obtained solution of N-hydroxysuccinimide ester of the Gd
complex of 10-(4-carboxy-1-methyl-2--
oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid
is now mixed at 22.degree. C. drop by drop with a solution of 4.94
g (6.03 mmol) of the title compound of Example 30d), in 15 ml of
absolute dimethyl sulfoxide, and it is stirred for another 12 hours
at room temperature. For working-up, the reaction solution is
slowly added in drops at 22.degree. C. in a solvent mixture that
consists of 250 ml of acetone and 250 ml of 2-propanol, whereby the
title compound has settled completely as a light yellowish-colored
oil after 12 hours at 10.degree. C. Supernatant eluant mixture is
carefully decanted out, and the oily product is taken up in 200 ml
of distilled water, whereby the latter goes completely into
solution in such a way that a light yellowish-colored aqueous
solution of the above-mentioned title compound is obtained.
Subsequently, the aqueous product solution is first filtered with a
membrane filter and then, for the purpose of desalination and
separation of low-molecular components, it is ultrafiltered three
times with a YM3-ultrafiltration membrane (AMICON.RTM.: cut-off:
3,000 Da). The thus obtained retentate is then freeze-dried.
[1041] Yield: 8.63 g (80.2% of theory, relative to the title
compound of Example 30d) that is used) as a colorless lyophilizate
with a water content of 7.65%.
[1042] Elementary analysis (relative to anhydrous substance): Cld:
C, 33.57; H, 3.80; N, 7.83; F, 22.57; Gd, 10.99; S, 2.24. Fnd: C,
33.57; H, 3.76; N, 7.82; F, 22.63; Gd, 11.06; S, 2.18.
EXAMPLE 51
a) 6-N-Benzyloxycarbonyl-2-N-[O-.beta.-D-galactopyranosyl
(1.fwdarw.4)-gluconosyl]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazin-
e]-amide
[1043] A solution of 13.3 g (37.2 mmol) of
O-.beta.-D-galactopyranosyl-(1.- fwdarw.4)-D-glucono-1,5-lactone
[lactobionolactone; production according to: (a) Williams, T. J.;
Plessas, N. R.; Goldstein, I. J. Carbohydr. Res. 1978, 67, Cl. (b)
Kobayashi, K.; Sumitomo, H.; Ina, Y. Polym. J. 1985, 17, 567, (c)
Hiromi Kitano, Katsuko Sohda, and Ayako Kosaka, Bioconjugate Chem.
1995, 6 131-134] in 40 ml of absolute dimethyl sulfoxide is added
drop by drop at room temperature to a stirred solution of 4.98 g
(6.0 mmol) of the title compound of Example 21c) in 40 ml of
absolute dimethyl sulfoxide. The thus obtained reaction solution is
then stirred for 14 hours at 40.degree. C. For working-up, it is
mixed at room temperature with 500 ml of absolute 2-propanol, and
the resulting colorless precipitate is suctioned off by means of a
G4 frit and thoroughly rewashed with a total of 250 ml of absolute
2-propanol. The thus obtained solid is now dissolved in 300 ml of
distilled water and ultrafiltered a total of three times with a
YM3-ultrafiltration membrane (AMICON.RTM.: cut-off: 3,000 Da). By
the third time of the ultrafiltration process, both the excess
lactobionolactone and also possibly still present low-molecular
components are separated from the desired product. The residue that
remains in the ultrafiltration membrane is subsequently dissolved
completely in 300 ml of distilled water and freeze-dried.
[1044] Yield: 6.51 g (92.7% of theory) as a colorless
lyophilizate
[1045] Water content: 10.03%
[1046] Elementary analysis (relative to anhydrous substance): Cld:
C, 38.98; H, 4.05; N, 4.79; F, 27.58; S, 2.74. Fnd: C, 39.04; H,
4.09; N, 4.82; F, 27.61; S, 2.71.
b) 2-N-[O-.beta.-D-Galactopyranosyl
(1.fwdarw.4)-gluoconosyl]-L-lysine-[1--
(4-perfluorooctylsulfonyl)-piperazine]-amide
[1047] 5.0 g (4.27 mmol) of the compound that is produced under 5
la) is dissolved in 100 ml of ethanol, mixed with 0.5 g of
Pearlman's catalyst (Pd 20%, C) and hydrogenated until quantitative
hydrogen uptake is reached at 1 atmosphere of hydrogen pressure.
Catalyst is suctioned out, rewashed with ethanol and evaporated to
the dry state in a vacuum. The title compound is obtained as a
colorless and viscous oil.
[1048] Yield: 4.36 g (98.5% of theory).
[1049] Elementary analysis: Cld: C, 34.76; H, 3.99; N, 5.40; F,
31.51; S, 3.09. Fnd: C, 34.78; H, 4.04; N, 5.34; F, 31.51; S,
3.15.
c)
2-N-[O-.beta.-D-Galactopyranosyl(1.fwdarw.4)-gluoconosyl]-6-N-[1,4,7-tr-
is(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pentanoyl)-1,4,7,10-te-
traazacyclododecane]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-am-
ide, Gd complex
[1050] 5.54 g [(8.8 mmol; 2.2 molar equivalents relative to the
amine component of Example 51b) that is used] of the Gd complex,
described in Patent Application DE 197 28 954 C1 under Example
31h), of
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1-
,4,7-triacetic acid and 0.37 g (8.8 mmol) of anhydrous lithium
chloride are dissolved at 40.degree. C. in 60 ml of absolute
dimethyl sulfoxide while being stirred and mixed at this
temperature with a total of 1.01 g (8.8 mmol) of
N-hydroxysuccinimide and 3.85 g (4.0 mmol) of the title compound of
Example 31Ab), dissolved in 60 ml of absolute dimethyl sulfoxide.
After cooling to room temperature, the reaction solution is mixed
with 1.82 g (8.8 mmol) of N,N'-dicyclohexylcarbodiimide and stirred
for 12 hours at room temperature. The suspension that is obtained
is then mixed with sufficient acetone/2-propanol (1:1) until the
above-mentioned title compound is completely precipitated, and the
precipitate is suctioned off. The thus obtained precipitate is
subsequently taken up in 300 ml of water, and insoluble
dicyclohexylurea is filtered out. The filtrate is ultrafiltered
three times with an AMICON.RTM. YM-3 ultrafiltration membrane
(cut-off: 3,000 Da). By the third time that the ultrafiltration
process is performed, both the excess Gd complex and possibly still
present, low-molecular components are separated from the desired
product. The residue that remains in the ultrafiltration membrane
is subsequently completely dissolved in 500 ml of distilled water
and freeze-dried.
[1051] Yield: 4.64 g (70.4% of theory) as a colorless
lyophilizate.
[1052] H.sub.2O content (Karl-Fischer): 10.08%.
[1053] Elementary analysis (relative to anhydrous substance): Cld:
C, 35.70; H, 4.22; N, 7.65; F, 19.59; Gd, 9.54; S, 1.95. Fnd: C,
35.77; H, 4.17; N, 7.71; F, 19.61; Gd, 9.60; S, 1.99.
EXAMPLE 52
a) 2-N-Trifluoroacetyl-6-N-benzyloxycarbonyl-lysine
[1054] 100 g (356.7 mmol) of 6-N-benzyloxycarbonyl-lysine is
dissolved in a mixture that consists of 1000 ml of trifluoroacetic
acid ethyl ester/500 ml of ethanol, and it is stirred for 24 hours
at room temperature. It is evaporated to the dry state, and the
residue is crystallized from diisopropyl ether.
[1055] Yield: 128.9 g (96% of theory) of a colorless, crystalline
powder.
[1056] Elementary analysis: Cld: C, 51.07; H, 5.09; F, 15.14; N,
7.44. Fnd: C, 51.25; H, 5.18; F, 15.03; N, 7.58.
b)
2-N-Trifluoroacetyl-6-N-benzyloxycarbonyl-lysine-[1-(4-perfluorooctylsu-
lfonyl)-piperazine]-amide
[1057] 164.2 g (0.664 mmol) of EEDQ
(2-ethoxy-1,2-dihydroquinoline-1-carbo- xylic acid ethyl ester) is
added at 0.degree. C. to 125 g (332 mmol) of the title compound of
Example 52a) and 188.7 g (332 mmol) of
1-perfluorooctylsulfonyl-piperazine (produced according to DE
19603033) in 800 ml of tetrahydrofuran, and it is stirred overnight
at room temperature. It is evaporated to the dry state in a vacuum
and chromatographed on silica gel (mobile
solvent:dichloromethane/methanol=20- :1).
[1058] Yield: 286 g (93% of theory) of a colorless solid.
[1059] Elementary analysis: Cld: C, 36.30; H, 2.83; F, 41.01; N,
6.05; S, 3.46. Fnd: C, 36.18; H, 2.94; F, 40.87; N, 5.98; S,
3.40.
c)
6-N-Benzyloxycarbonyl-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]--
amide
[1060] Ammonia gas is introduced at 0.degree. C. for one hour into
a solution that consists of 280 g (302.2 mmol) of the title
compound of Example 52b) in 2000 ml of ethanol. It is then stirred
for 4 hours at 0.degree. C. It is evaporated to the dry state, and
the residue is absorptively precipitated from water. The solid is
filtered off and dried in a vacuum (50.degree. C.).
[1061] Yield: 243.5 g (97% of theory) of an amorphous solid.
[1062] Elementary analysis: Cld: C, 37.60; H, 3.28; F, 38.89; N,
6.75; S, 3.86. Fnd: C, 37.15; H, 3.33; F, 38.78; N, 6.68; S,
3.81.
d)
6-N-Benzyloxycarbonyl-2-N-(3,6,9,12,15-pentaoxahexadecanoyl)-lysine[1-(-
4-perfluorooctylsulfonyl)-piperazine]-amide
[1063] A solution that consists of 19.93 g (70 mmol) of 3,6,9,12,15
pentaoxahexadecanoic acid chloride [produced according to Liebigs
Ann. Chem. (1980), (6), 852-62] in 50 ml of dichloromethane is
added in drops at 0.degree. C. to 50 g (60.20 mmol) of the title
compound of Example 52c) and 7.10 g (70 mmol) of triethylamine,
dissolved in 350 ml of dichloromethane, and it is stirred for 3
hours at 0.degree. C. 200 ml of 5% aqueous hydrochloric acid is
added, and it is stirred for 5 minutes at room temperature. The
organic phase is separated, dried on magnesium sulfate and
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile
solvent:dichloromethane/acetone=15:- 1).
[1064] Yield: 53.7 g (93% of theory) of a colorless, viscous
oil.
[1065] Elementary analysis: Cld: C, 33.83; H, 4.94; F, 3.34; N,
5.84; S, 33.69. Fnd: C, 33.75; H, 5.05; F, 3.29; N, 5.78; S,
33.75.
e)
2-N-(3,6,9,12,15-Pentaoxahexadecanoyl)-lysine[1-(4-perfluorooctylsulfon-
yl)-piperazine]-amide
[1066] 50 g (52.15 mmol) of the title compound of Example 52d) is
dissolved in 500 ml of ethanol, and 6 g of palladium catalyst (10%
Pd/C) is added. It is hydrogenated at room temperature. Catalyst is
filtered out, and the filtrate is evaporated to the dry state in a
vacuum.
[1067] Yield: 43.0 g (quantitative) of a colorless solid.
[1068] Elementary analysis: Cld: C, 27.68; H, 5.01; F, 39.17; N,
6.79; S, 3.89. Fnd: C, 27.60; H, 5.13; F, 39.09; N, 6.68; S,
3.81.
f)
6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(p-
entanoyl-3-aza-4-oxo-5-methyl-5-yl)]-2-N-(3,6,9,12,15-pentaoxahexadecanoyl-
)-lysine[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd
complex
[1069] 20 g (24.25 mmol) of the title compound of Example 52e),
2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of
lithium chloride and 15.27 g (24.25 mmol) of
1,4,7-tris(carboxylatomethyl)-10-[(3-
-aza-4-oxo-5-methyl-5-yl)]-pentanoic
acid]-1,4,7,10-tetraazacyclododecane, Gd complex are dissolved in
200 ml of dimethyl sulfoxide while being heated slightly. At
10.degree. C., 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is
added, and it is then stirred overnight at room temperature. The
solution is poured into 3000 ml of acetone, and it is stirred for
10 minutes. The precipitated solid is filtered off and then
purified by chromatography (silica gel RP-18, mobile solvent:
gradient that consists of water/ethanol/acetonitrile).
[1070] Yield: 28.21 g (81% of theory) of a colorless solid.
[1071] Water content: 11.0%
[1072] Elementary analysis (relative to anhydrous substance): Cld:
C, 31.78; H, 4.84; F, 22.49; N, 8.78; S, 2.23; Gd, 10.95. Fnd: C,
31.74; H, 4.98; F, 22.39; N, 8.69; S, 2.15; Gd, 10.87.
EXAMPLE 53
a)
6-N-[3,9-Bis(t-butyloxycarbonylmethyl)-3,6,9-triazaundecane-1,11-dicarb-
oxylic acid bis(t
butylester)-6-carbonylmethyl]-2-N-[3,6,9,12,15-pentaoxah-
exadecanoyl)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide
[1073] 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is added at
0.degree. C. to a solution that consists of 20 g (24.08 mmol) of
the title compound of Example 52e), 14.88 g (24.08 mmol) of
3,9-bis(t
butyloxycarbonylmethyl-3,6,9-triazaundecane-1,11-dicarboxylic
acid-bis(t butylester) and 2.77 g (24.08 mmol) of
N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide. It
is stirred for 3 hours at 0.degree. C., then overnight at room
temperature. Precipitated urea is filtered out, the filtrate is
evaporated to the dry state in a vacuum and chromatographed on
silica gel (mobile solvent:=dichloromethane/ethanol=20- :1).
[1074] Yield: 31.61 g (91% of theory) of a viscous oil.
[1075] Elementary analysis: Cld: C, 40.80; H, 6.71; F, 22.39; N,
6.80; S, 2.22. Fnd: C, 40.72; H, 6.82; F, 22.30; N, 6.75; S,
2.14.
b)
6-N-[6-Carbonylmethyl-3,9-bis(carboxylatomethyl)-3,6,9-triazaundecanedi-
carboxylic
acid-1-carboxy-11-carboxylato-]-2-N-(3,6,9,12,15-pentaoxahexade-
canoyl)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd
complex, sodium salt
[1076] 30 g (20.8 mmol) of the title compound of Example 53a) is
dissolved in 300 ml of trifluoroacetic acid, and it is stirred for
5 hours at room temperature. It is evaporated to the dry state, the
residue is taken up in 300 ml of water, and it is set at a pH of
2.5 with 10% aqueous NaOH. Then, 3.77 g (10.4 mmol) of gadolinium
oxide is added, and it is stirred for 3 hours at 60.degree. C. It
is allowed to reach room temperature, and it is set at a pH of 7.4
with sodium hydroxide solution. It is evaporated to the dry state,
and the residue is purified on silica gel RP-18 (mobile solvent:
gradient that consists of water/acetonitrile).
[1077] Yield: 19.18 g (67% of theory) of a colorless, amorphous
solid.
[1078] Water content: 9.8%
[1079] Elementary analysis (relative to anhydrous substance): Cld:
C, 28.80; H, 4.25; F, 23.47; N, 7.12; S, 2.33; Gd, 11.48; Na, 1.67.
Fnd: C, 28.67; H, 4.34; F, 23.38; N, 7.03; S, 2.27; Gd, 11.37; Na,
1.74.
EXAMPLE 54
a) Lysine-[1-(4-perfluorooctylsulfonyl-piperazine]-amide
[1080] 20 g (24.08 mmol) of the title compound of Example 52c) is
dissolved in 300 ml of ethanol, and 4 g of palladium catalyst (10%
Pd/C) is added. It is hydrogenated at room temperature. Catalyst is
filtered out, and the filtrate is evaporated to the dry state in a
vacuum.
[1081] Yield: 16.77 g (quantitative) of a colorless solid.
[1082] Elementary analysis: Cld: C, 31.04; H, 3.04; F, 46.38; N,
8.04; S, 4.60. Fnd: C, 30.97; H, 3.15; F, 46.31; N, 7.98; S,
4.51.
b)
2,6-N,N'-Bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododeca-
ne-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-lysine-[1-(4-perfluorooctylsu-
lfonyl-piperazine]-amide, Gd complex (metal complex XVI)
[1083] 10 g (14.36 mmol) of the title compound of Example 54a),
3.34 g (29 mmol) of N-hydroxysuccinimide, 2.54 g (mmol) of lithium
chloride and 18.26 g (29 mmol) of
1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-meth- yl-5yl)
1,4,7,10-tetraazacyclododecane-Gd complex are dissolved in 200 ml
of dimethyl sulfoxide while being heated slightly. At 10.degree.
C., 12.38 g (60 mmol) of N,N-dicyclohexylcarbodiimide is added, and
it is then stirred overnight at room temperature. The solution is
poured into 3000 ml of acetone and stirred for 10 minutes. The
precipitated solid is filtered off and then purified by
chromatography (silica gel RP-18, mobile solvent: gradient that
consists of water/ethanol/acetonitrile).
[1084] Yield: 19.02 g (69% of theory) of a colorless solid
[1085] Water content: 11.3%
[1086] Elementary analysis (relative to anhydrous substance): Cld:
C, 35.03; H, 4.04; F, 16.82; N, 10.21; S, 1.67; Gd, 16.38. Fnd: C,
34.96; H, 4.13; F, 16.74; N, 10.16; S, 1.61; Gd, 16.33.
EXAMPLE 55
a) 2-[4-(3-Oxapropionic acid ethyl ester)]-phenylacetic acid methyl
ester
[1087] 233.8 g (1.4 mol) of 2-bromoacetic acid-ethyl ester is added
to 200 g (1.204 mol) of 4-hydroxyphenylacetic acid methyl ester,
212 g (2 mol) of sodium carbonate in 2000 ml of acetone, and it is
refluxed for 5 hours. The solid is filtered off, and it is
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:-n-hexane/ethyl
acetate=15:1).
[1088] Yield: 288.5 g (95% of theory) of a colorless oil.
[1089] Elementary analysis: Cld: C, 61.90; H, 6.39. Fnd: C, 61.75;
H, 6.51.
b) 2-[4-(3-Oxapropionic acid ethyl ester)]-phenyl-2-bromoacetic
acid methyl ester
[1090] 201 g (1.13 mol) of N-bromosuccinimide and 100 mg of
dibenzylperoxide are added to 285 g (1.13 mol) of the title
compound of Example 55a), dissolved, in 2000 ml of carbon
tetrachloride, and it is refluxed for 8 hours. It is cooled in an
ice bath, the precipitated succinimide is filtered off, and the
filtrate is evaporated to the dry state in a vacuum. The residue is
purified on silica gel (mobile solvent:n-hexane/acetone=15:1).
[1091] Yield: 359.2 g (96% of theory) of a colorless, viscous
oil.
[1092] Elementary analysis: Cld: C, 47.28; H, 4.57; Br, 24.16. Fnd:
C, 47.19; H, 4.71; Br, 24.05.
c) 2-[4-(3-Oxapropionic acid ethyl
ester)]-phenyl-2-[1-(1,4,7,10-tetraazac- yclododecan-7-yl]-acetic
acid methyl ester
[1093] 350 g (1.057 mol) of the title compound of Example 55b) is
added to 603 g (3.5 mol) of 1,4,7,10-tetraazacyclododecane in 6000
ml of chloroform, and it is stirred overnight at room temperature.
It is extracted 3 times with 3000 ml of water, the organic phase is
dried on magnesium sulfate and evaporated to the dry state in a
vacuum. The residue is used without further purification in the
next reaction (3d).
[1094] Yield: 448 g (quantitative) of a viscous oil.
[1095] Elementary analysis: Cld: C, 59.70; H, 8.11; N, 13.26. Fnd:
C, 59.58; H, 8.20; N, 13.18.
d) 2-[4-(3-Oxapropionic
acid)]-phenyl-2-[1,4,7-tris(carboxymethyl)-1,4,7,1-
0-tetraaza-cyclododecan-10-yl]-acetic acid
[1096] 445 g (1.053 mol) of the title compound of Example 55c) and
496 g (5.27 mol) of chloroacetic acid are dissolved in 4000 ml of
water. It is set with 30% aqueous sodium hydroxide solution to a pH
of 10. It is heated to 70.degree. C., and the pH is kept at 10 by
adding 30% aqueous sodium hydroxide solution. It is stirred for 8
hours at 70.degree. C. It is then set at a pH of 13 and refluxed
for 30 minutes. The solution is cooled in an ice bath and set at a
pH of 1 by adding concentrated hydrochloric acid. It is evaporated
to the dry state in a vacuum. The residue is taken up in 4000 ml of
methanol and absorptively precipitated for one hour at room
temperature. Precipitated common salt is filtered out, the filtrate
is evaporated to the dry state, and the residue is purified on
silica gel.
[1097] RP-18 (mobile solvent: gradient that consists of
water/ethanol/acetonitrile).
[1098] Yield: 403 g (69% of theory) of a colorless solid.
[1099] Water content: 10.2%
[1100] Elementary analysis (relative to anhydrous substance): Cld:
C, 51.98; H, 6.18; N, 10.10. Fnd: C, 51.80; H, 6.31; N, 10.01.
e) 2-[4-(3-Oxapropionic
acid)]-phenyl-2-[1,4,7-tris(carboxymethyl)-1,4,7,1-
0-tetraazacyclododecan-10-yl]-acetic acid, Gd complex
[1101] 130.73 g (360.65 mmol) of gadolinium oxide is added to 400 g
(721.3 mmol) of the title compound of Example 55d) in 2000 ml of
water, and it is stirred for 5 hours at 80.degree. C. The solution
is filtered, and the filtrate is freeze-dried.
[1102] Yield: 511 g (quantitative) of an amorphous solid.
[1103] Water content: 11.0%
[1104] Elementary analysis (relative to anhydrous substance): Cld:
C, 40.67; H, 4.41; Gd, 22.19; N, 7.98. Fnd: C, 40.51; H, 4.52; Gd,
22.05; N, 8.03.
f) 2,6-N,N'-Bis
{2-[4-(3-oxapropionyl)-phenyl]-2-[1,4,7-tris(carboxylatome-
thyl)-1,4,7,10-tetraazacyclododecan-10-yl]-acetic
acid]-lysine-[4-perfluor- ooctylsulfonyl)-piperazine]-amide,
digadolinium complex, disodium salt
[1105] 10 g (14.36 mmol) of the title compound of Example 54a),
3.45 g (30 mmol) of N-hydroxysuccinimide, 2.54 g (60 mmol) of
lithium chloride and 21.26 g (30 mmol) of the title compound of
Example 4Be are dissolved in 250 ml of dimethyl sulfoxide while
being heated slightly. At 10.degree. C., 16.51 g (80 mmol) of
N,N-dicyclohexylcarbodiimide is added, and it is then stirred
overnight at room temperature. The solution is poured into 2000 ml
of acetone and stirred for 10 minutes. The precipitated solid is
filtered off and then purified by chromatography (silica gel RP-18,
mobile solvent: gradient that consists of
water/ethanol/-acetonitrile). It is dissolved in a little water,
set at a pH of 7.4 with sodium hydroxide solution and
freeze-dried.
[1106] Yield: 21.02 g (69% of theory) of a colorless solid.
[1107] Water content: 11.2%
[1108] Elementary analysis (relative to anhydrous substance): Cld:
C, 37.36; H, 3.66; F, 15.22; Gd, 14.82; N, 7.92; Na, 2.71; S, 1.51.
Fnd: C, 37.28; H, 3.74; F, 15.14; Gd, 14.75; N, 8.03; Na, 2.23; S,
1.46.
EXAMPLE 56
a) 2,6-N,N'-Bis[6-carbonylmethyl-3,9-bis(t
butyloxycarbonylmethyl)3,6,9-tr- iazaundecane-1,11-dicarboxylic
acid-bis(t butylester)]-lysine-[1-(4-perflu-
orooctylsulfonyl)-piperazine]-amide
[1109] 10.32 g (50 mmol) of N,N-dicyclohexylcarbodiimide is added
at 0.degree. C. to a solution that consists of 10 g (14.36 mmol) of
the title compound of Example 54a), 18.53 g (30 mmol) of 3,9-bis(t
butyloxycarbonylmethyl)-6-carboxymethyl-3,6,9-triazaundecane-1,11-dicarbo-
xylic acid-bis(t butylester), and 3.45 g (30 mol) of
N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide. It
is stirred for 3 hours at 0.degree. C., then overnight at room
temperature. Precipitated urea is filtered out, the filtrate is
evaporated to the dry state in a vacuum and chromatographed on
silica gel (mobile solvent:dichloromethane/ethanol=20:- 1).
[1110] Yield: 19.60 g (72% of theory) of a viscous oil.
[1111] Elementary analysis: Cld: C, 49.41; H, 6.75; F, 17.03; N,
7.39; S, 1.69. Fnd: C, 49.35; H, 6.82; F, 16.92; N, 7.32; S,
1.62.
b)
2,6-N,N-Bis[6-carbonylmethyl-3,9-bis(carboxylatomethyl)-3,6,9-triazaund-
ecanedicarboxylic
acid-1-carboxy-11-carboxylato-lysine-[1-(4-perfluoroocty-
lsulfonyl)-piperazine]-amide, Gd complex, sodium salt]
[1112] 15 g (7.91 mol) of the title compound of Example 56a) is
dissolved in 50 ml of chloroform, and 200 ml of trifluoroacetic
acid is added. It is stirred for 10 minutes at room temperature. It
is evaporated to the dry state in a vacuum, and the residue is
dissolved in 150 ml of water. 2.87 g (7.91 mmol) of gadolinium
oxide is added, and it is stirred for 5 hours at 80.degree. C. It
is allowed to cool to room temperature and set at pH 7.4 with 2N
sodium hydroxide solution. The solution is evaporated to the dry
state in a vacuum and purified on RP-18 (mobile solvent: gradient
that consists of water/ethanol/acetonitrile).
[1113] Yield: 8.11 g (57% of theory) of a colorless, amorphous
solid.
[1114] Water content: 9.6%
[1115] Elementary analysis (relative to anhydrous substance): Cld:
C, 30.70; H, 3.08; Gd, 17.48; N, 7.78; Na, 2.56; S, 1.78. Fnd: C,
30.58; H, 3.19; Gd, 17.42; N, 7.71; Na, 2.68; S, 1.72.
EXAMPLE 57
a)
6-N-Benzyloxycarbonyl-2-N-[6-carboxymethyl-3,9-bis(t-butyloxycarbonylme-
thyl)-3,6,9-triazaundecane-1,11-dicarboxylic acid-bis(t
butylester)]-lysine-[1(4-perfluorooctylsulfonyl)-piperazine]-amide
[1116] 8.25 g (40 mol) of N,N-dicyclohexylcarbodiimide is added at
0.degree. C. to a solution that consists of 20 g (24.08 mmol) of
the title compound of Example 52c), 14.88 g (24.08 mmol) of
3,9-bis(t
butyloxycarbonylmethyl)-6-carboxymethyl-3,6,9-triazaun-decane-1,11-dicarb-
oxylic acid-bis(t butylester) and 2.88 g (25 mol) of
N-hydroxysuccinimide, dissolved in 100 ml of dimethylformamide. It
is stirred for 3 hours at 0.degree. C., then overnight at room
temperature. Precipitated urea is filtered out, the filtrate is
evaporated to the dry state in a vacuum and chromatographed on
silica gel (mobile solvent:dichloromethane/ethanol=20:- 1).
[1117] Yield: 27.21 g (79% of theory) of a viscous oil
[1118] Elementary analysis: Cld: C, 47.03; H, 5.64; F, 22.58; N,
6.85; S, 2.24. Fnd: C, 46.94; H, 5.58; F, 22.65; N, 6.84; S,
2.31.
b) 2-N-[Carbonylmethyl-3,9-bis(t
butyloxycarbonylmethyl)-3,6,9-triazaundec- ane-1,11-dicarboxylic
acid-bis(t butylester)]-lysine-[1-(4-perfluorooctyls-
ulfonyl)-piperazine]-amide
[1119] 25 g (17.48 mmol) of the title compound of Example 57a) is
dissolved in 350 ml of ethanol, and 5 g of palladium catalyst (10%
Pd/C) is added. It is hydrogenated at room temperature. Catalyst is
filtered out, and the filtrate is evaporated to the dry state in a
vacuum.
[1120] Yield: 22.66 g (quantitative) of a colorless solid.
[1121] Elementary analysis: Cld: C, 44.48; H, 5.75; F, 24.92; N,
7.56; S, 2.47. Fnd: C, 44.59; H, 5.81; F, 25.03; N, 7.46; S,
2.52.
c)
6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(p-
entanoyl-3-aza-4-oxo-5-methyl-5yl)]-2-N-[6-carbonylmethyl-3,9-bis(t
butyloxycarbonylmethyl) 3,6,9-triazaundecane-1,11-dicarboxylic acid
bis (t
butylester)]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine-]-amide,
Gd complex
[1122] 20 g (15.43 mmol) of the title compound of Example 57b),
1.78 g (15.43 mmol) of N-hydroxysuccinimide, 1.48 g (35 mmol) of
lithium chloride and 9.72 g (15.43 mmol) of
1,4,7-tris(carboxylatomethyl)-10-(3-a-
za-4oxo-5-methyl-5yl)-pentanoic
acid-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in
150 ml of dimethyl sulfoxide while being heated slightly. At
10.degree. C., 5.16 g (25 mmol) of N,N-dicyclohexylcarbodiim- ide
is added, and then it is stirred overnight at room temperature. The
solution is poured into 2500 ml of acetone and stirred for 10
minutes. The precipitated solid is filtered off and then purified
by chromatography (silica gel RP-18, mobile solvent: gradient that
consists of water/ethanol/acetonitrile).
[1123] Yield: 22.94 g (78% of theory) of a colorless solid.
[1124] Water content: 7.9%
[1125] Elementary analysis (relative to anhydrous substance): Cld:
C, 42.22; H, 5.29; F, 16.95; Gd, 8.25; N, 8.82; S, 1.68. Fnd: C,
42.15; H, 5.41; F, 16.87; Gd, 8.13; N, 8.70; S, 1.60.
d)
6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(3-
-aza-4-oxo-5-methyl-5-yl-pentanoyl)]-2-N-[6-carbonylmethyl-3,9-bis(carboxy-
latomethyl) 3,6,9-triazaundecanedicarboxylic
acid-carboxy-11-carboxylato-z-
]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide,
digadolinium complex, sodium salt
[1126] 20 g (10.49 mmol) of the title compound of Example 57c) is
dissolved in 200 ml of trifluoroacetic acid. It is stirred for 60
minutes at room temperature. It is evaporated to the dry state in a
vacuum, and the residue is dissolved in 150 ml of water. 1.90 g
(5.25 mmol) of gadolinium oxide is added, and it is stirred for 5
hours at 80.degree. C. It is allowed to cool to room temperature
and set at a pH of 7.4 with sodium hydroxide solution. The solution
is evaporated to the dry state in a vacuum and purified on silica
gel RP-18 (mobile solvent: gradient that consists of
water/ethanol/acetonitrile).
[1127] Yield: 11.89 g (61% of theory) of a colorless, amorphous
solid.
[1128] Water content: 10.2%
[1129] Elementary analysis (relative to anhydrous substance): Cld:
C, 32.97; H, 3.47; F, 17.39; Gd, 16.93; N, 9.05; Na, 1.24; S, 1.73.
Fnd: C, 32.90; H, 3.53; F, 17.31; Gd, 16.87; N, 8.92; Na, 1.33; S,
1.67.
EXAMPLE 58
a) 5,6-Bis(benzyloxy)-3oxa-hexanoic acid-t butylester
[1130] 100 g (376.2 mmol) of 1,2-di-O-benzyl-glycerol [produced
according to Chem. Phys. Lipids (1987), 43(2), 113-277] and 5 g of
tetrabutylammonium hydrogen sulfate are dissolved in a mixture that
consists of 400 ml of toluene and 200 ml of 50% aqueous sodium
hydroxide solution. At 0.degree. C., 78 g (400 mmol) of
2-bromoacetic acid-t butyl ester is added in drops over 30 minutes,
and then it is stirred for 3 hours at 0.degree. C. The organic
phase is separated, dried on magnesium sulfate and evaporated to
the dry state in a vacuum. The residue is chromatographed on silica
gel (mobile solvent:n-hexane/acetone=20:1).
[1131] Yield: 133.4 g (94% of theory) of a colorless oil.
[1132] Elementary analysis: Cld: C, 71.48; H, 7.82. Fnd: C, 71.61;
H, 7.92.
b) 5,6-Bis(benzyloxy)-3-oxa-hexanoic acid
[1133] 130 g (336.4 mmol) of the title compound of Example 58a) is
dissolved in 200 ml of dichloromethane, and 100 ml of
trifluoroacetic acid is added at 0.degree. C. It is stirred for 4
hours at room temperature, and then it is evaporated to the dry
state. The residue is crystallized from pentane/diethyl ether.
[1134] Yield: 102.2 g (92% of theory) of a waxy solid
[1135] Elementary analysis: Cld: C, 69.07; H, 6.71. Fnd: C, 69.19;
H, 6.82.
c)
6-N-Benzyloxycarbonyl-2-N-[1,4,7-tris(carboxylatomethyl)1,4,7,10-tetraa-
zacyclo-dodecane-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-lysine-[1-(4-pe-
rfluorooctylsulfonyl)-piperazine]-amide, Gd complex
[1136] 50 g (60.20 mmol) of the title compound of Example 52c),
6.93 g (60.20 mmol) of N-hydroxysuccinimide, 5.09 g (120 mmol) of
lithium chloride, and 37.91 g (60.20 mmol) of
1,4,7-tris(carboxylatomethyl)-1,4,7-
,10-tetraazacyclododecane-10-pentanoyl-3-aza-4-oxo-5-methyl-5yl),
Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while
being heated slightly. At 10.degree. C., 20.63 g (100 mmol) of
N,N-dicyclohexylcarbodi- imide is added, and then it is stirred
overnight at room temperature. The solution is poured into 3000 ml
of acetone and stirred for 10 minutes. The precipitated solid is
filtered off and then purified by chromatography (silica gel RP-18,
mobile solvent: gradient that consists of
water/ethanol/acetonitrile).
[1137] Yield: 75.53 g (87% of theory) of a colorless solid.
[1138] Water content: 10.1%
[1139] Elementary analysis (relative to anhydrous substance): Cld:
C, 37.48; H, 3.84; F, 22.39; Gd, 10.90; N, 8.74; S, 2.22. Fnd: C,
37.39; H, 4.02; F, 22.29; Gd, 10.75; N, 8.70; S, 2.22.
d)
2-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(p-
entanoyl-3aza-4-oxo-5methyl-5yl]-lysine-[1-(4-perfluorooctylsulfonyl)-pipe-
razine]-amide, Gd complex
[1140] 70 g (48.53 mmol) of the title compound of Example 58c) is
dissolved in 500 ml of water/100 ml of ethanol, and 5 g of
palladium catalyst (10% Pd/C) is added. It is hydrogenated at room
temperature. Catalyst is filtered out, and the filtrate is
evaporated to the dry state in a vacuum.
[1141] Yield: 63.5 g (quantitative) of a colorless solid.
[1142] Water content: 9.8%
[1143] Elementary analysis (relative to anhydrous substance): Cld:
C, 37.48; H, 3.84; F, 22.39; Gd, 10.90; N, 8.74; S, 2.22. Fnd: C,
37.39; H, 4.03; F, 22.31; Gd, 10.78; N, 8.65; S, 2.20.
e)
6-N-[5,6-Bis(benzyloxy)-3-oxahexanoyl]-2-N-[1,4,7-tris(carboxylatomethy-
l)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3aza-4-oxo-5-methyl-5yl)]--
lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd
complex
[1144] 10 g (7.64 mmol) of the title compound of Example 58d), 3.30
g (10 mmol) of the title compound of Example 7b, 0.85 g (20 mmol)
of lithium chloride and 1.15 g (10 mmol) of N-hydroxysuccinimide
are dissolved in 150 ml of dimethyl sulfoxide while being heated
slightly. At 10.degree. C., 3.10 g (15 mmol) of
N,N'-dicyclohexylcarbodiimide is added, and it is stirred for 8
hours at room temperature. The reaction solution is poured into
2000 ml of acetone, and the deposited precipitate is isolated. The
title compound is purified on silica gel RP-18 (mobile
solvent:gradient that consists of water/ethanol/acetonitrile).
[1145] Yield: 11.14 g (90% of theory) of a colorless, amorphous
solid.
[1146] Water content: 4.3%
[1147] Elementary analysis (relative to anhydrous substance): Cld:
C, 41.51; H, 4.29; F, 19.93; N, 7.78; Gd, 9.70; S, 1.98. Fnd: C,
41.45; H, 4.38; F, 19.84; N, 7.70; Gd, 9.58; S, 1.90.
f) 6-N-(5,6,-Dihydroxy-3-oxahexanoyl)-2-N-[1,4,7-tris
carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-pentanoyl-3-aza-4-ox-
o-5-methyl-5-yl)]-lysine[1-(4-perfluorooctylsulfonyl)-piperazine]-amide,
Gd complex
[1148] 10 g (6.17 mmol) of the title compound of Example 58e) is
dissolved in 200 ml of ethanol, and 3 g of palladium catalyst (10%
Pd/C) is added. It is hydrogenated at room temperature. Catalyst is
filtered out, and the filtrate is evaporated to the dry state in a
vacuum.
[1149] Yield: 8.89 g (quantitative) of a colorless solid.
[1150] Water content: 3.1%
[1151] Elementary analysis (relative to anhydrous substance): Cld:
C, 35.03; H, 3.99; F, 22.42; Gd, 10.92; N, 8.75; S, 2.23. Fnd: C,
34.95; H, 4.12; F, 22.30; Gd, 10.78; N, 8.71; S, 2.18.
EXAMPLE 59
a)
6-N-Benzyloxycarbonyl-2-N[-5,6-bis(benzyloxy)-3-oxa-hexanoyl]-lysine-[1-
-(4-perfluorooctylsulfonyl)-piperazine]-amide
[1152] 9.28 g (45 mmol) of N,N-dicyclohexylcarbodiimide is added at
0.degree. C. to a solution that consists of 20 g (24.08 mmol) of
the title compound of Example 52c), 9.91 g (30 mmol) of the title
compound of Example 7b and 3.45 g (30 mmol) of
N-hydroxysuccinimide, dissolved in 100 ml of dimethylformamide. It
is stirred for 3 hours at 0.degree. C. and then overnight at room
temperature. Precipitated urea is filtered out, the filtrate is
evaporated to the dry state in a vacuum and chromatographed on
silica gel (mobile solvent:dichloromethane/ethanol=20:- 1).
[1153] Yield: 24.50 g (89% of theory) of a viscous oil.
[1154] Elementary analysis: Cld: C, 47.29; H, 4.14; F, 28.26; N,
4.90; S, 2.81. Fnd: C, 47.14; H, 4.26; F, 28.17; N, 4.91; S,
2.69.
b)
2-N-(5,6-Dihydroxy-3-oxahexanoyl)-lysine-[1-(4-perfluorooctylsulfonyl)--
piperazine]-amide
[1155] 20 g (17.5 mmol) of the title compound of Example 52d) is
dissolved in 300 ml of ethanol, and 5 g of palladium catalyst (10%
Pd/C) is added. It is hydrogenated at room temperature. Catalyst is
filtered out, and the filtrate is evaporated to the dry state in a
vacuum.
[1156] Yield: 17.65 g (quantitative) of a colorless solid.
[1157] Elementary analysis: Cld: C, 44.05; H, 4.10; F, 32.02; N,
5.55; S, 3.18. Fnd: C, 43.96; H, 4.21; F, 31.94; N, 5.48; S,
3.24.
c)
6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(p-
entanoyl-3-aza-4-oxo-5-methyl-5yl)]-lysine-[1-(4-perfluorooctylsulfonyl)-p-
iperazine]-amide, Gd complex
[1158] 15 g (14.87 mmol) of the title compound of Example 59b),
1.73 g (15 mmol) of N-hydroxysuccinimide, 1.27 g (30 mmol) of
lithium chloride and 9.48 g (15 mmol) of
1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methy-
l-5-yl)-pentanoic acid-1,4,7,10-tetraazacyclododecane, Gd complex,
are dissolved in 100 ml of dimethyl sulfoxide while being heated
slightly. At 10.degree. C., 5.16 g (25 mol) of
N,N-dicyclohexylcarbodiimide is added, and then it is stirred
overnight at room temperature. The solution is poured into 1500 ml
of acetone and stirred for 10 minutes. The precipitated solid is
filtered off and then purified by chromatography (silica gel RP-18
mobile solvent: gradient that consists of
water/ethanol/acetonitrile).
[1159] Yield: 19.28 g (80% of theory) of a colorless solid.
[1160] Water content: 10.3%
[1161] Elementary analysis (relative to anhydrous substance): Cld:
C, 41.51; H, 4.29; F, 19.93; Gd, 9.70; N, 7.78; S, 1.98. Fnd: C,
41.37; H, 4.40; F, 19.88; Gd, 9.58; N, 7.67; S, 1.85.
EXAMPLE 60
a)
6-N-Benzyloxycarbonyl-2-N-[2,6-N,N'-bis(benzyloxycarbonyl)-lysyl]-lysin-
e-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide
[1162] 20 g (24.08 mmol) of the title compound of Example 52c) and
2.53 g (25 mmol) of triethylamine are dissolved in 200 ml of
tetrahydrofuran (THF), and 14.46 g (27 mmol) of di-N,N'-Z-lysine
paranitrophenylester is added. It is stirred for 5 hours at
50.degree. C. It is evaporated to the dry state in a vacuum, and
the residue is chromatographed on silica gel. Mobile
solvent:dichloromethane/methanol=20:1).
[1163] Yield: 28.07 g (95% of theory) of a colorless solid.
[1164] Elementary analysis: Cld: C, 46.99; H, 4.19; F, 26.32; N,
6.85; S, 2.61. Fnd: C, 47.08; H, 4.32; F, 26.21; N, 6.75; S,
2.54.
b)
2-N-(Lysyl)-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide,
trihydrobromide
[1165] 100 ml of hydrobromic acid in glacial acetic acid (48%) is
added to 25 g (20.37 mmol) of the title compound of Example 60a)
and stirred for 2 hours at 40.degree. C. It is cooled to 0.degree.
C., 1500 ml of diethyl ester is added in drops, and the
precipitated solid is filtered off. After drying in a vacuum
(60.degree. C.), 21.52 g (99% of theory) of a slightly
yellow-colored, crystalline solid is obtained.
[1166] Elementary analysis: Cld: C, 27.01; H, 3.40; Br, 22.46; F,
30.26; N, 7.87; S, 3.00. Fnd: C, 26.92; H, 3.53; Br, 22.15; F,
30.14; N, 7.69; S, 2.87.
c)
6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(p-
entanoyl-3-aza-4-oxo-5-methyl-5yl)]-2-N-]2,6-N,N'-bis[1,4,7-tris
carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pentanoyl-3-aza-4-o-
xo-5-methyl-5yl)]-lysyl]-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]--
amide, trigadolinium complex
[1167] 31.49 g (50 mmol) of
1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo--
5-methyl-)-5-yl)-pentanoic acid, Gd complex
[1168] 6.91 g (60 mmol) of N-hydroxysuccinimide and 4.24 g (100
mmol) of lithium chloride are dissolved in 350 ml of dimethyl
sulfoxide while being heated slightly. At 10.degree. C., 16.51 g
(80 mmol) of N,N-dicyclohexylcarbodiimide is added, and it is
stirred for 5 hours at 10.degree. C. 10 g (9.37 mmol) of the title
compound of Example 60b) and 3.03 g (30 mmol) of triethylamine are
added to this mixture, and it is stirred for 12 hours at 60.degree.
C. It is allowed to cool to room temperature, and the mixture is
poured into 3000 ml of acetone. The deposited precipitate is
filtered off and purified on silica gel RP-18 (mobile
solvent:gradient that consists of water/ethanol/acetonitrile).
[1169] Yield: 16.7 g (67% of theory) of a colorless solid.
[1170] Water content: 7.9%
[1171] Elementary analysis (relative to anhydrous substance): Cld:
C, 36.58; H, 4.43; F, 12.14; Gd, 17.74; N, 11.06; S, 1.14. Fnd: C,
36.47; H, 4.54; F, 12.03; Gd, 17.65; N, 10.95; S, 1.21.
EXAMPLE 61
a)
1,7-Bis(benzyloxycarbonyl)-4-(3,6,9,12,15-pentaoxahexadecanoyl)-1,4,7,1-
0-tetraazacyclododecane
[1172] 24.73 g (100 mmol) of EEDQ
(2-ethoxy-1,2-dihydroquinoline-1-carboxy- lic acid ethyl ester) is
added at 0.degree. C. to 18.13 g (68.1 mmol) of
3,6,9,12,15-pentaoxahexadecanoic acid and 30 g (68.1 mmol) of
1,7di-Z-cyclene, produced according to Z. Kovacs and A. D. Sherry,
J. Chem. Soc. Chem. Commun. (1995), 2, 185, in 300 ml of
tetrahydrofuran, and it is stirred overnight at room temperature.
It is evaporated to the dry state in a vacuum and chromatographed
on silica gel (mobile solvent:dichloromethane/methanol=20:1).
[1173] Yield: 19.13 g (42% of theory) of a colorless solid
[1174] Elementary analysis: Cld: C, 61.03; H, 7.61; N, 8.13. Fnd:
C, 60.92; H, 7.75; N, 8.04.
b)
1,7-Bis(benzyloxycarbonyl)-4-(3,6,9,12,15-pentaoxahexadecanoyl)-10-(2H,-
2H,4H,5H,5H-3-oxa-perfluorotridecanoyl)-1,4,7,10-tetraazacyclododecane
[1175] 12.36 g (50 mmol) of EEDQ
(2-ethoxy-1,2-dihydroquinoline-1-carboxyl- ic acid ethyl ester) is
added at 0.degree. C. to 18 g (26.91 mmol) of the title compound of
Example 61a) and 14.05 g (26.91 mmol) of
2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid, produced
according to DE 19603033, in 300 ml of tetrahydrofuran, and it is
stirred overnight at room temperature. It is evaporated to the dry
state in a vacuum and chromatographed on silica gel (mobile
solvent:dichloromethane/methanol=20- :1).
[1176] Yield: 21.51 g (67% of theory) of a colorless solid
[1177] Elementary analysis: Cld: C, 47.32; H, 4.82; F, 27.07; N,
4.70. Fnd: C, 47.26; H, 5.01; F, 26.94; N, 4.59.
c)
1-(3,6,9,12,15-Pentaoxahexadecanoyl)-7-(2H,2H,4H,4H,5H,5H-3-oxaperfluor-
otridecanoyl)-1,4,7,10-tetraazacyclododecane
[1178] 20 g (16.77 mmol) of the title compound of Example 52d) is
dissolved in 200 ml of ethanol, and 2.5 g of palladium catalyst
(10% Pd/C) is added. It is hydrogenated at room temperature.
Catalyst is filtered out, and the filtrate is evaporated to the dry
state in a vacuum.
[1179] Yield: 15.5 g (quantitative) of a colorless solid.
[1180] Elementary analysis: Cld: C, 40.27; H, 4.90; F, 34.93; N,
6.06. Fnd: C, 40.15; H, 4.99; F, 34.87; N, 5.94.
d)
1,7-Bis(1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-
-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-4-(3,6,9,12,15-pentaoxahexadecanoy-
l)-10-(2H,2H,4H,4H,5H,5H,-3-oxaperfluorotridecanoyl)-1,4,7,10-tetraazacycl-
ododecane, Gd complex
[1181] 15 g (16.22 mmol) of the title compound of Example 61c),
4.60 g (40 mmol) of N-hydroxysuccinimide, 3.39 g (80 mmol) of
lithium chloride and 25.19 g (40 mmol) of
1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-meth-
yl-5-yl)-pentanoic acid, Gd complex, are dissolved in 300 ml of
dimethyl sulfoxide while being heated slightly. At 10.degree. C.,
24.73 g (100 mmol) of EEDQ is added, and then it is stirred
overnight at room temperature. The solution is poured into 3000 ml
of acetone and stirred for 10 minutes.
[1182] The precipitated solid is filtered off and then purified by
chromatography (silica gel RP-18, mobile solvent: gradient that
consists of water/ethanol/acetonitrile).
[1183] Yield: 19.86 g (57% of theory) of a colorless solid
[1184] Water content: 11.3%
[1185] Elementary analysis (relative to anhydrous substance): Cld:
C, 38.58; H, 4.74; F, 15.04; Gd, 14.64; N, 9.13. Fnd: C, 38.47; H,
4.91; F, 14.95; Gd, 14.57; N, 9.04.
EXAMPLE 62
a) 3,5-Dinitrobenzoic
acid-1-[(4-perfluorooctylsulfonyl)-piperazine]-amide
[1186] A solution that consists of 8.76 g (38 mmol) of
3,5-dinitrobenzoyl chloride in 55 ml of dichloromethane is added in
drops at 0.degree. C. to 20 g (35.2 mmol) and 8.1 g (80 mmol) of
triethylamine, dissolved in 200 ml of dichloromethane, and it is
stirred for 3 hours at 0.degree. C. 200 ml of 5% aqueous
hydrochloric acid is added, and it is stirred for 5 minutes at room
temperature. The organic phase is separated, dried on magnesium
sulfate and evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:dichloromethane/-
acetone=15:1).
[1187] Yield: 24.96 g (93% of theory) of a colorless solid.
[1188] Elementary analysis: Cld: C, 29.35; H, 1.45; F, 42.37; N,
7.35; S, 4.21. Fnd: C, 29.28; H, 1.61; F, 42.15; N, 7.25; S,
4.15.
b) 3,5 Diaminobenzoic
acid-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide
[1189] 20 g (26.23 mmol) of the title compound of Example 62a) is
dissolved in 400 ml of ethanol, and 6 g of palladium catalyst (10%
Pd/C) is added. It is hydrogenated at room temperature. Catalyst is
filtered out, and the filtrate is evaporated to the dry state in a
vacuum.
[1190] Yield: 18.43 g (quantitative) of a cream-colored solid.
[1191] Elementary analysis: Cld: C, 32.49; H, 2.15; F, 45.98; N,
7.98; S, 4.57. Fnd: C, 32.29; H, 2.35; F, 45.69; N, 7.81; S,
4.40.
c)
3,5-N,N'-Bis[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododeca-
ne-10-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl-)]-benzoic
acid-[1-(4-perfluorooctyl-sulfonyl)-piperazine]-amide, Gd
complex
[1192] 10 g (14.24 mmol) of the title compound of Example 62b),
3.45 g (30 mmol) of N-hydroxysuccinimide, 2.54 g (60 mol) of
lithium chloride and 18.89 g (30 mmol) of
1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-meth-
yl-5yl)-pentanoic acid, Gd complex, are dissolved in 200 ml of
dimethyl sulfoxide while being heated slightly. At 10.degree. C.,
10.32 g (50 mmol) of N,N-dicyclohexylcarbodiimide is added, and
then it is stirred overnight at room temperature. The solution is
poured into 2000 ml of acetone, and it is stirred for 10 minutes.
The precipitated solid is filtered off and then purified by
chromatography (silica gel RP-18, mobile solvent: gradient that
consists of water/ethanol/acetonitrile).
[1193] Yield: 19.74 g (72% of theory) of a colorless solid.
[1194] Water content: 11.8%
[1195] Elementary analysis (relative to anhydrous substance): Cld:
C, 35.55; H, 3.72; F, 16.77; Gd, 16.33; N, 10.18; S, 1.67. Fnd: C,
35.48; H, 3.84; F, 16.58; Gd, 16.24; N, 10.07; S, 1.58.
EXAMPLE 63
a) 3-Oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanecarboxylic
acid-t-butylester
[1196] 25.0 g (53.8 mmol) of 1H,1H,2H,2H-perfluoro-1-decanol
[commercially available from the Lancaster Company] is dissolved in
250 ml of absolute toluene and mixed at room temperature with a
catalytic amount (about 0.75 g) of tetra-n-butyl-ammonium hydrogen
sulfate. Then, a total of 7.55 g (134.6 mmol; 2.5 equivalents
relative to the alcohol component that is used) of fine-powder
potassium hydroxide powder is added at 0.degree. C., followed by
15.73 g (80.7 mmol; 1.5 equivalents relative to the alcohol
component that is used) of bromoacetic acid-tert-butylester, and it
is allowed to stir for 2 more hours at 0.degree. C. The thus
obtained reaction solution is stirred for 12 more hours at room
temperature, and for the purpose of working-up, it is mixed with a
total of 500 ml of ethyl acetate and 250 ml of water. The organic
phase is separated and washed twice with water. After the organic
phase is dried on sodium sulfate, salt is suctioned out, and the
solvent is drawn off in a vacuum. The remaining oily residue is
purified on silica gel with use of ethyl acetate/hexane (1:10) as
an eluant.
[1197] Yield: 26.3 g (84.6% of theory) of the above-mentioned title
compound as a colorless and strongly viscous oil.
[1198] Elementary analysis: Cld: C, 33.23; H, 2.61; F, 55.85. Fnd:
C, 33.29; H, 2.61; F, 55.90.
b) 3-Oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanecarboxylic acid
[1199] 20.0 g (34.58 mmol) of the title compound of Example 63a) is
suspended in 200 ml of a mixture that consists of methanol and 0.5
molar sodium hydroxide solution at a ratio of 2:1 while being
stirred at room temperature, and then it is heated to 60.degree. C.
After a reaction time of 12 hours at 60.degree. C., the now clear
reaction mixture is neutralized for working-up by mixing with
Amberlite.RTM. IR 120 (H.sup.+ form)-cation-exchange resin,
exchanger is suctioned out, and the thus obtained
methanolic-aqueous filtrate is drawn off in a vacuum until a dry
state is reached. The amorphous-oily residue that is obtained is
purified on silica gel with use of ethyl acetate/n-hexane (1:3) as
an eluant.
[1200] Yield: 16.0 g (88.6% of theory) of the above-mentioned title
compound as a colorless and strongly viscous oil.
[1201] Elementary analysis: Cld: C, 27.60; H, 1.35; F, 61.85. Fnd:
C, 27.58; H, 1.36; F, 61.90.
c)
1,7-Bis{[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pe-
ntanoyl)]-1,4,7,10-tetraazacyclododecane}-diethylenetriamine,
digadolinium complex
[1202] 2.48 g [(3.94 mmol); 2.05 molar equivalents relative to the
diethylenetriamine that is used] of the Gd complex, described in
Patent Application DE 197 28 954 C1 under Example 31h), of
10-(4-carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7,10-tetraazacyclododecane-1-
,4,7-triacetic acid and 167 mg of anhydrous lithium chloride (3.94
mmol) are dissolved at 40.degree. C. in 40 ml of absolute dimethyl
sulfoxide while being stirred and mixed at this temperature with a
total of 453 mg (3.94 mmol) of N-hydroxysuccinimide. After cooling
to room temperature, the thus obtained reaction solution is mixed
with 814 mg (3.946 mmol) of N,N'-dicyclohexylcarbodiimide and
stirred for 2 hours at room temperature. The suspension of active
ester that is obtained is then mixed with 198.3 mg (1.92 mmol) of
diethylenetriamine, dissolved in 5 ml of absolute dimethyl
sulfoxide, and it is stirred for 12 hours at room temperature. For
the purpose of working-up, the reaction mixture is mixed with
sufficient acetone until the above-mentioned title compound is
completely precipitated, the precipitate is suctioned off, dried,
taken up in water, insoluble dicyclohexylurea is filtered out, and
the filtrate is desalinated with an AMICON.RTM. YM-3
ultrafiltration membrane (cut-off 3,000 Da), and low-molecular
components are removed. The retentate is then freeze-dried.
[1203] Yield: 1.85 g (72.7% of theory) as a colorless
lyophilizate.
[1204] H.sub.2O content (Karl-Fischer): 3.89%.
[1205] Elementary analysis (relative to anhydrous substance): Cld:
C, 38.03; H, 5.24; N, 13.73; Gd, 23.71. Fnd: C, 37.98; H, 5.20; N,
13.69; Gd, 23.78.
d)
1,7-Bis{[1,4,7-tris(carboxylatomethyl)-10-(3-aza-4-oxo-5-methyl-5-yl-pe-
ntanoyl)]-1,4,7,10-tetraazacyclododecane}-4-(3-oxa-2H,2H,4H,4H,5H,5H-perfl-
uorotridecanoyl)-diethylenetriamine, digadolinium complex
[1206] 1.27 g (2.44 mmol) of the title compound of Example 63b),
dissolved in a mixture that consists of 15 ml of tetrahydrofuran
and 15 ml of dimethyl sulfoxide, is added drop by drop at
50.degree. C. and under nitrogen atmosphere to a solution of 3.23 g
(2.44 mmol) of the title compound of Example 63c), in a mixture
that consists of 30 ml of dimethyl sulfoxide and 3 ml of
tetrahydrofuran. Then, a total of 1.80 g (3.66 mmol) of EEDQ
[2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline] is added in
portions at 0.degree. C. and allowed to stir overnight at room
temperature. The reaction solution that is obtained is then mixed
with sufficient acetone until the above-mentioned title compound is
completely precipitated, the precipitate is suctioned off, dried,
taken up in water, insoluble components are filtered out, and the
filtrate is ultrafiltered with an AMICON.RTM. YM-3 ultrafiltration
membrane (cut-off 3,000 Da), which is used both for complete
desalination and for removing low-molecular components from the
title compound. The retentate is then freeze-dried.
[1207] Yield: 3.54 g (79.4% of theory) as a colorless
lyophilizate.
[1208] H.sub.2O content (Karl-Fischer): 5.87%.
[1209] Elementary analysis (relative to anhydrous substance): Cld:
C, 35.43; H, 4.07; N, 9.95; F, 17.64; Gd, 17.18. Fnd: C, 35.42; H,
4.01; N, 9.89; F, 17.67; Gd, 17.18.
EXAMPLE 64
a) 2-N-Trifluoroacetyl-6-N-benzyloxycarbonyl-L-lysine
[1210] 100.0 g (356.7 mmol) of 6-N-benzyloxycarbonyl-L-lysine is
dissolved in a mixture that consists of 1000 ml of trifluoroacetic
acid ethyl ester and 500 ml of ethanol, and it is stirred for 24
hours at room temperature. It is evaporated to the dry state, and
the residue is crystallized from diisopropyl ether.
[1211] Yield: 128.9 g (96% of theory) of a colorless crystalline
powder.
[1212] Melting point: 98.5.degree. C.
[1213] Elementary analysis: Cld: C, 51.07; H, 5.09; N, 7.44; F,
15.14. Fnd: C, 51.25; H, 5.18; N, 7.58; F, 15.03.
b)
2-N-Trifluoroacetyl-6-N-benzyloxycarbonyl-L-lysine[1-(4-perfluorooctyls-
ulfonyl)-piperazine]-amide
[1214] 164.2 g (0.664 mmol) of EEDQ
(2-ethoxy-1,2-dihydroquinoline-1-carbo- xylic acid ethyl ester) is
added at 0.degree. C. to 125.0 g (332.0 mmol) of the title compound
of Example 52a) and 188.7 g (332.0 mmol) of
1-perfluorooctylsulfonylpiperazine (produced according to DE
19603033) in 750 ml of tetrahydrofuran, and it is stirred overnight
at room temperature. It is evaporated to the dry state in a vacuum
and chromatographed on silica gel (mobile
solvent:dichloromethane/methanol=20- :1).
[1215] Yield: 286.0 g (93% of theory) of a colorless solid.
[1216] Melting point: 92.degree. C.
[1217] Elementary analysis: Cld: C, 36.30; H, 2.83; N, 6.05; F,
41.01; S, 3.46. Fnd: C, 36.18; H, 2.94; N, 5.98; F, 40.87; S,
3.40.
c)
6-N-Benzyloxycarbonyl-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine-
]-amide
[1218] Ammonia gas is introduced at 0.degree. C. for one hour into
a solution that consists of 280.0 g (302.2 mol) of the title
compound of Example 52b) in 2000 ml of ethanol. It is then stirred
for 4 hours at 0.degree. C. It is evaporated to the dry state, and
the residue is absorptively precipitated from water. The solid is
filtered off and dried in a vacuum at 50.degree. C.
[1219] Yield: 243.5 g (97.0% of theory) of an amorphous solid.
[1220] Elementary analysis: Cld: C, 37.60; H, 3.28; N, 6.75; F,
38.89; S, 3.86. Fnd: C, 37.55; H, 3.33; N, 6.68; F, 38.78; S,
3.81.
d) L-Lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide
[1221] 200.0 g (240.8 mmol) of the compound that is produced under
64c) is dissolved in 1000 ml of ethanol, mixed with 5.0 g of
Pearlman's catalyst (Pd 20%, C) and hydrogenated at room
temperature under a hydrogen atmosphere (1 atm) until no more
hydrogen absorption can be observed. Catalyst is suctioned out, it
is thoroughly rewashed with ethanol (three times with about 100 ml
each) and evaporated to the dry state in a vacuum. The title
compound is obtained as a strongly viscous and yellowish-colored
oil.
[1222] Yield: 162.5 g (96.9% of theory)
[1223] Elementary analysis: Cld: C, 31.04; H, 3.04; N, 8.05; F,
46.38; S, 4.60. Fnd: C, 31.11; H, 3.09; N, 8.08; F, 46.33; S,
4.62.
e)
6N-2N-Bis-{4-[2,3-bis-(N,N-bis(t-butyloxycarbonylmethyl)-amino)-propyl]-
-phenyl}-3-oxa-propionyl-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine-
]-amide
[1224] 5.25 g (7.72 mmol) of the
4-[2,3-bis-(N,N-bis(t-butyloxycarbonylmet-
hyl)-amino)-propyl]-phenyl}-3-oxa-propionic acid and 781.0 mg (7.72
mmol) of triethylamine are dissolved in 50 ml of methylene
chloride. At -15.degree. C., a solution that consists of 1.16 g
(8.5 mmol) of isobutyl chloroformate in 10 ml of methylene chloride
is added in drops within 5 minutes, and it is stirred for another
20 minutes at -15.degree. C. Then, the solution is cooled to
-25.degree. C., and a solution, consisting of 2.68 g (3.86 mmol) of
the title compound of Example 64d) and 2.12 g (21.0 mmol) of
triethylamine, in 70 ml of tetrahydrofuran is added in drops within
30 minutes and subsequently stirred for another 30 minutes at
-15.degree. C., and then stirring is continued overnight at room
temperature. For working-up, the solvent is drawn off in a vacuum,
and the remaining oily residue is taken up in 250 ml of chloroform.
The chloroform phase is extracted twice with 100 ml each of a 10%
aqueous ammonium chloride solution, the organic phase is dried on
magnesium sulfate and evaporated to the dry state in a vacuum. The
residue is chromatographed on silica gel (mobile solvent:methylene
chloride/ethanol=20:1).
[1225] Yield: 5.37 g (68.8% of theory) of a colorless and very
viscous oil.
[1226] Elementary analysis: Cld: C, 52.27; H, 6.43; N, 5.54; F,
15.97; S, 1.59. Fnd: C, 52.22; H, 6.51; N, 5.49; F, 15.99; S,
1.63.
f)
6N-2N-Bis-{4-[2,3-bis-(N,N-bis(carboxylatomethyl)-amino)-propyl]-phenyl-
}-3-oxa-propionyl-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide-
, octa-sodium salt
[1227] 5.0 g (2.47 mmol) of the title compound of Example 64e) is
dissolved in 60 ml of absolute dichloromethane. Then, it is mixed
drop by drop at 0.degree. C. with a total of 75 ml of
trifluoroacetic acid. After a reaction time of 12 hours at room
temperature, it is evaporated to the dry state in a vacuum. The
remaining residue is mixed with 100 ml of water and drawn off again
in a vacuum until a dry state is reached. The thus obtained residue
is dissolved in 200 ml of distilled water, and the aqueous product
solution of the above-mentioned title compound is extracted twice
with 60 ml of diethyl ether in each case. The resulting aqueous
product solution is made up to a total volume of 300 ml by mixing
with water, insoluble components are filtered out, and the filtrate
is ultrafiltered with an AMICON.RTM. YM-3 ultrafiltration membrane
(cut-off 3,000 Da), which is used both for complete desalination
and for removing low-molecular components from the title compound.
The retentate is made up to a total volume of 200 ml by mixing with
water, and the pH of this solution is then set at 10.0 with 15%
sodium hydroxide solution. The basic, aqueous product solution is
subsequently freeze-dried.
[1228] 4.0 g (92.8% of theory) of the title compound is obtained in
the form of the octa-sodium salt as an amorphous lyophilizate.
[1229] Water content: 5.37%
[1230] Elementary analysis (relative to anhydrous substance): Cld:
C, 38.46; H, 3.28; N, 6.41; F, 18.47; S, 1.83; Na, 10.52. Fnd: C,
38.42; H, 3.31; N, 6.39; F, 18.51; S, 1.87; Na, 10.38.
g)
6N-2N-Bis-{4-[2,3-bis-(N,N-bis(carboxymethyl)-amino)-propyl]-phenyl}-3--
oxa-propionyl-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide,
di-manganese complex, tetra-sodium salt
[1231] 1.94 g (1.11 mmol) of the title compound of Example 64f) is
dissolved in 100 ml of distilled water, and the resulting solution
is brought to a pH of 4.0 by mixing with 1 molar aqueous
hydrochloric acid. At 80.degree. C., it is now mixed in portions
with 0.25 g (2.22 mmol) of manganese(II) carbonate. Then, the thus
obtained reaction solution is refluxed for 5 hours. After cooling
to room temperature, the pH of the aqueous product solution is set
at 7.2 by mixing with 1N sodium hydroxide solution while being
stirred vigorously, and it is desalinated with an AMICON.RTM. YM-3
ultrafiltration membrane (cut-off 3,000 Da), and low-molecular
components are removed. The retentate is then freeze-dried.
[1232] Yield: 1.80 g (92.0% of theory) of the title compound as a
colorless lyophilizate.
[1233] H.sub.2O content (Karl-Fischer): 7.28%.
[1234] Elementary analysis (relative to anhydrous substance): Cld:
C, 38.07; H, 3.25; F, 18.28; Mn, 6.22; N, 6.34; Na, 5.20; S, 1.81.
Fnd: C, 38.01; H, 3.29; F, 18.29; Mn, 6.21; N, 6.36; Na, 5.28; S,
1.78.
EXAMPLE 65
a)
6-N-(Benzyloxycarbonyl)-2-N-[(N-pteroyl)-L-glutaminyl]-lysine-[1-(4-per-
fluorooctylsulfonyl)-piperazine]-amide
[1235] 20 g (45.31 mmol) of folic acid is dissolved in 300 ml of
dimethyl sulfoxide, and 9.49 g (46 mmol) of
N,N-dicyclohexylcarbodiimide is added at 10.degree. C. It is
stirred overnight at room temperature. 29.1 g (35 mmol) of the
title compound of Example 52c) and 20 ml of pyridine are added to
this mixture, and it is stirred for 3 hours at 50.degree. C. It is
cooled to room temperature, and a mixture that consists of 1500 ml
of diethyl ether/1500 ml of acetone is added. The deposited
precipitate is filtered off and purified on (RP-18) (mobile
solvent=gradient that consists of
water/ethanol/tetrahydrofuran).
[1236] Yield: 21.59 g (38% of theory) of a yellow solid.
[1237] Water content: 2.1%
[1238] Elementary analysis (relative to anhydrous substance): Cld:
C, 43.10; H, 3.54; F, 25.76; N, 11.29; S, 2.56. Fnd: C, 43.02; H,
3.62; F, 25.68; N, 11.21; S, 2.48.
b)
2-N-[(N-Pteroyl)-L-glutaminyl]-lysine-[1-(4-perfluorooctylsulfonyl)-pip-
erazine]-amide
[1239] 200 ml of hydrobromic acid in glacial acetic acid (48%) is
added to 20 g (15.95 mmol) of the title compound of Example 65a),
and it is stirred for 2 hours at 40.degree. C. It is cooled to
0.degree. C., 2000 ml of diethyl ether is added in drops, and the
precipitated solid is filtered off. After drying in a vacuum
(60.degree. C.), 18.96 g (99% of theory) of a yellow-colored,
crystalline solid is obtained.
[1240] Elementary analysis: Cld: C, 37.01; H, 3.27; Br, 6.65; F,
26.90; N, 12.83; S, 2.67. Fnd: C, 36.91; H, 3.42; Br, 6.31; F,
29.75; N, 12.72; S, 2.56.
c)
6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(p-
entanoyl-3-aza-4oxo-5-methyl-5yl]-2-N-[(N-pteroyl]-L-glutaminyl]-lysine-[1-
-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex
[1241] 0.92 g (8 mmol) of N-hydroxysuccinimide, 0.68 g (16 mol) of
lithium chloride and 5.04 g (8 mmol) of
1,4,7-tris(carboxylatomethyl-10-(3-aza-4--
oxo-5-methyl-5yl)-1,4,7-10-tetraazacyclododecane, Gd complex, are
dissolved in 80 ml of dimethyl sulfoxide while being heated
slightly. At 10.degree. C., 2.06 g (10 mol) of
N,N-dicyclohexylcarbodiimide is added, and then it is stirred for 3
hours at room temperature. 5 g (4.16 mmol) of the title compound of
Example 65b) and 10 ml of pyridine are added to this reaction
solution. It is stirred overnight at room temperature. The solution
is poured into 1000 ml of acetone and stirred for 10 minutes. The
precipitated solid is filtered off and then purified by
chromatography (silica gel RP-18, mobile solvent: gradient that
consists of water/ethanol/acetonitrile). It is dissolved in some
water, the pH is set at 7.4 with sodium hydroxide solution, and it
is freeze-dried.
[1242] Yield: 3.87 g (53% of theory) of a yellow solid.
[1243] Water content: 5.8%
[1244] Elementary analysis (relative to anhydrous substance): Cld:
C, 38.36; H, 3.74; F, 18.42; Gd, 8.97; N, 12.78; Na, 1.31; S, 1.83.
Fnd: C, 38.28; H, 3.85; F, 18.33; Gd, 8.85; N, 12.69; Na, 1.42; S,
1.75.
EXAMPLE 66
a) 2H,2H,4H,4H,5H,5H-3-Oxa)-perfluorotridecanoic
acid-N-(2,3-dihydroxyprop- yl)-amide
[1245] 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45
mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300
ml of dichloromethane, and it is stirred for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 100 ml of dichloromethane, and at 0.degree.
C., it is added in drops to a solution that consists of 5.47 g (60
mmol) of 2,3-dihydroxypropylamine and 6.07 g (60 mmol) of
triethylamine, dissolved in 200 ml of dichloromethane. It is
stirred for 3 hours at 0.degree. C., then for 6 hours at room
temperature. 300 ml of 5% aqueous hydrochloric acid is added, and
it is thoroughly stirred for 15 minutes. The organic phase is
separated, dried on magnesium sulfate and evaporated to the dry
state in a vacuum. The residue is chromatographed on silica gel
(mobile solvent:dichloromethane/ethanol=15:1).
[1246] Yield: 29.70 g (87% of theory) of a colorless solid
[1247] Elementary analysis: Cld: C, 30.32; H, 2.20; N, 2.36; F,
54.35. Fnd: C, 30.12; H, 2.41; N, 2.18; F, 54.15.
b)
N-(2,3-Dihydroxypropyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotride-
cyl)-amine
[1248] 30 g (48.8 mmol) of the title compound of Example 66a is
dissolved in 300 ml of tetrahydrofuran, and 50 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 300 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is
stirred for 8 hours at 60.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 300 ml of 5% aqueous
sodium hydroxide solution, and it is extracted 3 times with 300 ml
each of dichloromethane. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:dichloromethane/-
methanol=15:1).
[1249] Yield: 24.07 g (85% of theory) of a colorless solid
[1250] Elementary analysis: Cld: C, 31.05; H, 2.61; N, 2.41; F,
55.66. Fnd: C, 31.91; H, 2.78; N, 2.33; F, 55.47.
c)
1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(2,-
3-dihydroxypropyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-am-
ide]-1,4,7,10-tetraazacyclododecane, gadolinium complex
[1251] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 9.21 g (15.88 mmol) of the title
compound of Example 66b is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water and chromatographed
on silica gel RP-18 (mobile solvent: gradient that consists of
tetrahydrofuran/acetonitrile/water).
[1252] Yield: 16.09 g (85% of theory) of a colorless, amorphous
powder
[1253] Water content: 6.3%
[1254] Elementary analysis (relative to anhydrous substance): Cld:
C, 34.26; H, 3.64; N, 7.05; F, 27.10; Gd, 13.19. Fnd: C, 34.12; H,
3.83; N, 6.91; F, 26.88; Gd, 12.93.
EXAMPLE 67
1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(1H,1H-
,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amide]-1,4,7,10-tetraazacyclod-
odecane, gadolinium complex
[1255] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride and
3.66 g (31.76 mmol) of N-hydroxysuccinimide are dissolved at
60.degree. C. in 100 ml of dimethyl sulfoxide. It is cooled to
15.degree. C., 3.51 g (17 mmol) of N,N'-dicyclohexylcarbodiimide is
added, and it is stirred for 5 hours at 15.degree. C. To separate
the urea, the solution is filtered. 8.63 g (15.88 mmol) of the
title compound of Example 68b and 5.06 g (50 mmol) of triethylamine
are added to the filtrate, and it is stirred for 12 hours at room
temperature. The solution is poured into 1500 ml of diethyl
ether/100 ml of acetone, and it is stirred for 30 minutes. The
precipitated solid is filtered off and chromatographed on silica
gel RP-18 (mobile solvent:gradient that consists of
tetrahydrofuran/acetonitr- ile/water).
[1256] Yield: 13.86 g (78% of theory) of a colorless, amorphous
powder
[1257] Water content: 9.3%
[1258] Elementary analysis (relative to anhydrous substance): Cld:
C, 33.28; H, 3.42; N, 7.51; F, 28.87; Gd, 14.05. Fnd: C, 33.12; H,
3.61; N, 7.37; F, 28.69; Gd, 13.89.
EXAMPLE 68
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid amide
[1259] 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45
mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300
ml of dichloromethane, and it is stirred for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 200 ml of dichloromethane. Ammonia gas is
then directed into the solution for about 2 hours at 0.degree. C.
It is stirred for 4 more hours at 0.degree. C., then for 2 hours at
room temperature. 300 ml of 5% aqueous hydrochloric acid is added,
and it is thoroughly stirred for 15 minutes. The organic phase is
separated, dried on magnesium sulfate and evaporated to the dry
state in a vacuum. The residue is chromatographed on silica gel
(mobile solvent:dichloromethane/acetone=20:1).
[1260] Yield: 27.85 g (93% of theory)
[1261] Elementary analysis: Cld: C, 27.66; H, 1.55; N, 2.69; F,
61.97. Fnd: C, 27.49; H, 1.72; N, 2.54; F, 61.81.
b) 1H,1H,2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecylamine,
hydrochloride
[1262] 27 g (51.8 mmol) of the title compound of Example 68a is
dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 200 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
400 ml of ethanol/100 ml of 10% aqueous hydrochloric acid, and it
is stirred for 8 hours at 60.degree. C. It is evaporated to the dry
state in a vacuum, and the residue is crystallized from a little
ethanol/diethyl ether.
[1263] Yield: 26.75 g (95% of theory) of a colorless, crystalline
solid
[1264] Elementary analysis: Cld: C, 26.51; H, 2.04; N, 2.58; F,
59.41; Cl, 6.52. Fnd: C, 26.37; H, 2.21; N, 2.46; F, 59.25; Cl,
6.38.
c) 3,6,9,12,15-Pentaoxahexadecanoic
acid-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-
-perfluorotridecyl)-amide
[1265] 14.24 g (50 mmol) of 3,6,9,12,15-pentaoxahexadecanoic acid
chloride is added at 0.degree. C. to 26.5 g (48.74 mmol) of the
title compound of Example 68b, and 14.8 g (146.2 mmol) of
triethylamine, dissolved in 300 ml of dichloromethane, is added in
drops, and it is stirred for 3 hours at 0.degree. C. 300 ml of 5%
aqueous hydrochloric acid is added, and it is thoroughly stirred
for 30 minutes. The organic phase is separated, dried on magnesium
sulfate and evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile
solvent:dichloromethane/acetone: 20:1).
[1266] Yield: 32.03 g (87% of theory) of a colorless oil
[1267] Elementary analysis: Cld: C, 36.57; H, 4.00; N, 1.85; F,
42.75. Fnd: C, 36.46; H, 4.12; N, 1.76; F, 42.53.
d)
N-(3,6,9,12,15-Pentaoxahexadecyl)-N-(1H,1H,2H,2H,4H,4H-3-oxa)-perfluoro-
tridecyl)-amide
[1268] 31 g (41.03 mmol) of the title compound of Example 68c is
dissolved in 300 ml of tetrahydrofuran, and 25 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 200 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is
stirred for 8 hours at 40.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 300 ml of 5% aqueous
sodium hydroxide solution, and it is extracted 3 times with 300 ml
each of dichloromethane. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/2-propanol=15:1).
[1269] Yield: 27.68 g (91% of theory)
[1270] Elementary analysis: Cld: C, 37.26; H, 4.35; N, 1.89; F,
43.56. Fnd: C, 37.11; H, 4.51; N, 1.73; F, 43.41.
e)
1,4,7-Tris(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-ylic)-acid-[N-3,-
6,9,12,15-pentaoxa)-hexadexyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluoro-
tridecyl]-amide}-1,4,7,10-tetraazacyclododecane, gadolinium
complex
[1271] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 11.77 g (15.88 mmol) of the title
compound of Example 68d is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water and chromatographed
on silica gel RP-18 (mobile solvent:gradient that consists of
tetrahydrofuran/acetonitrile/water).
[1272] Yield: 18.05 g (84% of theory) of a colorless, amorphous
powder
[1273] Water content: 6.2%
[1274] Elementary analysis (relative to anhydrous substance): Cld:
C, 37.28; H, 4.47; N, 6.21; F, 23.87; Gd, 11.62. Fnd: C, 37.11; H,
4.61; N, 6.03; F, 23.64; Gd, 11.42.
EXAMPLE 69
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic
acid-N-(5-hydroxy-3-oxa-pe- ntyl)-amide
[1275] 8.90 g (70 mmol) of oxalyl chloride is added to 30 g (57.45
mmol) of 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic acid in 300
ml of dichloromethane, and it is stirred for 12 hours at room
temperature. It is evaporated to the dry state in a vacuum. The
residue is dissolved in 100 ml of dichloromethane and added in
drops at 0.degree. C. to a solution that consists of 6.25 g (60
mmol) of 5-hydroxy-3-oxa-pentylamine and 6.07 g (60 mmol) of
triethylamine, dissolved in 200 ml of dichloromethane. It is
stirred for 3 hours at 0.degree. C., then for 6 hours at room
temperature. 300 ml of 5% aqueous hydrochloric acid is added, and
it is thoroughly stirred for 15 minutes. The organic phase is
separated, dried on magnesium sulfate and evaporated to the dry
state in a vacuum. The residue is chromatographed on silica gel
(mobile solvent:dichloromethane/acetone=15:1).
[1276] Yield: 32.20 g (92% of theory) of a colorless solid
[1277] Elementary analysis: Cld: C, 31.54; H, 2.65; N, 2.30; F,
53.01. Fnd: C, 31.61; H, 2.84; N, 2.14; F, 52.85.
b)
N-(5-Hydroxy-3-oxa-pentyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotr-
idecyl-amine
[1278] 30 g (49.24 mmol) of the title compound of Example 69a is
dissolved in 300 ml of tetrahydrofuran, and 31 ml of 10 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0.degree. C., and 200 ml of
methanol is added in drops, then it is evaporated to the dry state
in a vacuum. The residue is taken up in a mixture that consists of
300 ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is
stirred for 10 hours at 50.degree. C. It is evaporated to the dry
state in a vacuum, the residue is taken up in 300 ml of 5% aqueous
sodium hydroxide solution, and it is extracted 3 times with 300 ml
each of dichloromethane. The organic phases are dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel (mobile solvent:dichloromethane/-
2-propanol=20:1).
[1279] Yield: 26.09 g (89% of theory) of a colorless solid
[1280] Elementary analysis: Cld: C, 32.28; H, 3.05; N, 2.35; F,
54.25. Fnd: C, 32.12; H, 3.21; N, 2.18; F, 54.09.
c)
1,4,7-Tris(carboxylatomethyl)-10-[(3-aza-4-oxo-hexan-5-ylic)-acid-N-(5--
hydroxy-3-oxa-pentyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-
-amide]-1,4,7,10-tetraazacyclododecane, gadolinium complex
[1281] 10 g (15.88 mmol) of the gadolinium complex of
10-[1-(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraazacyclododecane-1,4-
,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride are
dissolved at 60.degree. C. in 100 ml of dimethyl sulfoxide. It is
cooled to 15.degree. C., and 9.45 g (15.88 mmol) of the title
compound of Example 69b is added. It is stirred for 10 minutes, and
then 7.42 g (30 mmol) of
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is
stirred for 12 hours at room temperature. The solution is poured
into a mixture that consists of 200 ml of acetone/1300 ml of
diethyl ether, and it is stirred for 2 hours at room temperature.
The deposited precipitate is filtered off, it is dissolved in a
mixture that consists of a little ethanol/water and chromatographed
on silica gel RP-18 (mobile solvent: gradient that consists of
tetrahydrofuran/acetonitrile/water).
[1282] Yield: 16.10 g (84% of theory) of a colorless, amorphous
powder
[1283] Water content: 5.7%
[1284] Elementary analysis (relative to anhydrous substance): Cld:
C, 34.83; H, 3.84; N, 6.96; F, 26.76; Gd, 13.03. Fnd: C, 34.65; H,
3.96; N, 6.84; F, 26.62; Gd, 12.91.
EXAMPLE 70
a) 1,2,3,4,6-Penta-O-acetyl-.alpha.,.beta.-D-mannopyranose
[1285] Analogously to what is described in the literature [M. L.
Wolfrom and A. Thompson in Methods in Carbohydrate Chemistry (R. L.
Whistler, M. L. Wolfrom and J. N. BeMiller, Eds.), Academic Press,
New York, Vol. II, 53, pp. 211-215, (1963)], the reaction of 150 g
(832.5 mmol) of .alpha.,.beta.-D-mannopyranose with a mixture that
consists of 1500 ml of absolute pyridine and 1500 ml of acetic acid
anhydride yields, after working-up, 315 g (96.7%) of the
above-mentioned title compound as a crude product in the form of a
viscous and colorless oil. By .sup.1H-NMR spectroscopic study of
the thus obtained title compound, it was possible to determine the
a to .beta. ratio of both anomers at 4:1. Separation of the
.alpha.,.beta.-anomers of the above-mentioned title compound can be
eliminated to carry out the reaction steps below.
[1286] Elementary analysis: Cld: C, 49.21; H, 5.68. Fnd: C, 49.12;
H, 5.78.
b)
6-[1-O-.alpha.-(2,3,4,6-Tetra-O-acetyl-D-mannopyranosyl)-hexanoic
acid ethyl ester]
[1287] Analogously to what is described in the literature for the
synthesis of aryl glycopyranosides [J. Conchie and G. A. Levvy in
Methods in Carbohydrate Chemistry (R. L. Whistler, M. L. Wolfrom
and J. N. BeMiller, Eds.), Academic Press, New York, Vol. II, 90,
pp. 345-347, (1963)], the reaction of 156.2 g (400 mmol) of the
title compound of Example 70a as an .alpha.,.beta.-anomer mixture
with 67 ml (400 mmol) of 6-hydroxy-hexanoic acid ethyl ester and
60.8 ml (520 mmol) of tin(IV) chloride in a total of 600 ml of
1,2-dichloroethane after column-chromatographic purification
(eluant:hexane/ethyl acetate 2:1) results in the formation of
100.05 g (51% of theory) of the above-mentioned title compound as a
colorless and viscous oil. By .sup.1H-NMR-spectroscopic study of
the thus obtained title compound, it was possible to show that the
above-mentioned title compound is only the pure .alpha.-anomer.
[1288] Elementary analysis: Cld: C, 52.94; H, 6.77. Fnd: C, 52.80;
H, 6.78.
c)
6-[1-O-.alpha.-(2,3,4,6-Tetra-O-benzyl-D-mannopyranosyl)-hexanoic
acid
[1289] A stirred suspension of 141.0 g (289 mmol) of the title
compound of Example 70b in 200 ml of dioxane is mixed in portions
with a total of 238.5 g (4.26 mol) of fine-powder potassium
hydroxide powder at room temperature and with simultaneous vigorous
stirring. To make it easier to stir, the reaction mixture is mixed
with another 200 ml of dioxane, and the thus obtained suspension is
subsequently heated to boiling and mixed at this temperature drop
by drop with a total of 372 ml (3.128 mol) of benzyl bromide over a
period of two hours. After a reaction time of 4 hours at
110.degree. C. followed by 12 hours at room temperature, the
reaction mixture is slowly poured into a total of 2.5 liters of ice
water for the purpose of working-up, and the aqueous phase is
subsequently completely extracted with diethyl ether. After the
thus obtained ether phase is washed, and after the subsequent
drying of the same with sodium sulfate, salt is suctioned out, and
the diethyl ether is drawn off in a vacuum. Excess benzyl bromide
is then quantitatively distilled off from the reaction mixture in
an oil pump vacuum at an oil bath temperature of 180.degree. C. The
thus obtained, resinous-oily residue is purified on silica gel with
use of ethyl acetate/hexane (1:10) as an eluant.
[1290] Yield: 172.2 g (91.0% of theory) of the above-mentioned
title compound in the form of a colorless and extremely viscous
oil.
[1291] Elementary analysis: Cld: C, 75.68; H, 7.16. Fnd: C, 75.79;
H, 7.04.
d)
6-[1-O-.alpha.-(2,3,4,6-Tetra-O-benzyl-D-mannopyranosyl)-hexanoic
acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide
[1292] 100 g (134 mmol) of the acid that is described in Example
70c and 13.5 g (134 mmol) of triethylamine are dissolved in 1200 ml
of dry tetrahydrofuran. After cooling to -15.degree. C., a solution
of 18.45 g (135 mmol) of isobutyl chloroformate in 200 ml of dry
tetrahydrofuran is slowly added in drops while being stirred,
whereby the internal temperature does not exceed -10.degree. C.
After a reaction time of 15 minutes at -15.degree. C., a solution
of 165.5 g (134 mmol) of 1-amino-1H,1H,2H,2H-perfluorodecane and
13.5 g (134 mmol) of triethylamine in 250 ml of dry tetrahydrofuran
is added in drops at -20.degree. C. After a reaction time of one
hour at -15.degree. C. and two hours at room temperature, the
reaction solution is evaporated to the dry state in a vacuum. The
remaining residue is taken up in 300 ml of ethyl acetate and washed
twice with 400 ml each of saturated sodium bicarbonate solution and
once with 500 ml of water. After the organic phase is dried on
sodium sulfate, salt is suctioned out, and the ethyl acetate is
drawn off in a vacuum. The remaining oily residue is purified on
silica gel with use of dichloromethane/hexane/2-propanol (10:5:1)
as an eluant.
[1293] Yield: 143.8 g (86.9% of theory)
[1294] Elementary analysis: Cld: C, 57.38; H, 4.98; N, 1.13; F,
26.15. Fnd: C, 57.30; H, 5.44; N, 1.01; F, 26.25.
e) 6-[1-O-.alpha.-D-Mannopyranosyl)-hexanoic acid
N-(3-oxa-1H,1H,2H,2H,4H,- 4H,5H,5H-perfluorotridecyl)-amide
[1295] 40.0 g (32.38 mmol) of the title compound of Example 70d is
dissolved in 750 ml of 2-propanol and mixed with 2.0 g of palladium
catalyst (10% Pd/C). The reaction solution is hydrogenated for 12
hours at 22.degree. C. and 1 atmosphere of hydrogen pressure. Then,
catalyst is filtered out, and the filtrate is evaporated to the dry
state. The remaining residue is taken up in 300 ml of dimethyl
sulfoxide, and 21.52 g (88.0% of theory) of the above-mentioned
title compound is obtained as a colorless and crystalline powder
with the decomposition melting point of 88.5.degree. C. from the
thus obtained product solution by mixing with a total of 1000 ml of
diethyl ether after the precipitated solid is suctioned off.
[1296] Elementary analysis: Cld: C, 36.01; H, 5.92; N, 1.75; F,
40.34. Fnd: C, 36.07; H, 6.08; N, 1.76; F, 40.66.
f) Production of a formulation that consists of metal complex I and
6-[1-O-.alpha.-D-mannopyranosyl)-hexanoic acid
N-(3-oxa-1H,1H,2H,2H,4H,4H- ,5H,5H-perfluorotridecyl)-amide
[1297] 3.17 g (4.2 mmol) of the title compound of Example 70e is
added to 35 ml of a solution of metal complex I (280 mmol/L),
dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L
of CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common
salt solution to a total of 98 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A solution that is produced in such a way
can be used directly for biological experiments. (The concentration
is 100 mmol of Gd/L.)
EXAMPLE 71
a)
1-O-.alpha.-D-[(1-Perfluorooctylsulfonylpiperazine-4-carbonyl)-pentyl-5-
]-2,3,4,6-tetra-O-benzyl-mannopyranose
[1298] 74.59 g (100 mmol) of the acid that is described in Example
71c and 10.11 g (100 mmol) of triethylamine are dissolved in 800 ml
of a mixture that consists of tetrahydrofuran/acetonitrile (mixing
ratio 7:3). Then, it is mixed drop by drop at room temperature with
500 ml of a tetrahydrofuran solution of 58.0 g (102.0 mmol) of
1-perfluorooctylsulfonylpiperazine, 10.11 g (100 mmol) of
triethylamine and 16.84 g (110 mmol) of 1-hydroxybenzotriazole. The
thus obtained reaction solution is mixed at -5.degree. C. with a
solution of 22.7 g (110 mmol) of dicyclohexylcarbodiimide,
dissolved in 100 ml of tetrahydrofuran, and then it is stirred at
-5.degree. C. for another two hours. After the reaction solution
has thawed, it is stirred at room temperature for another 12 hours,
precipitated dicyclohexylurea is filtered out, and the filtrate
that is obtained is evaporated to the dry state in a vacuum. The
remaining residue is taken up in 600 ml of ethyl acetate and washed
twice with 300 ml each of saturated sodium bicarbonate solution and
twice with 300 ml each of water. After the organic phase is dried
on sodium sulfate, salt is suctioned out, and the ethyl acetate is
drawn off in a vacuum. The remaining oily residue is purified on
silica gel with use of dichloromethane/acetone/2-propanol (16:2:1)
as an eluant.
[1299] Yield: 113.01 g (79.8% of theory) of a colorless and viscous
oil
[1300] Elementary analysis: Cld: C, 58.52; H, 4.27; N, 1.98; S,
2.26; F, 22.80. Fnd: C, 58.42; H, 4.41; N, 1.80; S, 2.28; F,
23.02.
b)
1-O-.alpha.-D-[(1-Perfluorooctylsulfonyl-piperazine-4-carbonyl)-pentyl--
5]-mannopyranose
[1301] 50 g (35.30 mmol) of the title compound of Example 71a is
dissolved in a mixture that consists of 500 ml of 2-propanol and 50
ml of water, and 2 g of palladium catalyst (10% Pd on activated
carbon) is added. It is hydrogenated for 12 hours at room
temperature. Catalyst is filtered out, and the filtrate is
evaporated to the dry state in a vacuum. The residue is dissolved
in 200 ml of methanol, and the reaction product is precipitated by
mixing with a total of 800 ml of diethyl ether. After the thus
obtained solid is suctioned off, the latter is dried in a vacuum at
50.degree. C.
[1302] Yield: 29.51 g (99% of theory) of an amorphous solid
[1303] Elementary analysis: Cld: C, 34.13; H, 3.46; N, 3.32; S,
3.80; F, 38.23. Fnd: C, 34.28; H, 3.81; N, 3.25; S, 3.80; F,
38.01.
c) Production of a formulation that consists of metal complex II
and
1-O-.alpha.-D-[(1-perfluorooctylsulfonyl-piperazine-4-carbonyl)-pentyl-5]-
-mannopyranose
[1304] 9.92 g (11.75 mmol) of the title compound of Example 71b is
added to 47 ml of a solution of metal complex II (250 mmol/L),
dissolved in 0.45% aqueous sodium chloride solution, and it is
heated for 10 minutes in the microwave. The solution is cooled to
room temperature, filtered with a 0.2 .mu.m filter, and the
filtrate is decanted into vials. A thus produced solution can be
used directly for biological experiments. (The concentration is 250
mmol of Gd/L.)
EXAMPLE 72
a)
2-Acetamido-2-deoxy-1,3,4,6-(tetra-O-benzyl)-.alpha.,.beta.-D-glucopyra-
nose
[1305] A total of 24.0 g (108.5 mmol) of
2-acetamido-2-deoxy-.alpha.,.beta- .-D-glucopyranose, dissolved in
500 ml of absolute dimethyl sulfoxide, is added drop by drop at
room temperature to a stirred suspension of 20.16 g (700 mmol; 80%
in mineral oil) of sodium hydride in 150 ml of dimethyl sulfoxide.
Then, it is allowed to stir for another 120 minutes at room
temperature, and then 159.5 g (1.26 mol) of benzyl chloride is
added in drops. The thus obtained reaction solution is subsequently
stirred for another 12 hours at room temperature. For working-up,
the reaction solution is slowly poured into 1.5 liters of ice water
and then exhaustively extracted with diethyl ether. The combined
diethyl ether phases are subsequently washed twice with 600 ml each
of saturated sodium bicarbonate solution and twice with 800 ml each
of water. After the organic phase is dried on sodium sulfate, salt
is suctioned out, and the solvent is drawn off in a vacuum. The
remaining oily residue is purified on silica gel with use of ethyl
acetate/hexane (1:5) as an eluant.
[1306] Yield: 48.68 g (73.6% of theory) of the above-mentioned
title compound in the form of a viscous and colorless oil.
[1307] Elementary analysis: Cld: C, 70.92; H, 6.45; N, 6.89. Fnd:
C, 71.43; H, 6.44; N, 7.02.
b)
1-O-Benzyl-3,4,6-tri-O-benzyl-2-amino-2-deoxy-.alpha.,.beta.-D-glucopyr-
anose
[1308] 30.0 g (49.2 mmol) of the title compound of Example 72a is
suspended in a mixture that consists of 750 ml of methanol and 215
ml of water, and it is mixed drop by drop at room temperature with
a total of 440 ml (49.2 mmol) of a 0.112 molar aqueous perchloric
acid solution. After the addition has been completed, the reaction
solution is stirred for 10 more minutes at room temperature, and
the thus obtained, now homogenous reaction solution is subsequently
evaporated to the dry state in a vacuum. By mixing the remaining
oily residue with a mixture that consists of equal parts of hexane
and dichloromethane, the latter is brought to crystallization. The
crystalline reaction product is suctioned off, washed with hexane
and dried in a vacuum at room temperature.
[1309] Yield: 27.08 g (86% of theory) of the above-mentioned title
compound in the form of its perchlorate, which is present as a
colorless, crystalline compound.
[1310] Melting point: 180.5-181.5.degree. C.
[1311] Elementary analysis: Cld: C, 63.68; H, 5.98; N, 2.19; Cl,
5.54. Fnd: C, 63.43; H, 6.04; N, 2.02; Cl, 5.71.
c)
1,3,4,6-Tetra-O-benzyl-2-deoxy-2-[acetyl-(2-amino-N-ethyl-N-perfluorooc-
tylsulfonyl)-amino]-1-.alpha.,.beta.-D-glucopyranose
[1312] 20.8 g (35.6 mmol) of the
2-[N-ethyl-N-perfluorooctylsulfonyl)-amin- oacetic acid and 3.60 g
(35.6 mmol) of triethylamine are dissolved in 350 ml of dry
tetrahydrofuran. After the reaction solution is cooled to
-15.degree. C. to -20.degree. C., a solution of 4.92 g (35.6 mmol)
of isobutyl chloroformate in 75 ml of dry tetrahydrofuran is slowly
added in drops at this temperature while being stirred, whereby the
rate of addition by drops can be selected in such a way that an
internal temperature of -10.degree. C. is not exceeded. After a
reaction time of 15 minutes at -15.degree. C., a solution of 22.78
g (35.6 mmol) of the perchlorate (title compound of Example 72b)
and 3.60 g (35.6 mmol) of triethylamine, in 100 ml of dry
tetrahydrofuran at -20.degree. C. is then slowly added in drops.
After a reaction time of one hour at -15.degree. C. and two hours
at room temperature, the reaction solution is evaporated to the dry
state in a vacuum. The remaining residue is taken up in 250 ml of
ethyl acetate and washed twice with 100 ml each of saturated sodium
bicarbonate solution and once with 200 ml of water. After the
organic phase is dried on sodium sulfate, salt is suctioned out,
and the ethyl acetate is drawn off in a vacuum. The remaining oily
residue is purified on silica gel with use of ethyl acetate/hexane
(1:5) as an eluant.
[1313] Yield: 33.3 g (84.6% of theory) of the above-mentioned title
compound as a colorless and strongly viscous oil.
[1314] Elementary analysis: Cld: C, 49.92; H, 3.92; N, 2.53; F,
29.18; S, 2.90. Fnd: C, 49.99; H, 4.11; N, 2.69; F, 29.22; S,
3.01.
d)
2-Deoxy-2-[acetyl-(2-amino-N-ethyl-N-perfluorooctylsulfonyl)-amino]-1-.-
alpha.,.beta.-D-glucopyranose
[1315] 20.0 g (18.06 mmol) of the title compound of Example 72c is
dissolved in 250 ml of 2-propanol and mixed with 1.5 g of palladium
catalyst (10% Pd/C). The reaction solution is hydrogenated for 12
hours at 22.degree. C. and 1 atmosphere of hydrogen pressure. Then,
catalyst is filtered out, and the filtrate is evaporated to the dry
state. The remaining residue is taken up in 300 ml of dimethyl
sulfoxide, and 12.65 g (93.8% of theory) of the above-mentioned
title compound is obtained as a colorless and crystalline powder
from the thus obtained product solution by mixing with 750 ml of a
mixture that consists of equal parts of diethyl ether and ethyl
acetate after the precipitated solid is suctioned off. The
above-mentioned title compound is present as an
.alpha./.beta.-anomer mixture, whereby the ratio relative to the
two possible anomers was determined at about 1:1.2 by
.sup.1H-NMR-spectroscop- ic studies. The title compound is
accordingly an almost approximately evenly distributed
.alpha./.beta.-anomer mixture.
[1316] Melting point: 132.5-133.degree. C.
[1317] Elementary analysis: Cld: C, 28.97; N, 2.57; N, 3.75; F,
43.27; S, 4.30. Fnd: C, 29.09; N, 2.56; N, 3.84; F, 43.36; S,
4.42.
e) Production of a formulation that consists of metal complex XIV
and
2-deoxy-2-[acetyl-(2-amino-N-ethyl-N-perfluorooctylsulfonyl)-amino]-1-.al-
pha.,.beta.-D-glucopyranose
[1318] A solution that consists of 4.90 g (6.57 mmol) of the title
compound of Example 3d, dissolved in 200 ml of ethanol, is added to
51 ml of a solution of metal complex XIV (300 mmol/L), dissolved in
0.45% sodium chloride solution (pH 7.4/0.25 mg/L of
CaNa.sub.3DTPA), and it is stirred for 2 hours at 50.degree. C. The
solution is evaporated to the dry state in a vacuum, and the
residue is made up with distilled water to a total of 153 ml. It is
stirred for 10 minutes at 40.degree. C. and filtered with a 0.2
.mu.m filter. The filtrate is decanted into vials. A thus produced
solution can be used directly for biological experiments. (The
concentration is 100 mmol of Gd/L.)
EXAMPLE 73
a) 1,2,3,4,6-Penta-O-acetyl-.alpha.-D-glucopyranose
[1319] Analogously to what is described for the synthesis of title
compound 70a, the reaction of 100 g (555.0 mmol) of
.alpha.-D-glucopyranose with a mixture that consists of 1000 ml of
absolute pyridine and 1000 ml of acetic acid anhydride after
working-up and recrystallization from 95% aqueous ethanol yields
190.6 g (88.0%) of the above-mentioned title compound as a
colorless and crystalline compound. By .sup.1H-NMR-spectroscopic
study of the thus obtained title compound, it was possible to
determine the .alpha. to .beta. ratio of two possible anomers at
.gtoreq.98:2. The title compound accordingly is the exclusively
.alpha.-configured anomer.
[1320] Melting point: 110.5.degree. C.
[1321] Elementary analysis: Cld: C, 49.21; H, 5.68. Fnd: C, 49.24;
H, 5.68.
b)
5-(Ethoxycarbonyl)pentyl-2,3,4,6-tetra-O-acetyl-.alpha.-D-glucopyranosi-
de
[1322] Analogously to what is described in the synthesis of the
title compound of Example 70b, the reaction of 130.0 g (332.8 mmol)
of the title compound of Example 4a) with 55.8 ml (332.8 mmol) of
6-hydroxy-hexanoic acid ethyl ester and 50.6 ml (520 mmol) of
tin(IV) chloride in 500 ml of 1,2-dichloroethane after
column-chromatographic purification (eluant:hexane/ethyl acetate
2:1) yields 101.85 g (62.4% of theory) of the above-mentioned title
compound as a colorless and viscous oil. After
.sup.1H-NMR-spectroscopic study of the title compound, the presence
of the .beta.-configuration at the anomeric center was definitively
established based on the size of the coupling constant of
J.sub.1,2=8.8 Hz; moreover, said configuration represents the sole
existing configuration at the anomeric center. The above-mentioned
title compound thus could be shown only in the form of the
.beta.-configured anomer.
[1323] Elementary analysis: Cld: C, 52.94; H, 6.77. Fnd: C, 52.77;
H, 6.70.
c)
5-(Carboxy)pentyl-2,3,4,6-tetra-O-benzyl-.alpha.-D-glucopyranoside
[1324] A stirred suspension of 100.0 g (204.96 mmol) of the title
compound of Example 73b in 150 ml of dioxane is mixed in portions
at room temperature and with simultaneous, vigorous stirring with a
total of 169.14 g (3.02 mol) of fine-powder potassium hydroxide
powder. To make it easier to stir, the reaction mixture is mixed
with another 150 ml of dioxane, and the thus obtained suspension is
subsequently heated to boiling and mixed drop by drop at this
temperature with a total of 264 ml (2.218 mol) of benzyl bromide
over a period of two hours. After a reaction time of 4 hours at
110.degree. C. followed by 12 hours at room temperature, the
reaction mixture is slowly poured into a total of 2.0 liters of ice
water for the purpose of working-up, and the aqueous phase is
subsequently completely extracted with diethyl ether. After the
thus obtained ether phase is washed and after the subsequent drying
of the organic phase on sodium sulfate, salt is suctioned out, and
the diethyl ether is drawn off in a vacuum. Excess benzyl bromide
is then quantitatively distilled off from the reaction mixture in
an oil pump vacuum at an oil bath temperature of 180.degree. C. The
thus obtained, remaining oily residue is purified on silica gel
with use of ethyl acetate/hexane (1:10) as an eluant.
[1325] Yield: 128.8 g (84.3% of theory) of the above-mentioned
title compound in the form of a colorless and extremely viscous
oil
[1326] Elementary analysis: Cld: C, 75.68; H, 7.16. Fnd: C, 75.66;
H, 7.23.
d) 2,3,4,6-Tetra-O-benzyl-1-O-.beta.-D-[6-hexanoic
acid-N-(3-oxa-1H,1H,2H,-
2H,4H,4H,5H,5H-perfluorotridecyl)-amide]-glucopyranose
[1327] 68.5 g (91.79 mmol) of the acid that is described in Example
73c and 9.25 g (91.79 mmol) of triethylamine are dissolved in 825
ml of dry tetrahydrofuran. After the reaction solution is cooled to
-15.degree. C. to -20.degree. C., a solution of 12.64 g (92.5 mmol)
of isobutyl chloroformate in 150 ml of dry tetrahydrofuran is
slowly added in drops at this temperature while being stirred,
whereby the rate of addition by drops can be selected in such a way
that an internal temperature of -10.degree. C. is not exceeded.
After a reaction time of 15 minutes at -15.degree. C., a solution
of 46.40 g (91.79 mmol) of
1H,1H,2H,2H-heptadecafluoro-1-(2-aminoethoxy)-decane and 9.25 g
(91.79 mmol) of triethylamine is then slowly added in drops as a
solution to 200 ml of dry tetrahydrofuran at -20.degree. C. After a
reaction time of one hour at -15.degree. C. and two hours at room
temperature, the reaction solution is evaporated to the dry state
in a vacuum. The remaining residue is taken up in 250 ml of ethyl
acetate and washed twice with 300 ml each of saturated sodium
bicarbonate solution and once with 400 ml of water. After the
organic phase is dried on sodium sulfate, salt is suctioned out,
and the ethyl acetate is drawn off in a vacuum. The remaining oily
residue is purified on silica gel with use of
dichloromethane/hexane/2-propanol (10:5:1) as an eluant.
[1328] Yield: 104.7 g (92.4% of theory) of the above-mentioned
title compound as a colorless and strongly viscous oil
[1329] Elementary analysis: Cld: C, 57.38; H, 4.98; N, 1.13; F,
26.15. Fnd: C, 57.27; H, 5.09; N, 1.11; F, 26.08.
e) 1-O-.beta.-D-[6-Hexanoic
acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfluor-
otridecyl)-amide]-glucopyranose
[1330] 40.0 g (32.38 mmol) of the title compound of Example 73d is
dissolved in 750 ml of 2-propanol and mixed with 2.0 g of palladium
catalyst (10% Pd/C). The reaction solution is hydrogenated for 12
hours at 22.degree. C. and 1 atmosphere of hydrogen pressure. Then,
catalyst is filtered out, and the filtrate is evaporated to the dry
state. The remaining residue is taken up in 300 ml of dimethyl
sulfoxide, and 22.05 g (90.2% of theory) of the title compound is
obtained as a colorless and crystalline powder with a decomposition
melting point of 122-124.degree. C. from the thus obtained product
solution by mixing with a total of 1000 ml of diethyl ether and
subsequent suctioning-off of the precipitated solid.
[1331] Elementary analysis: Cld: C, 36.01; H, 5.92; N, 1.75; F,
40.34. Fnd: C, 36.07; H, 6.08; N, 1.76; F, 40.66.
f) Production of a formulation that consists of the title compound
of Example 12 from WO 99/01161
(1,4,7-tris{1,4,7-tris(N-carboxylatomethyl)-1-
0-(N-1-methyl-3-aza-2,5-dioxo-pentane-1,5-diyl]-1,4,7,10-tetraazacyclodode-
cane, Gd
complex}-10-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1-
,4,7,10-tetraazacyclododecane) and 1-O-.beta.-D-[6-hexanoic
acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide]-glucopyra-
nose
[1332] 20.29 g (25.9 mmol) of the title compound of Example 73e is
added to 37 ml of a solution of 1,4,7-tris
{1,4,7-tris(N-carboxylatomethyl)-10--
(N-1-methyl-3-aza-2,5-dioxo-pentane-1,5-diyl]-1,4,7,10-tetraazacyclododeca-
ne, Gd
complex}-10-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1,4-
,7,10-tetraazacyclododecane (300 mmol/L), dissolved in 0.45%
aqueous common salt solution (pH 7.4; 0.25 mg/L of CaNa.sub.3DTPA),
and it is made up with a 0.9% aqueous common salt solution to a
total of 111 ml. It is heated for 2 hours at 60.degree. C. in an
ultrasound bath. The solution is cooled to room temperature and set
at pH 7.4 with aqueous 2N sodium hydroxide solution. It is filtered
with a 0.2 .mu.m filter, and the filtrate is decanted into vials. A
thus produced solution can be used directly for biological
experiments. (The concentration is 100 mmol of Gd/L.)
EXAMPLE 74
a)
1-O-(1H,1H,2H,2H-Perfluorodecyl)-(2,3,4,6-tetra-O-acetyl)-.alpha.-D-man-
nopyranose
[1333] The reaction of 50 g (128.09 mmol) of the title compound of
Example 70a, which is used as a 4:1 mixture relative to the
.alpha.,.beta.-anomers, with a solution of 75.84 g (128.1 mmol) of
1-hydroxy-1H,1H,2H,2H-perfluorodecane in 150 ml of
1,2-dichloroethane and a total of 19.47 g (166.53 mmol) of tin(IV)
chloride, analogously to what is described for the syntheses of the
title compounds of Examples 1b) and 4b), results, after working-up
and column-chromatographic purification (eluant:hexane/ethyl
acetate, 2:1), in the formation of 74.2 g (63.4% of theory) of the
above-mentioned title compound in the form of a viscous and
colorless oil. After .sup.1H-NMR-spectroscopic study of the title
compound, the presence of the .alpha.-configuration at the anomeric
center was definitively established based on the size of the
coupling constant of J.sub.1,2=1.3 Hz; moreover, said configuration
represents the sole existing configuration at the anomeric center,
so that the above-mentioned title compound accordingly could be
represented only in the form of the pure .alpha.-configured
anomer.
[1334] Elementary analysis: Cld: C, 44.65; H, 2.53; F, 35.32. Fnd:
C, 44.77; H, 2.61; F, 35.09.
b) 1-O-(1H,1H,2H,2H-Perfluorodecyl)-.alpha.-D-mannopyranose
[1335] 25 g (27.33 mmol) of the title compound of Example 74a is
suspended in 400 ml of absolute methanol and mixed at 5.degree. C.
with a catalytic amount of sodium methanolate. After a reaction
time of 3 hours at room temperature, even thin-layer
chromatographic checking (eluant:chloroform/methanol 9:1) of the
course of the reaction indicates quantitative reaction. For the
purpose of working-up, the now clear reaction solution is
neutralized by mixing with Amberlite IR 120 (H.sup.+
form)-cation-exchange resin, exchanger is suctioned out, and the
thus obtained methanolic filtrate is drawn off in a vacuum until a
dry state is reached. The crystalline residue that is obtained is
purified by twice-repeated recrystallization of ethanol. After
.sup.1H-NMR-spectroscopic study of the title compound, the presence
of the a-configuration at the anomeric center was definitively
established based on the size of the coupling constant of
J.sub.1,2=1.0 Hz. The existing .alpha.-configuration is the sole
existing configuration at the anomeric center, i.e., the amount of
.beta.-configured anomer of the title compound that can possibly be
formed lies below the .sup.1H-NMR-spectroscopic detection limit.
The above-mentioned title compound was accordingly represented only
in the form of the pure .alpha.-configured anomer.
[1336] Yield: 16.2 g (94.6% of theory) of a colorless and
crystalline solid Melting point: 172-174.degree. C. while
decomposing.
[1337] Elementary analysis: Cld: C, 30.69; H, 2.41; F, 51.57. Fnd:
C, 30.57; H, 2.48; F, 51.65.
c) Production of a formulation that consists of metal complex II
and 1-O-(1H,1H,2H,2H-perfluorodecyl)-.alpha.-D-mannopyranose
[1338] A solution that consists of 2.01 g (3.21 mmol) of the title
compound of Example 74b, dissolved in 200 ml of ethanol, is added
to 50 ml of a solution of metal complex II (150 mmol/L), dissolved
in 0.45% sodium chloride solution (pH 7.4/0.25 mg/L of
CaNa.sub.3DTPA), and it is stirred for 2 hours at 50.degree. C. The
solution is evaporated to the dry state in a vacuum, and the
residue is made up with distilled water to a total of 75 ml. It is
stirred for 10 minutes at 40.degree. C. and filtered with a 0.2
.mu.m filter. The filtrate is decanted into vials. A thus produced
solution can be used directly for biological experiments. (The
concentration is 100 mmol of Gd/L.)
EXAMPLE 75
a)
1-O-(1H,1H,2H,2H-Perfluorododecyl)-2,3,4,6-tetra-O-acetyl-.alpha.-D-man-
nopyranose
[1339] The reaction of 35 g (89.66 mmol) of the title compound of
Example 70a, which is used as a 4:1 mixture relative to the
.alpha.,.beta.-anomers, with a solution of 50.60 g (89.7 mmol) of
1-hydroxy-1H,1H,2H,2H-perfluorododecane in 100 ml of
1,2-dichloroethane and a total of 13.63 g (16.61 mmol) of tin(IV)
chloride, analogously to what is described for the syntheses of the
title compounds of Examples 1b), 4b) and 5b), results, after
working-up and column-chromatographic purification
(eluant:hexane/ethyl acetate=2:1), in the formation of 62.49 g
(68.7% of theory) of the above-mentioned title compound in the form
of a viscous and colorless oil. After .sup.1H-NMR-spectroscopic
study of the title compound, the presence of the
.alpha.-configuration at the anomeric center was definitively
established based on the size of the coupling constant of
J.sub.1,2=1.4 Hz; moreover, said a-configuration represents the
sole existing configuration at the anomeric center, so that
accordingly the above-mentioned title compound can be represented
only in the form of the pure .alpha.-configured anomer.
[1340] Elementary analysis: Cld: C, 42.62; H, 2.28; F, 39.32. Fnd:
C, 42.55; H, 2.38; F, 39.40.
b) 1-O-(1H,1H,2H,2H-Perfluorododecyl)-.alpha.-D-mannopyranose
[1341] 25 g (24.64 mmol) of the title compound of Example 75a is
suspended in 400 ml of absolute methanol and mixed at 5.degree. C.
with a catalytic amount of sodium methanolate. After a reaction
time of 3 hours at room temperature, even thin-layer
chromatographic checking (eluant:chloroform/methanol=9:1) of the
course of the reaction indicates quantitative reaction. For the
purpose of working-up, the now clear reaction solution is
neutralized by mixing with Amberlite IR 120 (H.sup.+
form)-cation-exchange resin, exchanger is suctioned out, and the
thus obtained methanolic filtrate is drawn off in a vacuum until a
dry state is reached. The crystallization residue that is obtained
is purified by twice-repeated recrystallization of a mixture that
consists of 2-propanol/ethanol (1:1). After
.sup.1H-NMR-spectroscopic study of the title compound, the presence
of the .alpha.-configuration at the anomeric center was
definitively established based on the size of the coupling constant
of J.sub.1,2=0.9 Hz. The existing .alpha.-configuration is the sole
existing configuration at the anomeric center, i.e., the amount of
.beta.-configured anomer of the title compound that can possibly be
formed lies below the .sup.1H-NMR-spectroscopic detection limit.
The above-mentioned title compound was accordingly represented only
in the form of the pure .alpha.-configured anomer.
[1342] Yield: 16.96 g (90.8% of theory) of a colorless and
crystalline solid
[1343] Melting point: 187-188.degree. C. while decomposing.
[1344] Elementary analysis: Cld: C, 29.77; H, 2.08; F, 54.93. Fnd:
C, 29.70; H, 2.28; F, 54.83.
c) Production of a formulation that consists of metal complex VI
and 1-O-(1H,1H,2H,2H-perfluorodecyl)-.alpha.-D-mannopyranose
[1345] 1.70 g (2.34 mmol) of the title compound of Example 75b is
added to 52 ml of a solution of metal complex VI (180 mmol/L),
dissolved in 0.45% aqueous sodium chloride solution, and it is
heated for 10 minutes in the microwave. The solution is cooled to
room temperature, filtered with a 0.2 .mu.m filter, and the
filtrate is decanted into vials. A thus produced solution can be
used directly for biological experiments. (The concentration is 180
mmol of Gd/L.)
EXAMPLE 76
a)
2,3,4,6-Tetra-O-acetyl)-1-O-.alpha.-D-[3,6,9-trioxa-(C.sub.12-C.sub.19--
heptadecafluoro)-nonadecyl]-mannopyranose
[1346] The reaction of 20 g (51.23 mmol) of the title compound of
Example 70a, which is used as a 4:1 mixture relative to the
.alpha.,.beta.-anomers, with a solution of 30.54 g (51.23 mmol) of
1-hydroxy-tris-(1H,1H,2H,2H-O)-1H,1H,2H,2H-perfluorodecane in 100
ml of 1,2-dichloroethane and a total of 5.98 g (51.23 mmol) of
tin(IV) chloride, analogously to what is described for the
syntheses of the title compounds of Examples 1b), 4b) and 5b),
results, after working-up and column-chromatographic purification
(eluant:hexane/ethyl acetate=1:1), in the formation of 34.22 g
(72.1% of theory) of the above-mentioned title compound in the form
of a viscous and colorless oil. After .sup.1H-NMR-spectroscopic
study of the title compound, the presence of the
.alpha.-configuration at the anomeric center was definitively
established based on the size of the coupling constant of
J.sub.1,2=1.1 Hz; moreover, said a-configuration represents the
sole existing configuration at the anomeric center, so that
accordingly the above-mentioned title compound can be represented
only in the form of the pure .alpha.-configured anomer.
[1347] Elementary analysis: Cld: C, 38.89; H, 3.81; F, 34.86. Fnd:
C, 39.02; H, 3.77; F, 34.90.
b)
1-O-.alpha.-D-[3,6,9-Trioxa-(C.sub.12-C.sub.19-heptadecafluoro)-nonadec-
yl]-mannopyranose
[1348] 20 g (21.58 mmol) of the title compound of Example 76a is
suspended in 350 ml of absolute methanol and mixed at 5.degree. C.
with a catalytic amount of sodium methanolate. After a reaction
time of 3 hours at room temperature, even thin-layer
chromatographic checking (eluant:chloroform/methanol=6:1) of the
course of the reaction indicates quantitative reaction. For
working-up, the now clear reaction solution is neutralized by
mixing with Amberlite IR 120 (H.sup.+ form)-cation-exchange resin,
exchanger is suctioned out, and the thus obtained methanolic
filtrate is drawn off in a vacuum until a dry state is reached. The
crystalline residue that is obtained is purified by twice-repeated
recrystallization from a mixture that consists of ethyl
acetate/2-propanol/ethanol (1:0.5:1). After
.sup.1H-NMR-spectroscopic study of the title compound, the presence
of the .alpha.-configuration at the anomeric center was
definitively established based on the size of the coupling constant
of J.sub.1,2=1.0 Hz. The existing .alpha.-configuration is the sole
existing configuration at the anomeric center, i.e., the amount of
.beta.-configured anomer of the title compound that can possibly be
formed lies below the .sup.1H-NMR-spectroscopic detection limit.
The above-mentioned title compound was accordingly represented only
in the form of the pure .alpha.-configured anomer.
[1349] Yield: 15.20 g (92.9% of theory) of a colorless, crystalline
solid
[1350] Melting point: 141.degree. C.
[1351] Elementary analysis: Cld: C, 34.84; H, 3.59; F, 42.58. Fnd:
C, 34.72; H, 3.66; F, 42.67.
c) Production of a formulation that consists of the title compound
of Example 68 and
1-O-.alpha.-D-[3,6,9-trioxa-(C.sub.12-C.sub.19-heptadecafl-
uoro)-nonadecyl]-mannopyranose
[1352] 3.71 g (4.89 mmol) of the title compound of Example 76b is
added to 38 ml of a solution of the title compound of Example 68
(300 mmol/L), dissolved in 0.45% aqueous common salt solution (pH
7.4; 0.25 mg/L of CaNa.sub.3DTPA), and it is made up with a 0.9%
aqueous common salt solution to a total of 114 ml. It is heated for
2 hours at 60.degree. C. in an ultrasound bath. The solution is
cooled to room temperature and set at pH 7.4 with aqueous 2N sodium
hydroxide solution. It is filtered with a 0.2 .mu.m filter, and the
filtrate is decanted into vials. A thus produced solution can be
used directly for biological experiments. (The concentration is 100
mmol of Gd/L.)
EXAMPLE 77
a) 2,3,4,6-Tetra-O-acetyl-1-.alpha.-D-[3-thiopropionic
acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl)-amide]-mannopyra-
nose
[1353] 25.0 g (57.28 mmol) [production according to: Ponpipom,
Mitree M.; Bugianesi, Robert L.; Robbins, James C.; Doebber, T. W.;
Shen, T. Y.; J. Med. Chem.; 24; 12; 1981; 1388-1395] of
3-(tetra-O-acetyl-.alpha.-D-manno- pyranosylmercapto)-propionic
acid and 5.77 g (57.28 mmol) of triethylamine are dissolved in 500
ml of dry tetrahydrofuran. After the reaction solution is cooled to
-15.degree. C. to -20.degree. C., a solution of 7.82 g (57.28 mmol)
of isobutyl chloroformate in 100 ml of dry tetrahydrofuran is
slowly added in drops at this temperature while being stirred,
whereby the rate of addition by drops can be selected in such a way
that an internal temperature of -10.degree. C. is not exceeded.
After a reaction time of 15 minutes at -15.degree. C., a solution
of 29.05 g (57.28 mmol) of
1H,1H,2H,2H-heptadecafluoro-1-(2-aminoethyoxy)-decane and 5.77 g
(57.28 mmol) of triethylamine is subsequently slowly added in drops
as a solution to 200 ml of dry tetrahydrofuran at -20.degree. C.
After a reaction time of one hour at -15.degree. C. and two hours
at room temperature, the reaction solution is evaporated to the dry
state in a vacuum. The remaining residue is taken up in 250 ml of
ethyl acetate, and it is washed twice with 200 ml each of saturated
sodium bicarbonate solution and once with 300 ml of water. After
the organic phase is dried on sodium sulfate, salt is suctioned
out, and the ethyl acetate is drawn off in a vacuum. The remaining
oily residue is purified on silica gel with use of
dichloromethane/hexane/2-propanol (8:5:1) as an eluant.
[1354] Yield: 44.90 g (84.7% of theory) of the above-mentioned
title compound as a colorless and strongly viscous oil.
[1355] Elementary analysis: Cld: C, 37.63; H, 3.48; N, 1.51; S,
3.46; F, 34.89. Fnd: C, 37.77; H, 3.37; N, 1.61; S, 3.57; F,
35.21.
b) 1-.alpha.-D-[3-Thiopropionic
acid-N-(3-oxa-1H,1H,2H,2H,4H,4H,5H,5H-perf-
luorotridecyl)-amide]-mannopyranose
[1356] 30 g (32.41 mmol) of the title compound of Example 77a is
suspended in 400 ml of absolute methanol and mixed at 5.degree. C.
with a catalytic amount of sodium methanolate. After a reaction
time of 3 hours at room temperature, even thin-layer
chromatographic checking (eluant:chloroform/methanol=9:1) of the
course of the reaction indicates quantitative reaction. For
working-up, the now clear reaction solution is neutralized by
mixing with Amberlite IR 120 (H.sup.+ form)-cation-exchange resin,
exchanger is suctioned out, and the thus obtained methanolic
filtrate is drawn off in a vacuum until a dry state is reached. The
crystalline residue that is obtained is purified by
recrystallization from a mixture that consists of ethyl
acetate/methanol (0.5:1). After .sup.1H-NMR-spectroscopic study of
the title compound, the presence of the .alpha.-configuration at
the anomeric center was definitively established based on the size
of the coupling constant of J.sub.1,2=1.1 Hz. The existing
a-configuration is the sole existing configuration at the anomeric
center, i.e., the amount of .beta.-configured anomer of the title
compound that can possibly be formed lies below the
.sup.1H-NMR-spectroscopic detection limit. The above-mentioned
title compound was accordingly represented only in the form of the
pure .alpha.-configured anomer.
[1357] Yield: 23.76 g (96.8% of theory) of a colorless and
crystalline solid
[1358] Melting point: 113-114.5.degree. C.
[1359] Elementary analysis: Cld: C, 33.30; H, 3.19; N, 1.85; S,
4.23; F, 42.64. Fnd: C, 33.21; H, 3.26; N, 1.96; S, 4.08; F,
42.77.
c) Production of a formulation that consists of the title compound
of Example 66 and 1-.alpha.-D-[3-thiopropionic
acid-N-(3-oxa-1H,1H,2H,2H,4H,-
4H,5H,5H-perfluorotridecyl)-amide]-mannopyranose
[1360] A solution that consists of 27.41 g (36.19 mmol) of the
title compound of Example 77b, dissolved in 200 ml of ethanol, is
added to 47 ml of a solution of the title compound of Example 66
(330 mmol/L), dissolved in 0.45% sodium chloride solution (pH
7.4/0.25 mg/L of CaNa.sub.3DTPA), and it is stirred for 2 hours at
50.degree. C. The solution is evaporated to the dry state in a
vacuum, and the residue is made up with distilled water to a total
of 155 ml. It is stirred for 10 minutes at 40.degree. C. and
filtered with a 0.2 .mu.m filter. The filtrate is decanted into
vials. A thus produced solution can be used directly for biological
experiments. (The concentration is 100 mmol of Gd/L.)
EXAMPLE 78
a)
2,3,4,6-Tetra-O-acetyl-1-.beta.-D-[3,6,9-trioxa-(C.sub.12-C.sub.19-hept-
adecafluoro)-nonadecyl]-glucopyranosyluronic acid
[1361] 20.2 g (50.85 mmol) of methyl
(1-bromo-2,3,4-tri-O-acety-.alpha.-D-- glucopyranoside)uronate
[production according to: Pelzer; Hoppe-Seyler's Z. Physiol. Chem.;
314; 1949; 234, 237 and Goebel; Babers; J. Biol. Chem.; 111; 1935;
347, 350 and Bollenback et al.; J. Amer. Chem. Soc.; 77; 1955;
3310, 3313] and 60.64 g (101.7 mmol) of 3,6,9-trioxa-(C.sub.12--
C.sub.19-heptadecafluoro)-nonadecan-1-ol are dissolved in 250 ml of
anhydrous acetonitrile and mixed at room temperature with 13.0 g of
freshly precipitated silver oxide. After a reaction time of 12
hours at room temperature, insoluble silver salts are filtered out,
the salts are thoroughly rewashed with dichloromethane, and the
thus obtained filtrate is drawn off in a vacuum until a dry state
is reached. The remaining residue is purified by column
chromatography (eluant:hexane/ethyl acetate=3:1).
[1362] Yield: 22.99 g (53.3% of theory) of the above-mentioned
title compound as a colorless, highly viscous oil.
[1363] Elementary analysis: Cld: C, 41.05; H, 3.92; F, 38.06. Fnd:
C, 41.20; H, 3.76; F, 38.22.
b)
1-O-.beta.-D-[3,6,9-Trioxa-(C.sub.12-C.sub.19-heptadecafluoro)-nonadecy-
l]-glucopyranosyluronic acid
[1364] 10.0 g (11.78 mmol) of the title compound of Example 78a is
suspended in 200 ml of a mixture that consists of methanol and 0.5
molar sodium hydroxide solution at a ratio of 2:1 while being
stirred at room temperature. After a reaction time of 12 hours at
room temperature, the now clear reaction mixture is neutralized for
working-up by mixing with Amberlite IR 120 (H.sup.+
form)-cation-exchange resin, exchanger is suctioned out, and the
thus obtained methanolic-aqueous filtrate is drawn off in a vacuum
until a dry state is reached. The crystalline residue that is
obtained is purified by recrystallization from a mixture that
consists of ethyl acetate/methanol (0.25:1). After
.sup.1H-NMR-spectroscopic study of the title compound, the presence
of the .beta.-configuration at the anomeric center was definitively
established based on the size of the coupling constant of
J.sub.1,2=9.2 Hz. The existing P-configuration is the sole existing
configuration at the anomeric center, i.e., the amount of
.beta.-configured anomer of the title compound that can possibly be
formed lies below the .sup.1H-NMR-spectroscopic detection limit.
The above-mentioned title compound was accordingly represented only
in the form of the pure .beta.-configured anomer.
[1365] Melting point: 78.5.degree. C.
[1366] Elementary analysis: Cld: C, 34.21; H, 3.26; F, 41.81. Fnd:
C, 34.38; H, 3.26; F, 41.90.
c) Production of a formulation that consists of metal complex I and
1-O-.beta.-D-[3,6,9-trioxa-(C.sub.12-C.sub.19-heptadecafluoro)-nonadecyl]-
-glucopyranosyluronic acid
[1367] 19.18 g (24.83 mmol) of the title compound of Example 78b is
added to 38 ml of a solution of metal complex 1 (280 mmol/L),
dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L
of CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common
salt solution to a total of 53.2 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The concentration is 200 mmol
of Gd/L.)
EXAMPLE 79
a)
6-(2-Oxa-1H,1H,3H,3H,4H,4H-perfluorodecyl)-O.sup.1,O.sup.2,O.sup.3,O.su-
p.4-diisopropylidene-.alpha.-D-galactopyranose
[1368] A total of 12.15 g (46.66 mmol) of
O.sup.1,O.sup.2,O.sup.3,O.sup.4--
diisopropylidene-.alpha.-galactopyranose [production according to:
Levene; Meyer; J. Biol. Chem.; 64; 1925; 473 and McCreath; Smith;
J. Chem. Soc.; 1939; 387, 389 and Freudenberg; Hixon; Chem. Ber.;
56; 1923; 2119, 2122], dissolved in 200 ml of absolute
dimethylformamide, is added drop by drop at room temperature to a
stirred suspension of 2.01 g (70.0 mmol; 80% in mineral oil) of
sodium hydride in 25 ml of dimethylformamide. It is then allowed to
stir for 120 more minutes at room temperature, and subsequently a
total of 30.09 g (48.0 mmol) of 1-bromo-1H,1H,2H,2H-perflu-
orododecane, dissolved in 150 ml of absolute dimethylformamide, is
slowly added in drops. The thus obtained reaction solution is
subsequently stirred for another 12 hours at room temperature. For
working-up, the reaction solution is slowly poured into 1 liter of
ice water and then exhaustively extracted with diethyl ether. The
combined organic phases are subsequently washed twice with 200 ml
each of saturated sodium bicarbonate solution and twice with 200 ml
each of water. After the organic phase is dried on sodium sulfate,
salt is suctioned out, and the solvent is drawn off in a vacuum.
The remaining oily residue is purified on silica gel with use of
ethyl acetate/hexane (1:10) as an eluant.
[1369] Yield: 29.8 g (79.3% of theory) of the above-mentioned title
compound in the form of a viscous, colorless oil.
[1370] Elementary analysis: Cld: C, 35.75; H, 2.87; F, 49.47. Fnd:
C, 35.64; H, 2.98; F, 49.54.
b)
6-(2-Oxa-1H,1H,3H,3H,4H,4H-perfluorodecyl)-.alpha.-D-galactopyranose
[1371] 20 g (24.8 mmol) of the title compound of Example 79a is
mixed with 300 ml of a 1% aqueous sulfuric acid solution and
stirred for 3 hours at 80.degree. C. After cooling to room
temperature, it is neutralized by mixing with aqueous barium
hydroxide solution, precipitated barium sulfate is subsequently
filtered out, and the thus obtained clear aqueous product solution
is freeze-dried. By .sup.1H-NMR-spectroscopic study of the title
compound, it was possible to show clearly the presence of two
possible configurations at the anomeric center, whereby the
existing .alpha./.beta.-configuration ratio according to
.sup.1H-NMR-spectroscopic study was determined with 1:1.4
(.alpha.:.beta.) at the anomeric center. The above-mentioned title
compound was accordingly isolated only in the form of 1:1.4
(.alpha.:.beta.)-anomer mixture, i.e., an anomeric separation was
eliminated.
[1372] Yield: 15.28 g (98.4% of theory) of the above-mentioned
title compound as a colorless lyophilizate
[1373] Elementary analysis (relative to anhydrous substance): Cld:
C, 35.75; H, 2.87; F, 49.47. Fnd: C, 35.64; H, 2.98; F, 49.54.
c) Production of a formulation that consists of the title compound
of Example 67 and
6-(2-oxa-1H,1H,3H,3H,4H,4H-perfluorodecyl)-.alpha.-D-galac-
topyranose
[1374] A solution that consists of 1.68 g (2.69 mmol) of the title
compound of Example 79b, dissolved in 200 ml of ethanol, is added
to 43 ml of a solution of the title compound of Example 67 (250
mmol/L), dissolved in 0.45% sodium chloride solution (pH 7.4/0.25
mg/L of CaNa.sub.3DTPA), and it is stirred for 2 hours at
50.degree. C. The solution is evaporated to the dry state in a
vacuum, and the residue is made up with distilled water to a total
of 107.5 ml. It is stirred for 10 minutes at 40.degree. C. and
filtered with a 0.2 .mu.m filter. The filtrate is decanted into
vials. A thus produced solution can be used directly for biological
experiments. (The concentration is 100 mmol of Gd/L.)
EXAMPLE 80
a)
1-O-.alpha.-D-[(1-Perfluorooctylsulfonylpiperazine-4-carbonyl-)-methyl]-
-mannopyranose
[1375] 30 g (52.8 mmol) of 1-perfluorooctylsulfonylpiperazine
(production described in DE 196 03 033) and 31.73 g (53 mmol) of
2,3,4,6-tetra-O-benzyl-.alpha.-D-carboxymethyl-mannopyranose
(production described in DE 197 28 954) are dissolved in 300 ml of
tetrahydrofuran. At 0.degree. C., 24.73 g (100 mmol) of EEDQ
(=1,2-dihydro-2-ethoxyquinoli- ne-1-carboxylic acid ethyl ester) is
added, and it is stirred for 3 hours at 0.degree. C., then for 6
hours at room temperature. The solution is evaporated to the dry
state in a vacuum, and the residue is purified by flash
chromatography on silica gel (mobile solvent:hexane/ethyl
acetate=10:1). The product-containing fractions are evaporated to
the dry state, the residue is dissolved in a mixture that consists
of 200 ml of methanol/150 ml of dichloromethane, and it is
hydrogenated for 8 hours on palladium/carbon (10% Pd/C 2 g).
Hydrogenating catalyst is filtered out, and the filtrate is
evaporated to the dry state. The residue is recrystallized from
acetone/diethyl ether.
[1376] Yield: 30.39 g (73% of theory) of a waxy, colorless
solid
[1377] Elementary analysis: Cld: C, 30.47; H, 2.68; F, 40.96; N,
3.55; S, 4.07. Fnd: C, 30.61; H, 2.75; F, 41.10; N, 3.46; S,
4.12.
b) Production of a formulation that consists of metal complex I and
1-O-.alpha.-D-[(1-perfluorooctylsulfonylpiperazine-4-carbonyl-)-methyl]-m-
annopyranose
[1378] 4.71 g (5.97 mmol) of the title compound of Example 80a is
added to 32 ml of a solution of metal complex I (280 mmol/L),
dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L
of CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common
salt solution to a total of 55 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The concentration is 200 mmol
of Gd/L.)
EXAMPLE 81
a) 3-Oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid, sodium
salt
[1379] 20 g (38.3 mmol) of
3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid (production
described in DE 196 03 033) is dissolved in 300 ml of ethanol, and
7.7 ml of 5N aqueous sodium hydroxide solution is added. It is
evaporated to the dry state, and the residue is dried in a vacuum
drying oven (8 hours, 60.degree. C.).
[1380] Yield: 20.85 g (quantitative) of a colorless, crystalline
powder
[1381] Elementary analysis: Cld: C, 26.49; H, 1.11; F, 59.35; Na,
4.22. Fnd: C, 26.60; H, 1.19; F, 59.47; Na, 4.30.
b) Production of a formulation that consists of metal complex I and
3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid, sodium salt
[1382] 2.09 g (3.84 mmol) of the title compound of Example 81a is
added to 32 ml of a solution of metal complex 1 (280 mmol/L),
dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L
of CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common
salt solution to a total of 90 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The concentration is 100 mmol
of Gd/L.)
c) Production of a formulation that consists of metal complex I and
3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid, sodium salt
[1383] 1.00 g (1.84 mmol) of the title compound of Example 81a is
added to 32 ml of a solution of metal complex I (280 mmol/L),
dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L
of CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common
salt solution to a total of 90 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The concentration is 100 mmol
of Gd/L.)
d) Production of a formulation that consists of metal complex I and
3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid, sodium salt
[1384] 0.54 g (1.0 mmol) of the title compound of Example 81 a is
added to 32 ml of a solution of metal complex I (280 mmol/L),
dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L
of CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common
salt solution to a total of 90 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The concentration is 100 mmol
of Gd/L.)
EXAMPLE 82
a)
1-Perfluorooctylsulfonyl-4-(3,6,9,12,15-pentaoxahexadecanoyl)-piperazin-
e
[1385] 20 g (35.2 mmol) of perfluorooctylsulfonylpiperazine (see
Example 80a) is dissolved in 300 ml of dichloromethane, and 5.06 g
(50 mmol) of triethylamine is added. It is cooled to 0.degree. C.
and 14.24 g (50 mmol) of 3,6,9,12,15-pentaoxahexanoic acid chloride
is added in drops within 20 minutes, and it is stirred for 3 hours
at 0.degree. C. 400 ml of 5% aqueous hydrochloric acid is added,
and it is thoroughly stirred. The organic phase is separated, dried
on magnesium sulfate and evaporated to the dry state in a vacuum.
The residue is chromatographed on silica gel (mobile
solvent=dichloromethane/methanol: 15:1).
[1386] Yield: 26.44 (92% of theory) of a waxy solid
[1387] Elementary analysis: Cld: C, 33.83; H, 3.58; N, 3.43; F,
39.55; S, 3.93. Fnd: C, 33.96; H, 3.66; N, 3.50; F, 39.67; S,
3.82.
b) Production of a formulation that consists of metal complex I and
1-perfluorooctylsulfonyl-4-(3,6,9,12,15-pentaoxahexadecanoyl)-piperazine
[1388] 4.61 g (5;,64 mmol) of the title compound of Example 82a is
added to 47 ml of a solution of metal complex I (280 mmol/L),
dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L
of CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common
salt solution to a total of 66 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The concentration is 200 mmol
of Gd/L.)
EXAMPLE 83
a) 1H,1H,2H,2H-Perfluorodecyl-p-toluenesulfonic acid ester
[1389] 20 g (43.1 mmol) of 1H,1H,2H,2H-perfluorodecanol is
dissolved in 200 ml of pyridine, and 9.53 g (50 mmol) of
p-toluenesulfonic acid chloride is added in portions at 0.degree.
C. It is stirred for 5 hours at room temperature. The solution is
poured into 1000 ml of ice water and stirred for 10 minutes. The
precipitate is filtered off, washed with a lot of water and then
recrystallized from acetone.
[1390] Yield: 22.04 g (97% of theory) of a colorless, crystalline
solid
[1391] Elementary analysis: Cld: C, 22.78; H, 0.76; F, 61.26; S,
6.08. Fnd: C, 22.89; H, 0.70; F, 61.39; S, 6.15.
b)
C.sub.18-C.sub.25-Heptadeca-fluoro-3,6,9,12,15-pentaoxa-pentacosan-1-ol
[1392] 20 g (37.94 mmol) of the title compound of Example 83a,
35.74 g (150 mmol) of pentaethylene glycol and 1 g of 18-crown-6
are dissolved in 300 ml of tetrahydrofuran, and 10.1 g (180 mmol)
of fine-powder potassium hydroxide is added. It is stirred for 10
hours at room temperature. Solid is filtered out, and the filtrate
is evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile
solvent:dichloromethane/methanol=15:1).
[1393] Yield: 5.45 g (21% of theory) of a colorless, viscous
oil
[1394] Elementary analysis: Cld: C, 35.10; H, 3.68; F, 47.19. Fnd:
C, 35.22; H, 3.77; F, 47.10.
c) Production of a formulation that consists of the title compound
of Example 69 and
C.sub.18-C.sub.25-heptadeca-fluoro-3,6,9,12,15-pentaoxa-pe-
ntacosan-1-ol
[1395] 44.98 g (65.72 mmol) of the title compound of Example 83b)
is added to 53 ml of a solution of the title compound of Example 69
(310 mmol/L), dissolved in 0.45% aqueous sodium chloride solution,
and it is heated for 10 minutes in the microwave. The solution is
cooled to room temperature, filtered with a 0.2 .mu.m filter, and
the filtrate is decanted into vials. A thus produced solution can
be used directly for biological experiments. (The concentration is
310 mmol of Gd/L.)
EXAMPLE 84
a) N,N-Bis(8-hydroxy-3,6-dioxa-octyl)-perfluorooctylsulfonic acid
amide
[1396] 15 g (29.23 mmol) of perfluorooctylsulfonic acid amide and
22.16 g (87.7 ml) of 9-(tetrahydropyran-2-yl)-3,6,9-trioxa-nonyl
chloride are dissolved in 200 ml of acetonitrile. 41.46 g (300
mmol) of potassium carbonate and 1 g (6 mmol) of potassium iodide
are added, and it is refluxed for 10 hours. The solid is filtered
off, and the filtrate is evaporated to the dry state in a vacuum.
The residue is dissolved in 400 ml of ethanol, and 30 ml of 10%
aqueous hydrochloric acid is added. It is stirred for 2 hours at
room temperature. It is set at pH 7 with sodium hydroxide solution,
and the solution is concentrated by evaporation in a vacuum. The
residue is chromatographed on silica gel (mobile
solvent:dichloromethane/methanol=10:1).
[1397] Yield: 11.38 g (51% of theory) of a colorless, viscous
oil
[1398] Elementary analysis: Cld: C, 31.46; H, 3.43; N, 1.83; F,
42.30; S, 4.20. Fnd: C, 31.59; H, 3.50; N, 1.90; F, 42.46; S,
4.08.
b) Production of a formulation that consists of metal complex I and
N,N-bis(8-hydroxy-3,6,-dioxa-octyl)-perfluorooctylsulfonic acid
amide
[1399] 7.91 g (10.36 mmol) of the title compound of Example 84a is
added to 37 ml of a solution of metal complex 1 (280 mmol/L),
dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L
of CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common
salt solution to a total of 104 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The concentration is 100 mmol
of Gd/L.)
EXAMPLE 85
a) N,N-Bis(t-butyloxycarbonylmethyl)-perfluorooctylsulfonic acid
amide
[1400] 20 g (38.97 mmol) of perfluorooctylsulfonic acid amide and
20.73 g (150 mol) of potassium carbonate are suspended in 200 ml of
acetone, and 17.56 g (90 mmol) of bromoacetic acid-tert-butyl ester
is added. It is refluxed for 3 hours. The solid is filtered off,
and the filtrate is evaporated to the dry state in a vacuum. The
residue is chromatographed on silica gel (mobile
solvent:n-hexane/ethyl acetate=10:1).
[1401] Yield: 23.53 g (83% of theory) of a colorless, waxy
solid
[1402] Elementary analysis: Cld: C, 33.02; H, 3.05; F, 44.40; N,
1.93; S, 4.41. Fnd: C, 33.19; H, 3.11; F, 44.30; N, 1.99; S,
4.32.
b) N,N-Bis(carboxymethyl)-perfluorooctylsulfonic acid amide,
disodium salt
[1403] 23 g (31.62 mmol) of the title compound of Example 85a is
dissolved in 300 ml of trifluoroacetic acid and stirred for 5 hours
at room temperature. It is evaporated to the dry state in a vacuum,
and the residue is recrystallized from acetone. The crystals are
suctioned off and dried at 50.degree. C. in a vacuum.
[1404] Yield: 17.7 g (91% of theory) of a colorless, crystalline
powder
[1405] 17 g (27.63 mmol) of the thus obtained dioic acid is
dissolved in 100 ml of water/300 ml of ethanol, and 9.2 ml of 3N
aqueous sodium hydroxide solution is added. It is stirred for 20
minutes at room temperature and then evaporated to the dry state in
a vacuum. The residue is dried in a vacuum (60.degree. C./8
hours).
[1406] Yield: 18.2 g of colorless, crystalline powder
[1407] Elementary analysis: Cld: C, 21.87; H, 0.61; N, 2.12; F,
49.00; S, 4.86 Na, 6.98. Fnd: C, 22.00; H, 0.70; N, 2.20; F, 49.17;
S, 4.93 Na, 7.10.
c) Production of a formulation that consists of metal complex II
and N,N-bis(carboxymethyl)-perfluorooctylsulfonic acid amide,
disodium salt
[1408] 2.89 g (4.39 mmol) of the title compound of Example 85b is
added to 41 ml of a solution of metal complex 11 (250 mmol/L),
dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L
of CaNa.sub.3DTPA, and it is made up with a 0.9% aqueous common
salt solution to a total of 52 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The concentration is 200 mmol
of Gd/L.)
EXAMPLE 86
a) 1H,1H,2H,2H-Perfluorododecyl-sulfuric acid monoester, sodium
salt
[1409] 10 g (17.73 mmol) of 1H,1H,2H,2H-perfluorododecanol is
dissolved in 300 ml of chloroform, and 2.82 g (17.73 mmol) of
sulfur trioxide-pyridine complex is added at 0.degree. C. It is
stirred for one hour at 0.degree. C. and then evaporated to the dry
state in a vacuum. The residue is dissolved in 300 ml of ethanol
and mixed with 17.8 ml of 1N aqueous sodium hydroxide solution. The
solution is evaporated to the dry state, and the residue is dried
in a vacuum (60.degree. C./2 hours).
[1410] Yield: 11.81 g (quantitative)
[1411] Elementary analysis: Cld: C, 21.64; H, 0.61; F, 59.89; Na,
3.45; S, 4.81. Fnd: C, 21.70; H, 0.72; F, 60.00; Na, 3.57; S,
4.92.
b) Production of a formulation that consists of metal complex VI
and 1H,1H,2H,2H-perfluorododecyl-sulfuric acid monoester, sodium
salt
[1412] 4.90 g (7.35 mmol) of the title compound of Example 86a is
added to 38 ml of a solution of metal complex VI (290 mmol/L),
dissolved in 0.45% aqueous sodium chloride solution), and it is
heated for 10 minutes in the microwave. The solution is cooled to
room temperature, filtered with a 0.2 .mu.m filter, and the
filtrate is decanted into vials. A thus produced solution can be
used directly for biological experiments. (The concentration is 290
mmol of Gd/L.)
EXAMPLE 87
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluoropentadecanoic acid, sodium
salt
[1413] 10 g (16.07 mmol) of
2H,2H,4H,4H,5H,5H-3-oxa-perfluoropentadecanoic acid is dissolved in
300 ml of ethanol, and it is mixed with 16.1 ml of 1N aqueous
sodium hydroxide solution. The solution is evaporated to the dry
state, and the residue is dried in a vacuum (60.degree. C./2
hours).
[1414] Yield: 10.35 g (quantitative) of a colorless, amorphous
powder
[1415] Elementary analysis: Cld: C, 26.10; H, 0.94; F, 61.94; Na,
3.57. Fnd: C, 26.22; H, 1.00; F, 62.05; Na, 3.66.
b) Production of a formulation that consists of the title compound
of Example 66 and 2H,2H,4H,4H,5H,5H-3-oxa-perfluoropentadecanoic
acid, sodium salt
[1416] A solution that consists of 3.36 g (5.21 mmol) of the title
compound of Example 87a, dissolved in 200 ml of ethanol, is added
to 45 ml of a solution of the title compound of Example 66 (270
mmol/L), dissolved in 0.45% sodium chloride solution (pH 7.4/0.25
mg/L of CaNa.sub.3DTPA), and it is stirred for 2 hours at
50.degree. C. The solution is evaporated to the dry state in a
vacuum, and the residue is made up with distilled water to a total
of 122 ml. It is stirred for 10 minutes at 40.degree. C. and
filtered with a 0.2 .mu.m filter. The filtrate is decanted into
vials. A thus produced solution can be used directly for biological
experiments. (The concentration is 100 mmol of Gd/L.)
EXAMPLE 88
a) Ethylenediamine-N,N-tetraacetic
acid-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-p-
erfluorotridecyl)-monoamide
[1417] 10.14 g (20 mmol) of
1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecy- lamine is added in
portions at 50.degree. C. to 30 g (117.1 mmol) of
EDTA-bisanhydride, suspended in 200 ml of dimethylformamide, and 50
ml of pyridine, and it is stirred for 6 hours at 50.degree. C. 10
ml of water is added, it is stirred for 10 minutes at 50.degree.
C., and the residue is evaporated to the dry state. The residue is
taken up in a little water and brought to pH 4 with glacial acetic
acid. The insoluble precipitate is filtered off and chromatographed
on RP-18 (mobile solvent:acetonitrile/water/gradient).
[1418] Yield: 9.58 g (61% of theory) of a colorless solid
[1419] Water content: 8%
[1420] Elementary analysis: Cld: C, 33.64; H, 3.59; N, 5.35; F,
41.12. Fnd: C, 33.51; H, 3.69; N, 5.44; F, 41.24.
b) Ethylenediamine-N,N-tetraacetic
acid-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-p-
erfluorotridecyl)-monoamide, calcium salt, sodium salt
[1421] 9.0 g (11.46 mmol) of the title substance of Example 88a is
suspended in 300 ml of water, and 11.4 ml of 1N aqueous sodium
hydroxide solution is added. Then, 1.15 g (11.46 mmol) of calcium
carbonate is added, and it is stirred for 5 hours at 50.degree. C.
The solution is filtered, and the filtrate is freeze-dried.
[1422] Yield: 9.7 g (100% of theory) of a colorless, amorphous
solid
[1423] Water content: 7.5%
[1424] Elementary analysis: Cld: C, 31.25; H, 2.98; N, 4.97; F,
38.20; Na, 2.72; Ca, 4.74. Fnd: C, 31.40; H, 3.09; N, 5.10; F,
38.07; Na, 2.81; Ca, 4.82.
c) Production of a formulation that consists of metal complex I and
ethylenediamine-N,N-tetraacetic
acid-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-per-
fluorotridecyl)-monoamide, calcium salt, sodium salt
[1425] 2.54 g (3.01 mmol) of the title compound of Example 88b is
added to 43 ml of a solution of metal complex I (280 mmol/L),
dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L
of CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common
salt solution to a total of 121 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The concentration is 100 mmol
of Gd/L.)
EXAMPLE 89
a)
1H,1H,2H,2H-Perfluorodecyl-(2,2-dimethyl-5-hydroxy-1,3-dioxepan-6-yl)-e-
ther
[1426] 30 g (64.64 mmol) of 1H,1H,2H,2H-perfluorodecanol is
dissolved in 200 ml of tetrahydrofuran, and 1.68 g (70 mmol) of
sodium hydride is added at 0.degree. C. It is stirred for 2 hours
at room temperature, then for 4 hours at 60.degree. C. The solution
is added to a metal autoclave, then 9.31 g (64.64 mmol) of
2,2-dimethyl-1,3,6-trioxabicyclo[5.1.0]octane is added and then
heated for 10 hours to 150.degree. C. The reaction solution is
poured onto ice water and extracted 2 times with diethyl ether. The
combined organic phases are evaporated to the dry state, and the
residue is chromatographed on silica gel (mobile
solvent:dichloromethane/acetone=10:1.)
[1427] Yield: 16.12 g (41% of theory) of a colorless solid
[1428] Elementary analysis: Cld: C, 33.57; H, 2.82; F, 53.10. Fnd:
C, 33.69; H, 2.90; F, 53.35.
b)
1H,1H,2H,2H-Perfluorodecyl-(1-hydroxymethyl-2,3-dihydroxypropyl)-ether
[1429] 15 g (24.66 mmol) of the title compound of Example 89a is
dissolved in 300 ml of ethanol, and 30 ml of 10% aqueous
hydrochloric acid is added. It is refluxed for 5 hours. It is set
at pH 7 with sodium hydroxide solution, then evaporated to the dry
state, and the residue is chromatographed on RP-18 (mobile
solvent:acetonitrile/water/gradient).
[1430] Yield: 12.75 g (91% of theory) of a colorless solid
[1431] Water content: 4.5%
[1432] Elementary analysis: Cld: C, 29.59; H, 2.31; F, 56.84. Fnd:
C, 29.48; H, 2.37; F, 56.99.
c) Production of a formulation that consists of the title compound
of Example 12 of WO 99/01161
(1,4,7-tris{1,4,7-tris(N-carboxylatomethyl)-10--
(N-1-methyl-3-aza-2,5-dioxo-pentane-1,5-diyl]-1,4,7,10-tetraazacyclododeca-
ne, Gd
complex}-10-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1,4-
,7,10-tetraazacyclododecane) and
1H,1H,2H,2H-perfluorodecyl-(1-hydroxymeth-
yl-2,3-dihydroxypropyl)-ether
[1433] 9.46 g (16.65 mmol) of the title compound of Example 89b is
added to 37 ml of a solution of
1,4,7-tris{1,4,7-tris(N-carboxylatomethyl)-10-(-
N-1-methyl-3-aza-2,5-dioxo-pentane-1,5-diyl]-1,4,7,10-tetraazacyclododecan-
e, Gd
complex}-10-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1,4,-
7,10-tetraazacyclododecane (300 mmol/L), dissolved in 0.45% aqueous
common salt solution (pH 7.4; 0.25 mg/L of CaNa.sub.3DTPA), and it
is made up with a 0.9% aqueous common salt solution to a total of
111 ml. It is heated for 2 hours at 60.degree. C. in an ultrasound
bath. The solution is cooled to room temperature and set at pH 7.4
with aqueous 2N sodium hydroxide solution. It is filtered with a
0.2 .mu.m filter, and the filtrate is decanted into vials. A thus
produced solution can be used directly for biological experiments.
(The concentration is 100 mmol of Gd/L.)
EXAMPLE 90
a)
1H,1H,2H,2H-Perfluorodecyl-[1,2-bis(2,2-dimethyl-1,3-dioxolan-4-yl)-2-h-
ydroxyethyl]-ether
[1434] 30 g (64.64 mmol) of 1H,1H,2H,2H-perfluorodecanol is
dissolved in 200 ml of tetrahydrofuran, and 1.68 g (70 mmol) of
sodium hydride is added at 0.degree. C. It is stirred for 2 hours
at room temperature, then for 4 hours at 60.degree. C. The solution
is added to a metal autoclave, then 15.78 g (64.64 mmol) of
1,2-bis-(2,2-dimethyl-1,3-dioxolan-4-yl)-oxi- ran is added, and
then it is heated for 10 hours to 150.degree. C. The reaction
solution is poured onto ice water and extracted 2 times with
diethyl ether. The combined organic phases are evaporated to the
dry state, and the residue is chromatographed on silica gel (mobile
solvent:dichloromethane/acetone=10:1).
[1435] Yield: 14.2 g (31% of theory) of a colorless solid
[1436] Elementary analysis: Cld: C, 37.30; H, 3.56; F, 45.59. Fnd:
C, 37.48; H, 3.66; F, 45.71.
b)
1H,1H,2H,2H-Perfluorodecyl-[1,2-bis(1,2-dihydroxy-ethyl)-2-hydroxyethyl-
]-ether
[1437] 14 g (19.76 mmol) of the title compound of Example 90a is
dissolved in 300 ml of ethanol, and 30 ml of 10% aqueous
hydrochloric acid is added. It is refluxed for 5 hours. It is set
at pH 7 with sodium hydroxide solution, then it is evaporated to
the dry state, and the residue is chromatographed on RP-18 (mobile
solvent:acetonitrile/water/gr- adient).
[1438] Yield: 10.55 g (85% of theory) of a colorless solid
[1439] Water content: 3.2%
[1440] Elementary analysis: Cld: C, 30.59; H, 2.73; F, 51.41. Fnd:
C, 30.73; H, 2.81; F, 51.58.
c) Production of a formulation that consists of metal complex II
and
1H,1H,2H,2H-perfluorodecyl-[1,2-bis(1,2-dihydroxy-ethyl)-2-hydroxyethyl]--
ether
[1441] 11.98 g (19.07 mmol) of the title compound of Example 90b is
added to 41 ml of a solution of metal complex 11 (300 mmol/L),
dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L
of CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common
salt solution to a total of 64 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The concentration is 200 mmol
of Gd/L.)
EXAMPLE 91
a) Perfluorooctylsulfonic acid-N,N-bis[(8-sulfuric acid-monoester,
sodium salt)-3,6-dioxaoctyl]-amide
[1442] 13.54 g (17.73 mmol) of the title compound of Example 84a is
dissolved in 300 ml of chloroform, and 2.82 g (17.73 mmol) of
sulfur trioxide-pyridine complex is added at 0.degree. C. It is
stirred for one hour at 0.degree. C., and then it is evaporated to
the dry state in a vacuum. The residue is dissolved in 300 ml of
ethanol and mixed with 17.8 ml of 1N aqueous sodium hydroxide
solution. The solution is evaporated to the dry state, and the
residue is dried in a vacuum (60.degree. C./2 hours).
[1443] Yield: 17.15 g (quantitative)
[1444] Elementary analysis: Cld: C, 24.83; H, 2.50; F, 33.83; N,
1.45; S, 9.94; Na, 4.75. Fnd: C, 24.96; H, 2.62; F, 33.97; N, 1.53;
S, 10.05; Na, 4.86.
b) Production of a formulation that consists of metal complex I and
perfluorooctylsulfonic acid-N,N-bis[(8-sulfuric acid-monoester,
sodium salt)-3,6-dioxaoctyl]-amide
[1445] 142.29 g (147.06 mmol) of the title compound of Example 91a
is added to 43 ml of a solution of metal complex I (380 mmol/L),
dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L
of CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common
salt solution to a total of 164 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The concentration is 100 mmol
of Gd/L.)
EXAMPLE 92
a)
2-(2H,2H,3H,3H,5,5H,6H,6H-1,4-Dioxaperfluorotetradec-1-yl)-succinic
acid-diethyl ester
[1446] 30 g (59.03 mmol) of
1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotrideca- nol is added to 300
ml of tetrahydrofuran, and at 0.degree. C., 1.68 g (70 mmol) of
sodium hydride is added. It is stirred for one hour at 0.degree.
C., then for 5 hours at 40.degree. C. In this 40.degree. C.
solution, 20.25 g (80 mmol) of bromosuccinic acid diethyl ester is
added in drops within 10 minutes, and it is then stirred for 12
hours at this temperature. 500 ml of ice water is added, and it is
extracted 2 times with 300 ml of diethyl ether. The combined
organic phases are evaporated to the dry state in a vacuum, and the
residue is chromatographed on silica gel (mobile
solvent:n-hexane/ethanol=20:1).
[1447] Yield: 12.05 g (30% of theory)
[1448] Elementary analysis: Cld: C, 35.31; H, 3.11; F, 47.47. Fnd:
C, 35.19; H, 3.20; F, 47.59.
b)
2-(2H,2H,3H,3H,5H,5H,6H,6H-1,4-Dioxa-perfluorotetradec-1-yl)-succinic
acid, disodium salt
[1449] 50 ml of 3N aqueous sodium hydroxide solution is added to
11.5 g (16.90 mmol) of the title compound of Example 92a, dissolved
in 300 ml of methanol, and it is refluxed for 8 hours. It is
evaporated to the dry state, and the residue is taken up in 300 ml
of water. The aqueous phase is extracted 2 times with 300 ml of
diethyl ether. The aqueous phase is acidified with concentrated
hydrochloric acid to pH 1 and extracted 2 times with 300 ml of
chloroform. The combined chloroform phases are dried on magnesium
sulfate and evaporated to the dry state. The residue is dissolved
in 300 ml of water and set at pH 7.4 with 5% aqueous sodium
hydroxide solution. Then, it is freeze-dried.
[1450] Yield: 10.50 g (93% of theory) of a colorless, amorphous
solid
[1451] Water content: 5.7%
[1452] Elementary analysis: Cld: C, 28.76; H, 1.66; F, 48.33; Na,
6.88. Fnd: C, 28.88; H, 1.71; F, 48.25; Na, 6.95.
c) Production of a formulation that consists of metal complex II
and
2-(2H,2H,3H,3H,5H,5H,6H,6H-1,4-dioxa-perfluorotetradec-1-yl)-succinic
acid, disodium salt
[1453] 1.14 g (1.71 mmol) of the title compound of Example 92b is
added to 57 ml of a solution of metal complex 11 (300 mmol/L),
dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L
of CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common
salt solution to a total of 154 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The concentration is 100 mmol
of Gd/L.)
EXAMPLE 93
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic
acid-N-(succin-2-yl)-amide
[1454] 16.51 g (80 mmol) of N,N'-dicyclohexylcarbodiimide is added
at 0.degree. C. to 20 g (38.30 mmol) of
2H,2H,4H,4H,5H,5H-3-oxa-perfluorotri- decanoic acid and 9.21 g (80
mmol) of N-hydroxysuccinimide, dissolved in 150 ml of
dimethylformamide, and it is stirred for 3 hours at this
temperature. A solution, cooled to 0.degree. C., of 5.10 g (38.30
mmol) of L-asparaginic acid, dissolved in 300 ml of 5% aqueous
sodium carbonate solution, is added to the thus produced active
ester solution, and it is stirred for 2 hours at 0.degree. C. It is
poured onto 500 ml of ice water, precipitated dicyclohexylurea is
filtered out, and it is set at pH 1 with concentrated hydrochloric
acid. It is extracted 3 times with 300 ml of chloroform. The
combined, organic phases are evaporated to the dry state, and the
residue is chromatographed on RP-18 (mobile
solvent:acetonitrile/water/gradient). The thus obtained dioic acid
is dissolved in 400 ml of water and set at pH 7.4 with 1N aqueous
sodium hydroxide solution. It is filtered, and the filtrate is
freeze-dried.
[1455] Water content: 6.3%
[1456] Yield: 21.13 g (81% of theory) of a colorless, amorphous
powder
[1457] Elementary analysis: Cld: C, 28.21; H, 1.48; N, 2.06; F,
47.41; Na, 6.75. Fnd: C, 28.30; H, 1.53; N, 2.11; F, 47.53; Na,
6.83.
b) Production of a formulation that consists of metal complex XIV
and 2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecanoic
acid-N-(succin-2-yl)-amide
[1458] 422 mg (0.62 mmol) of the title compound of Example 93a is
added to 37 ml of a solution of metal complex XIV (300 mmol/L),
dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L
of CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common
salt solution to a total of 111 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The concentration is 100 mmol
of Gd/L.)
EXAMPLE 94
Production of a Formulation that Consists of the Title Compound of
Example 67 and Perfluorooctanesulfonic Acid, Sodium Salt.
[1459] A solution that consists of 1.34 g (2.69 mmol) of
perfluorooctanesulfonic acid, sodium salt, dissolved in 200 ml of
ethanol, is added to 43 ml of a solution of the title compound of
Example 67 (250 mmol/L), dissolved in 0.45% sodium chloride
solution (pH 7.4/0.25 mg/L of CaNa.sub.3DTPA), and it is stirred
for 2 hours at 50.degree. C. The solution is evaporated to the dry
state in a vacuum, and the residue is made to up a total of 108 ml
with distilled water. It is stirred for 10 minutes at 40.degree. C.
and filtered with a 0.2 .mu.m filter. The filtrate is decanted into
vials. A thus produced solution can be used directly for biological
experiments. (The concentration is 100 mmol of Gd/L.)
EXAMPLE 95
Production of a Formulation that Consists of the Title Compound of
Example 68 and Perfluorodecanesulfonic Acid, Sodium Salt
[1460] 3.03 g (5.06 mmol) of perfluorodecanesulfonic acid, sodium
salt, is added to 49 ml of a solution of the title compound of
Example 68 (310 mmol/L), dissolved in 0.45% aqueous sodium chloride
solution, and it is heated for 10 minutes in a microwave. The
solution is cooled to room temperature, filtered with a 0.2 .mu.m
filter, and the filtrate is decanted into vials. A thus produced
solution can be used directly for biological experiments. (The
concentration is 310 mmol of Gd/L.)
EXAMPLE 96
a) (1H,1H,2H,2H-Perfluorodecyl)-5-[(1,3-dicarboxy, disodium
salt)-phenyl]-ether
[1461] 42.5 g (80.62 mmol) of the title compound of Example 14a is
added to 20 g (80.62 mmol) of trisodium salt of
5-hydroxy-isophthalic acid in 300 ml of dimethylformamide, and it
is stirred for 10 hours at 60.degree. C. It is poured onto 1500 ml
of ice water and set at pH 1 with concentrated hydrochloric acid.
It is extracted 3 times with 300 ml of chloroform. The combined,
organic phases are concentrated by evaporation, and the residue is
chromatographed on RP-18 (mobile
solvent:acetonitrile/water/gradient). The dioic acid that is
purified in such a way is dissolved in 400 ml of water, and the pH
is brought to 7.4 with 1N aqueous sodium hydroxide solution. It is
filtered, and the filtrate is freeze-dried.
[1462] Yield: 20.05 g (37% of theory) of a colorless, amorphous
solid
[1463] Water content: 5.0%
[1464] Elementary analysis: Cld: C, 32.16; H, 1.05; F, 48.05; Na,
6.84. Fnd: C, 32.30; H, 1.15; F, 48.20; Na, 6.95.
b) Production of a Formulation that Consists of the Title Compound
of Example 12 of WO 99/01161
(1,4,7-tris{1,4,7-tris(N-carboxylatomethyl)-10--
(N-1-methyl-3-aza-2,5-dioxo-pentane-1,5-diyl]-1,4,7,10-tetraazacyclododeca-
ne, Gd
complex}-10-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1,4-
,7,10-tetraazacyclododecane) and
(1H,1H,2H,2H-perfluorodecyl)-5-[(1,3-dica- rboxy, disodium
salt)-phenyl]-ether
[1465] 6.86 g (10.2 mmol) of the title compound of Example 96a is
added to 51 ml of a solution of
1,4,7-tris{1,4,7-tris(N-carboxylatomethyl)-10-(N-1-
-methyl-3-aza-2,5-dioxo-pentane-1,5-diyl]-1,4,7,10-tetraazacyclododecane,
Gd complex
}-10-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-1,4,7-
,10-tetraazacyclododecane (300 mmol/L), dissolved in 0.45% aqueous
common salt solution (pH 7.4; 0.25 mg/L of CaNa.sub.3DTPA), and it
is made up with a 0.9% aqueous common salt solution to a total of
153 ml. It is heated for 2 hours at 60.degree. C. in an ultrasound
bath. The solution is cooled to room temperature and set at pH 7.4
with aqueous 2N sodium hydroxide solution. It is filtered with a
0.2 .mu.m filter, and the filtrate is decanted into vials. A thus
produced solution can be used directly for biological experiments.
(The concentration is 100 mmol of Gd/L.)
EXAMPLE 97
Production of a Formulation that Consists of Metal Complex XIV and
3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid, sodium salt
[1466] 434 mg (0.55 mmol) of the title compound of Example 80a is
added to 4 ml of a solution of metal complex XIV (320 mmol/L),
dissolved in 0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L
of CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common
salt solution to a total of 12.8 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The concentration is 100 mmol
of Gd/L.)
EXAMPLE 98
a) (Adamant-1-yl)-3-oxa-propionic acid-t-butylester
[1467] 29.26 g (150 mmol) of bromoacetic acid-tert-butyl ester is
added at 0.degree. C. to 15.22 g (100 mmol) of 1-adamantanol in 300
ml of 50% aqueous potassium hydroxide solution, 200 ml of toluene,
and it is vigorously and thoroughly stirred for 2 hours. It is
poured onto 1500 ml of water and extracted 2 times with 300 ml of
diethyl ether. The combined organic phases are dried on magnesium
sulfate and evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:n-hexane/diethyl
ether 20:1).
[1468] Yield: 21.58 g (81% of theory) of a viscous, colorless
oil
[1469] Elementary analysis: Cld: C, 72.14; H, 9.84. Fnd: C, 72.26;
H, 9.95.
b) (Adamant-1-yl)-3-oxa-propionic acid
[1470] 20 g (75 mmol) of the title compound of Example 98a is
dissolved at 0.degree. C. in 200 ml of trifluoroacetic acid, and it
is stirred for 8 hours at room temperature. It is evaporated to the
dry state, and the residue is recrystallized from diisopropyl
ether.
[1471] Yield: 14.68 g (93% of theory) of colorless flakes
[1472] Elementary analysis: Cld: C, 68.55; H, 8.63. Fnd: C, 68.41;
H, 8.74.
c)
1-(Perfluorooctylsulfonyl)-4-[(adamant-1-yl)-oxapropionyl]-piperazine
[1473] 14 g (66.6 mmol) of the title compound of Example 98b and
37.50 g (66.6 mmol) of 1-perfluorooctylsulfonyl-piperazine are
dissolved in 300 ml of tetrahydrofuran, and 32.15 g (130 mmol) of
1,2 dihydro-2-ethoxyquinoline-1-carboxylic acid ethyl ester (=EEDQ)
is added at 0.degree. C. It is stirred for 5 hours at room
temperature. The solution is evaporated to the dry state in a
vacuum, and the residue is chromatographed on silica gel (mobile
solvent:dichloromethane/diethyl ether=30:1).
[1474] Yield: 43.05 g (85% of theory) of a colorless solid
[1475] Elementary analysis: Cld: C, 37.90; H, 3.31; N, 3.68; S,
4.22; F, 42.47. Fnd: C, 38.04; H, 3.42; N, 3.49; S, 4.11; F,
42.30.
d) Preparation that Consists of 0.5 Part of Metal Complex I and 0.5
Part of an Inclusion Compound of .beta.-cyclodextrin-hydrate and
1-(perfluorooctylsulfonyl)-4-[(adamant-1-yl)-oxapropionyl]-piperazine
[1476] 6.81 g (8.96 mmol) of the title compound of Example 98c and
10.33 g (8.96) of .beta.-cyclodextrin monohydrate are added to 32
ml of a solution of metal complex 1 (280 mmol/L), dissolved in
0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of
CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common salt
solution to a total of 98 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The Gd concentration is 100
mmol of Gd/L.)
EXAMPLE 99
a) 3-Oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic
acid-N-(1-adamantyl)-amide
[1477] 30.95 g (150 mmol) of N,N-dicyclohexylcarbodiimide is added
at 0.degree. C. to 15.12 g (100 mmol) of 1-amino-adamantane, 52.21
(100 mmol) of 3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic acid and
11.51 g (100 mmol) of N-hydroxysuccinimide, dissolved in 300 ml of
tetrahydrofuran. It is stirred for 2 hours at 0.degree. C., then
for 6 hours at room temperature. Precipitated urea is filtered out,
the filtrate is evaporated to the dry state, and the residue is
chromatographed on silica gel (mobile
solvent:dichloromethane/acetone=30:- 1).
[1478] Yield: 54.4 g (83% of theory) of a waxy solid
[1479] Elementary analysis: Cld: C, 40.32; H, 3.38; N, 2.14; F,
49.28. Fnd: C, 40.47; H, 3.49; N, 2.03; F, 49.09.
b) Preparation that Consists of 0.6 Part of Metal Complex II and
0.4 Part of an Inclusion Compound that Consists of
.beta.-cyclodextrin-hydrate and
3-oxa-2H,2H,4H,4H,5H,5H-perfluorotridecanoic
acid-N-(1-adamantyl)-amide
[1480] 4.48 g (6.83 mmol) of the title compound of Example 99a and
7.87 g (6.83 mmol) of .beta.-cyclodextrin monohydrate are added to
41 ml of a solution of metal complex 11 (250 mmol/L), dissolved in
0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of
CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common salt
solution to a total of 103 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The Gd concentration is 100
mmol of Gd/L.)
EXAMPLE 100
a) 2-[N-(Ethyl)-N-(perfluorooctylsulfonyl)-amino]-acetic
acid-N-(adamantyl)-amide
[1481] 30.95 g (150 mmol) of N,N-dicyclohexylcarbodiimide is added
at 0.degree. C. to 15.12 g (100 mmol) of 1-aminoadamantane, 58.52 g
(100 mmol) of N-(ethyl)-N-(perfluorooctylsulfonyl)-aminoacetic acid
and 11.51 g (100 mmol) of N-hydroxysuccinimide, dissolved in 300 ml
of tetrahydrofuran. It is stirred for 2 hours at 0.degree. C., then
for 6 hours at room temperature. Precipitated urea is filtered out,
the filtrate is evaporated to the dry state, and the residue is
chromatographed on silica gel (mobile
solvent:dichloromethane/acetone=30:- 1).
[1482] Yield: 55.65 g (79% of theory) of an amorphous solid
[1483] Elementary analysis: Cld: C, 37.51; H, 3.29; F, 45.85; N,
1.99; S, 4.55. Fnd: C, 37.64; H, 3.41; F, 45.99; N, 2.12; S,
4.43.
b) Preparation that Consists of 0.6 Part of Metal Complex I and 0.4
Part of an Inclusion Compound that Consists of
.beta.-cyclodextrin-hydrate and
2-[N-(ethyl)-N-(perfluoroacetylsulfonyl)-amino]-acetic
acid-N-(1-adamantyl)-amide
[1484] 4.20 g (5.97 mmol) of the title compound of Example 100a and
6.88 g (5.97 mmol) of .beta.-cyclodextrin monohydrate are added to
32 ml of a solution of metal complex I (280 mmol/L), dissolved in
0.45% aqueous common salt solution (pH 7.4; 0.25 mg/L of
CaNa.sub.3DTPA), and it is made up with a 0.9% aqueous common salt
solution to a total of 90 ml. It is heated for 2 hours at
60.degree. C. in an ultrasound bath. The solution is cooled to room
temperature and set at pH 7.4 with aqueous 2N sodium hydroxide
solution. It is filtered with a 0.2 .mu.m filter, and the filtrate
is decanted into vials. A thus produced solution can be used
directly for biological experiments. (The Gd concentration is 100
mmol of Gd/L.)
EXAMPLE 101
a)
6-N-a)Benzyloxycarbonyl-2-N-(3,6,9,12-tetraoxatridecanoyl)lysine[1-(4-p-
erfluorooctylsulfonyl)-piperazine]-amide
[1485] A solution that consists of 16.85 g (70 mmol) of 3,6,9,12
tetraoxatridecanoic acid chloride in 50 ml of dichloromethane is
added in drops at 0.degree. C. to 50 g (60.20 mmol) of the title
compound of Example 1c and 7.10 g (70 mmol) of triethylamine,
dissolved in 350 ml of dichloromethane, and it is stirred for 3
hours at 0.degree. C. 200 ml of 5% aqueous hydrochloric acid is
added, and it is stirred for 5 minutes at room temperature. The
organic phase is separated, dried on magnesium sulfate and
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile
solvent:dichloromethane/acetone=15:- 1).
[1486] Yield: 30.94 g (92% of theory) of a colorless, viscous
oil.
[1487] Elementary analysis: Cld.: C, 40.63; H, 4.19; F, 31.21; N,
5.41; S, 3.10. Fnd.: C, 40.75; H, 4.08; F, 31.29; N, 5.58; S,
3.25.
b)
2-N-(3,6,9,12-Tetraoxatridecanoyl)-lysine[1-(4-perfluorooctylsulfonyl)--
piperazine]
[1488] 53.96 g (52.15 mmol) of the title compound of Example 101a
is dissolved in 500 ml of ethanol, and 6 g of palladium catalyst
(10% Pd/C) is added. It is hydrogenated at room temperature.
Catalyst is filtered out, and the filtrate is evaporated to the dry
state in a vacuum.
[1489] Yield: 43.0 g (quantitative) of a colorless solid.
[1490] Elementary analysis: Cld.: C, 36.01; H, 4.14; F, 35.86; N,
6.22; S, 3.56. Fnd.: C, 36.20; H, 4.23; F, 35.99; N, 6.38; S,
3.71.
c)
6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(p-
entanoyl-3-aza-4-oxo-5-methyl-5-yl)]-2-N-(3,6,9,12-tetraoxatridecanoyl)-ly-
sine[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd complex
[1491] 21.84 (24.25 mmol) of the title compound of Example 101b,
2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of
lithium chloride and 15.27 g (24.25 mmol) of
1,4,7-tris(carboxylatomethyl)-10-[(3-
-aza-4-oxo-5-methyl-5-yl)]-pentanoic
acid]-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in
200 ml of dimethyl sulfoxide while being heated slightly. At
10.degree. C., 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is
added and then stirred overnight at room temperature. The solution
is poured into 3000 ml of acetone and stirred for 10 minutes. The
precipitated solid is filtered off and then purified by
chromatography (silica gel RP-18, mobile solvent:gradient that
consists of water/ethanol/acetonitrile).
[1492] Yield: 28.21 g (81% of theory) of a colorless solid.
[1493] Water content: 11.0%
[1494] Elementary analysis (relative to anhydrous substance): Cld.:
C, 36.53; H, 4.33; F, 21.36; N, 8.34; S, 2.12; Gd, 10.40. Fnd.: C,
36.64; H, 4.48; F, 21.39; N, 8.29; S, 2.15; Gd, 10.57.
EXAMPLE 102
a) 6-N-Benzyloxycarbonyl-2-N-(propyl-3-sulfonic
acid)-lysine[1-(4-perfluor- ooctyl-sulfonyl)-piperazine]-amide
[1495] A solution that consists of 7.33 g (60 mol) of
propanesultone in 50 ml of tetrahydrofuran is added in drops at
50.degree. C. to 50 g (60.20 mmol) of the title compound of Example
1c and 7.10 g (70 mmol) of triethylamine, dissolved in 250 ml of
dry tetrahydrofuran, and it is stirred for 3 hours at 60.degree. C.
200 ml of 5% aqueous hydrochloric acid is added, and it is stirred
for 5 minutes at room temperature. The organic phase is separated,
dried on magnesium sulfate and evaporated to the dry state in a
vacuum. The residue is chromatographed on silica gel (mobile
solvent:dichloromethane/acetone=15:1).
[1496] Yield: 45.16 g (79% of theory) of a colorless, viscous
oil.
[1497] Elementary analysis: Cld.: C, 36.56; H, 3.49; F, 33.90; N,
5.88; S, 6.73. Fnd.: C, 36.72; H, 3.35; F, 33.79; N, 5.78; S,
6.75.
b) 2-N-(Propyl-3-sulfonic
acid)-lysine[1-(4-perfluorooctylsulfonyl)-pipera- zine]-amide
[1498] 49.68 g (52.15 mmol) of the title compound of Example 102a
is dissolved in 500 ml of ethanol, and 6 g of palladium catalyst
(10% Pd/C) is added. It is hydrogenated at room temperature.
Catalyst is filtered out, and the filtrate is evaporated to the dry
state in a vacuum.
[1499] Yield: 42.69 g (quantitative) of a colorless solid.
[1500] Elementary analysis: Cld.: C, 30.81; H, 3.32; F, 39.46; N,
6.84; S, 7.83. Fnd.: C, 30.64; H, 4.1; F, 39.29; N, 6.68; S,
7.89.
c)
6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(p-
entanoyl-3-aza-4-oxo-5-methyl-S-yl)]-2-N-(propyl-3-sulfonic
acid)-lysine[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd
complex
[1501] 19.85 g (24.25 mmol) of the title compound of Example 102b,
2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of
lithium chloride, and 15.27 g (24.25 mmol) of
1,4,7-tris(carboxylatomethyl)-10-[(-
3-aza-4-oxo-5-methyl-5-yl)]-pentanoic
acid]-1,4,7,10-tetraazacyclododecane- , Gd complex, are dissolved
in 200 ml of dimethyl sulfoxide while being heated slightly. At
10.degree. C., 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is
added, and then it is stirred overnight at room temperature. The
solution is poured into 3000 ml of acetone and stirred for 10
minutes. The precipitated solid is filtered off and then purified
by chromatography (silica gel RP-18, mobile solvent:gradient that
consists of water/ethanol/acetonitrile).
[1502] Yield: 28.13 g (81% of theory) of a colorless solid.
[1503] Water content: 11.0%
[1504] Elementary analysis (relative to anhydrous substance): Cld.:
C, 33.27; H, 3.70; F, 22.36; N, 8.73; S, 4.44; Gd, 10.89. Fnd.: C,
32.41; H, 3.88; F, 22.49; N, 8.69; S, 4.35; Gd, 10.97.
EXAMPLE 103
a) 6-N-Benzyloxycarbonyl-2-N,N-bis(propyl-3-sulfonic
acid)-lysine[1-(4-perfluorooctylsulfonyl)-piperazine]-amide
[1505] A solution that consists of 14.65 g (120 mmol) of
1,3-propanesultone in 100 ml of tetrahydrofuran is added in drops
at 50.degree. C. to 50 g (60.20 mmol) of the title compound of
Example 1c and 12.14 g (120 mmol) of triethylamine, dissolved in
250 ml of dry tetrahydrofuran, and it is stirred for 3 hours at
60.degree. C. 400 ml of 5% aqueous hydrochloric acid is added, it
is stirred for 5 minutes at room temperature, mixed with sodium
chloride, the organic phase is separated, it is dried on magnesium
sulfate and evaporated to the dry sttate in a vacuum. The residue
is chromatographed on silica gel (mobile
solvent:dichloromethane/acetone=15:1).
[1506] Yield: 52.24 g (81% of theory) of a colorless, viscous
oil.
[1507] Elementary analysis: Cld.: C, 35.76; H, 3.66; F, 30.05; N,
5.21; S, 8.95. Fnd.: C, 35.75; H, 3.55; F, 30.19; N, 5.08; S,
9.04.
b) 2-N,N Bis(propyl-3-sulfonic
acid)-lysine[1-(4-perfluorooctylsulfonyl)-p- iperazine]-amide
[1508] 53.74 g (52.15 mmol) of the title compound of Example 103a
is dissolved in 500 ml of ethanol, and 6 g of palladium catalyst
(10% Pd/C) is added. It is hydrogenated at room temperature.
Catalyst is filtered out, and the filtrate is evaporated to the dry
state in a vacuum.
[1509] Yield: 49.06 g (quantitative) of a colorless solid.
[1510] Elementary analysis: Cld.: C, 30.64; H, 3.54; F, 34.33; N,
5.96; S, 10.23. Fnd.: C, 30.69; H, 3.71; F, 34.19; N, 6.08; S,
10.38.
c)
6-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(p-
entanoyl-3-aza-4-oxo-5-methyl-5-yl)]-2-N,N bis(propyl-3-sulfonic
acid)-lysine[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd
complex, disodium salt
[1511] 38.76 g (24.25 mmol) of the title compound of Example 103b,
2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of
lithium chloride and 15.27 g (24.25 mmol) of
1,4,7-tris(carboxylatomethyl)-10-[(3-
-aza-4-oxo-5-methyl-5-yl)]-pentanoic
acid]-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in
200 ml of dimethyl sulfoxide while being heated slightly. At
10.degree. C., 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is
added, and it then is stirred overnight at room temperature. The
solution is poured into 3000 ml of acetone and stirred for 10
minutes. The precipitated solid is filtered off and then purified
by chromatography (silica gel RP-18, mobile solvent:gradient that
consists of water/ethanol/acetonitrile).
[1512] Yield: 31.63 g (81% of theory) of a colorless solid.
[1513] Water content: 11.0%
[1514] Elementary analysis (relative to anhydrous substance): Cld.:
C, 32.07; H, 3.57; F, 20.06; N, 7.83; S, 5.97; Gd, 9.76; Na, 2.86.
Fnd.: C, 31.94; H, 3.48; F, 20.19; N, 7.69; S, 5.85; Gd, 9.87; Na,
2.99.
EXAMPLE 104
a) N-Trifluoroacetyl-L-glutamic acid-5-benzylester
[1515] 100 g (421.5 mmol) of L-glutamic acid-5-benzylester is
dissolved in a mixture that consists of 1000 ml of trifluoroacetic
acid ethyl ester/500 ml of ethanol, and it is stirred for 24 hours
at room temperature. It is evaporated to the dry state, and the
residue is crystallized from diisopropyl ether.
[1516] Yield: 140.47 g (96% of theory) of a colorless, crystalline
powder.
[1517] Elementary analysis: Cld.: C, 50.46; H, 4.23; F, 17.10; N,
4.20. Fnd.: C, 51.35; H, 4.18; F, 17.03; N, 4.28.
b) 2-N-Trifluoroacetyl-L-glutamic
acid-5-benzylester-N-bis(2-hydroxyethyl)- -amide
[1518] 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is added at
0.degree. C. to a solution that consists of 24.9 g (24.08 mmol) of
the title compound of Example 104a, 2.53 g (24.08 mmol) of
diethanolamine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide,
dissolved in 150 ml of dimethylformamide. It is stirred for 3 hours
at 0.degree. C., then overnight at room temperature. Precipitated
urea is filtered out, the filtrate is evaporated to the dry state
in a vacuum, and it is chromatographed on silica gel (mobile
solvent:=dichloromethane/ethanol=20- :1).
[1519] Yield: 9.11 g (90% of theory) of a viscous oil.
[1520] Elementary analysis: Cld.: C, 51.43; H, 5.51; F, 13.56; N,
6.66. Fnd.: C, 51.22; H, 5.41; F, 13.40; N, 6.75.
c) N-Trifluoroacetyl-L-glutamic acid-N
bis(2-hydroxyethyl)-monoamide
[1521] 21.92 g (52.15 mmol) of the title compound of Example 104b
is dissolved in 500 ml of ethanol, and 3 g of palladium catalyst
(10% Pd/C) is added. It is hydrogenated at room temperature.
Catalyst is filtered out, and the filtrate is evaporated to the dry
state in a vacuum.
[1522] Yield: 43.0 g (quantitative) of a colorless solid.
[1523] Elementary analysis: Cld.: C, 40.01; H, 5.19; F, 17.26; N,
8.48. Fnd.: C, 39.84; H, 5.13; F, 17.09; N, 8.68.
c) Trifluoroacetyl-L-glutamic
acid-N-bis(2-hydroxyethyl)-amide-5-[1-(4-per-
fluorooctylsulfonyl)-piperazine]-amide
[1524] 16.42 g (66.4 mmol) of EEDQ
(2-ethoxy-1,2-dihydroquinoline-1-carbox- ylic acid ethyl ester) is
added at 0.degree. C. to 10.96 g (33.2 mmol) of the title compound
of Example 104a and 18.87 g (33.2 mmol) of
1-perfluorooctylsulfonyl-piperazine (produced according to DE
19603033) in 80 ml of tetrahydrofuran, and it is stirred overnight
at room temperature. It is evaporated to the dry state in a vacuum,
and it is chromatographed on silica gel (mobile
solvent:dichloromethane/methanol=20- :1).
[1525] Yield: 30.93 g (93% of theory) of a colorless solid.
[1526] Elementary analysis: Cld.: C, 39.61; H, 2.89; F, 35.66; N,
6.19; S, 3.54. Fnd.: C, 39.68; H, 2.74; F, 35.81; N, 6.13; S,
3.40.
e) L-Glutamic
acid-N-bis(2-hydroxyethyl)-amide-5-[1-(4-perfluorooctylsulfo-
nyl)-piperazine]-amide
[1527] Ammonia gas is introduced at 0.degree. C. for one hour into
200 ml of ethanol. It is then stirred for 4 hours at 0.degree. C.
It is evaporated to the dry state, and the residue is absorptively
precipitated from water. The solid is filtered off and dried in a
vacuum (50.degree. C.).
[1528] Yield: 26.55 g (97% of theory) of an amorphous solid.
[1529] Elementary analysis: Cld.: C, 41.12; H, 2.89; F, 35.66; N,
6.19; S, 3.54. Fnd.: C, 41.15; H, 2.83; F, 35.78; N, 6.28; S,
3.71.
f)
N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pen-
tanoyl-3-aza-4-oxo-5-methyl-5-yl)]-L-glutamic
acid-N-bis(2-hydroxyethyl)-a-
mide-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd
complex
[1530] 211.96 g (24.25 mmol) of the title compound of Example 104e,
2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of
lithium chloride and 15.27 g (24.25 mmol) of
1,4,7-tris(carboxylatomethyl)-10-[(3-
-aza-4-oxo-5-methyl-5-yl)]-pentanoic
acid]-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in
200 ml of dimethyl sulfoxide while being heated slightly. At
10.degree. C., 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is
added, and it then is stirred overnight at room temperature. The
solution is poured into 3000 ml of acetone, and it is stirred for
10 minutes. The precipitated solid is filtered off and then
purified by chromatography (silica gel RP-18, mobile
solvent:gradient that consists of water/ethanol/acetonitrile).
[1531] Yield: 27.43 g (81% of theory) of a colorless solid.
[1532] Water content: 11.0%
[1533] Elementary analysis (relative to anhydrous substance): Cld.:
C, 34.41; H, 3.83; F, 23.13; N, 9.03; S, 2.30; Gd, 11.26. Fnd.: C,
34.34; H, 3.98; F, 23.29; N, 9.19; S, 2.15; Gd, 11.07.
EXAMPLE 105
a) N-Trifluoroacetyl-L-glutamic
acid-5-benzylester-N-dimethyl-bis(1,1-dihy- droxymethyl)-amide
[1534] 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is added at
0.degree. C. to a solution that consists of 8.03 g (24.08 mmol) of
the title compound of Example 104a, 3.98 g (24.08 mmol) of
dimethyl-bis(1,1-dihydroxymethyl)-amine and 2.77 g (24.08 mmol) of
N-hydroxysuccinimide, dissolved in 150 ml of dimethylformamide. It
is stirred for 3 hours at 0.degree. C., then overnight at room
temperature. Precipitated urea is filtered out, the filtrate is
evaporated to the dry state in a vacuum, and it is chromatographed
on silica gel (mobile solvent:dichloromethane/ethanol=20:1).
[1535] Yield: 110.53 g (91% of theory ) of a viscous oil.
[1536] Elementary analysis: Cld.: C, 50.00; H, 5.66; F, 11.86; N,
7.18. Fnd.: C, 50.17; H, 5.82; F, 11.80; N, 7.15.
b) N-Trifluoroacetyl-L-glutamic
acid-5-benzylester-[1-(4-perfluorooctylsul-
fonyl)-piperazine]-amide
[1537] 25.05 g (52.15 mmol) of the title compound of Example 105a
is dissolved in 500 ml of ethanol, and 6 g of palladium catalyst
(10% Pd/C) is added, hydrogenated at room temperature. Catalyst is
filtered out, and the filtrate is evaporated to the dry state in a
vacuum.
[1538] Yield: 20.36 g (quantitative) of a colorless solid.
[1539] Elementary analysis: Cld.: C, 40.00; H, 5.42; F, 14.60; N,
7.18. Fnd.: C, 40.10; H, 5.53; F, 14.69; N, 7.28.
c) N-Trifluoroacetyl-L-glutamic
acid-N-dimethyl-bis(1,1-dihydroxymethyl)-a-
mide-5-[1-(4-perfluorooctylsulfonyl)piperazine]-amide
[1540] 16.42 g (66.4 mmol) of EEDQ
(2-ethoxy-1,2-dihydroquinoline-1-carbox- ylic acid ethyl ester) is
added at 0.degree. C. to 12.96 g (33.2 mmol) of the title compound
of Example 105b and 18.87 g (33.2 mmol) of
1-perfluorooctylsulfonyl-piperazine (produced according to DE
19603033) in 800 ml of tetrahydrofuran, and it is stirred overnight
at room temperature. It is evaporated to the dry state in a vacuum
and chromatographed on silica gel (mobile
solvent:dichloromethane/methanol=20- :1).
[1541] Yield: 28.42 g (91% of theory) of a colorless solid.
[1542] Elementary analysis: Cld.: C, 31.93; H, 3.00; F, 40.40; N,
5.96; S, 3.41. Fnd.: C, 32.08; H, 2.94; F, 40.57; N, 5.88; S,
3.31.
d) L-Glutamic
acid-N-[dimethyl-bis(1,1-dihydroxymethyl)]-amide-5-[(1-4-per-
fluorooctylsulfonyl)-piperazine]-amide
[1543] Ammonia gas is introduced at 0.degree. C. for one hour into
a solution that consists of 28.41 g (30.2 mmol) of the title
compound of Example 105c in 200 ml of ethanol. It then is stirred
for 4 hours at 0.degree. C. It is evaporated to the dry state, and
the residue is absorptively precipitated from water. The solid is
filtered off and dried in a vacuum (50.degree. C.).
[1544] Yield: 24.74 g (97% of theory) of an amorphous solid.
[1545] Elementary analysis: Cld.: C, 32.71; H, 3.46; F, 38.24; N,
6.63; S, 3.80. Fnd.: C, 32.75; H, 3.33; F, 38.38; N, 6.68; S,
3.81.
e)
2-N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(p-
entanoyl-3-aza-4-oxo-5-methyl-5-yl)]-L-glutamic
acid-N-[dimethyl-bis(1,1-d-
ihydroxymethyl)-amide]-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide,
Gd complex
[1546] 20.48 g (24.25 mmol) of the title compound of Example 105d,
2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of
lithium chloride and 15.27 g (24.25 mmol) of
1,4,7-tris(carboxylatomethyl)-10-[(3-
-aza-4-oxo-5-methyl-5-yl)]-pentanoic
acid]-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in
200 ml of dimethyl sulfoxide while being heated slightly. At
10.degree. C., 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is
added, and it then is stirred overnight at room temperature. The
solution is poured into 3000 ml of acetone and stirred for 10
minutes. The precipitated filtrate is filtered off and then
purified by chromatography (silica gel RP-18, mobile
solvent:gradient that consists of water/ethanol/acetonitrile).
[1547] Yield: 29.05 g (83% of theory) of a colorless solid.
[1548] Water content: 11.0%
[1549] Elementary analysis (relative to anhydrous substance): Cld.:
C, 34.12; H, 3.91; F, 22.38; N, 8.73; S, 2.22; Gd, 10.90. Fnd.: C,
34.24; H, 3.98; F, 22.39; N, 8.69; S, 2.15; Gd, 10.87.
EXAMPLE 106
a) N-Trifluoromethylacetyl-L-glutamic
acid-5-benzylester-[1-(4-perfluorooc-
tylsulfonyl)-piperazine]-amide
[1550] 16.42 g (66.4 mmol) of EEDQ
(2-ethoxy-1,2-dihydroquinoline-1-carbox- ylic acid ethyl ester) is
added at 0.degree. C. to 11.06 g (33.2 mmol) of the title compound
of Example 104a and 18.87 g (33.2 mmol) of
1-perfluorooctylsulfonyl-piperazine (produced according to DE
19603033) in 80 ml of tetrahydrofuran, and it is stirred overnight
at room temperature. It is evaporated to the dry state in a vacuum
and chromatographed on silica gel (mobile
solvent:dichloromethane/methanol=20- :1).
[1551] Yield: 27.28 g (93% of theory) of a colorless solid.
[1552] Elementary analysis: Cld.: C, 35.35; H, 2.40; F, 43.01; N,
4.76; S, 3.63. Fnd.: C, 35.48; H, 2.51; F, 42.87; N, 4.73; S,
3.50.
b) N-Trifluoroacetyl-L-glutamic
acid-5-[1-[4-perfluorooctylsulfonyl)-piper- azine]-amide
[1553] 21.92 g (52.15 mmol) of the title compound of Example 106a
is dissolved in 500 ml of ethanol, and 3 g of palladium catalyst
(10% Pd/C) is added. It is hydrogenated at room temperature.
Catalyst is filtered out, and the filtrate is evaporated to the dry
state in a vacuum.
[1554] Yield: 41.37 g (quantitative) of a colorless solid.
[1555] Elementary analysis: Cld.: C, 28.76; H, 1.91; F, 47.89; N,
5.30; S, 4.40. Fnd.: C, 28.84; H, 2.03; F, 47.79; N, 5.28; S,
4.19.
c) N-Trifluoroacetyl-L-glutamic
acid-N-bis(2-hydroxyethyl)-amide-5-[1-(4-p-
erfluorooctylsulfonyl)-piperazine]-amide
[1556] 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is added at
0.degree. C. to a solution that consists of 24.9 g (24.08 mmol) of
the title compound of Example 106a, 2.53 g (24.08 mmol) of
diethanolamine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide,
dissolved in 150 ml of dimethylformamide. It is stirred for 3 hours
at 0.degree. C., then overnight at room temperature. Precipitated
urea is filtered out, the filtrate is evaporated to the dry state
in a vacuum and chromatographed on silica gel (mobile
solvent:=dichloromethane/ethanol=20:1).
[1557] Yield: 9.11 g (90% of theory) of a viscous oil.
[1558] Elementary analysis: Cld.: C, 31.37; H, 2.75; F, 43.15; N,
6.36; S, 3.64. Fnd.: C, 31.22; H, 2.61; F, 43.30; N, 6.25; S,
3.81.
d) L-Glutamic
acid-N-bis(2-hydroxyethyl)-amide-5-[1-(4-perfluorooctylsulfo-
nyl)-piperazine]-amide
[1559] Ammonia gas is introduced at 0.degree. C. for one hour into
a solution that consists of 26.61 g (30.22 mmol) of the title
compound of Example 106c in 200 ml of ethanol. It then is stirred
for 4 hours at 0.degree. C. It is evaporated to the dry state, and
the residue is absorptively precipitated from water. The solid is
filtered off and dried in a vacuum (50.degree. C.).
[1560] Yield: 23.93 g (97% of theory) of an amorphous solid.
[1561] Elementary analysis: Cld.: C, 30.89; H, 3.09; F, 39.56; N,
6.86; S, 3.93. Fnd.: C, 30.75; H, 3.13; F, 39.78; N, 6.75; S,
3.81.
e)
N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pen-
tanoyl-3-aza-4-oxo-5-methyl-5-yl)]-L-glutamic
acid-N-bis(2-hydroxyethyl)-a-
mide-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd
complex
[1562] 16.43 g (24.25 mmol) of the title compound of Example 106d,
2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of
lithium chloride and 15.27 g (24.25 mmol) of
1,4,7-tris(carboxylatomethyl)-10-[(3-
-aza-4-oxo-5-methyl-5-yl)]-pentanoic
acid]-1,4,7,10-tetraazacyclododecane, Gd complex, are dissolved in
200 ml of dimethyl sulfoxide while being heated slightly. At
10.degree. C., 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is
added, and it then is stirred overnight at room temperature. The
solution is poured into 3000 ml of acetone and stirred for 10
minutes. The precipitated solid is filtered off and then purified
by chromatography (silica gel RP-18, mobile solvent:gradient that
consists of water/ethanol/acetonitrile).
[1563] Yield: 28.10 g (83% of theory) of a colorless solid.
[1564] Water content: 11.0%
[1565] Elementary analysis (relative to anhydrous substance): Cld.:
C, 34.41; H, 3.83; F, 23.13; N, 9.03; S, 2.30; Gd, 11.26. Fnd.: C,
34.44; H, 4.98; F, 23.19; N, 8.89; S, 2.15; Gd, 11.17.
EXAMPLE 107
a) N-Trifluoroacetyl-glutamic
acid-5-benzylester-[1-(4-perfluorooctylsulfo-
nyl)-piperazine]-amide
[1566] 16.42 g (66.4 mmol) of EEDQ
(2-ethoxy-1,2-dihydroquinoline-1-carbox- ylic acid ethyl ester) is
added at 0.degree. C. to 11.06 g (33.2 mmol) of the title compound
of Example 104a and 18.87 g (33.2 mmol) of
1-perfluorooctylsulfonyl-piperazine (produced according to DE
19603033) in 80 ml of tetrahydrofuran, and it is stirred overnight
at room temperature. It is evaporated to the dry state in a vacuum
and chromatographed on silica gel (mobile
solvent:dichloromethane/methanol=20- :1).
[1567] Yield: 27.28 g (93% of theory) of a colorless solid.
[1568] Elementary analysis: Cld.: C, 33.35; H, 2.40; F, 43.01; N,
4.76; S, 3.63. Fnd.: C, 35.48; H, 2.54; F, 42.87; N, 4.73; S,
3.40.
b) N-Trifluoroacetyl-L-glutamic
acid-5-[1-[4-perfluorooctylsulfonyl)-piper- azine]-amide
[1569] 21.92 g (52.15 mmol) of the title compound of Example 107a
is dissolved in 500 ml of ethanol, and 3 g of palladium catalyst
(10% Pd/C) is added. It is hydrogenated at room temperature.
Catalyst is filtered out, and the filtrate is evaporated to the dry
state in a vacuum.
[1570] Yield: 41.37 g (quantitative) of a colorless solid.
[1571] Elementary analysis: Cld.: C, 28.76; H, 1.91; F, 47.89; N,
5.30; S, 4.04. Fnd.: C, 28.84; H, 1.81; F, 47.79; N, 5.28; S,
4.16.
EXAMPLE 108
a)
6-N-Benzyloxycarbonyl-2-N-(2,3,4,5-pentahydroxy-hexanoyl)L-lysine-[1-(4-
-perfluorooctylsulfonyl)-piperazine]-amide
[1572] A solution that consists of 21.45 g (120.4 mol) of
5-gluoconolactone in 50 ml of tetrahydrofuran is added in drops at
50.degree. C. to a solution that consists of 100.0 g (120.4 mol) of
the title compound of Example 21c), in 500 ml of dry
tetrahydrofuran. It is stirred for 3 hours at 60.degree. C. and
then overnight at room temperature. It is evaporated to the dry
state in a vacuum, and the residue is chromatographed on silica
gel. (Mobile solvent:dichloromethane- /ethanol=20:1).
[1573] Yield: 98.37 g (82% of theory of a viscous oil).
[1574] Elementary analysis: Cld.: C, 38.10; H, 3.70; F, 32.02; N,
5.55; S, 3.18. Fnd.: C, 38.22; H, 3.79; F, 32.02; N, 5.42; S,
3.29.
b)
2-N-(2,3,4,5-Pentahydroxy-hexanoyl)-L-lysine-1-[(4-perfluorooctylsulfon-
yl)-piperazine]-amide
[1575] 100.9 g (100.0 mmol) of the title compound of Example 108a)
is dissolved in 2000 ml of ethanol, and 10.0 g of palladium
catalyst (10% Pd/C) is added thereto. It is hydrogenated for 12
hours at room temperature. Catalyst is filtered out, and the
filtrate is evaporated to the dry state in a vacuum.
[1576] Yield: 87.46 g (quantitative) of a colorless solid.
[1577] Elementary analysis: Cld.: C, 32.96; H, 3.57; N, 6.41; S,
3.67; F, 36.93. Fnd.: C, 32.91; H, 3.72; N, 6.34; S, 3.50; F,
36.78.
f)
6-N-[1,4,7-Tris(carboxylatomethyl)]-1,4,7,10-tetraazacyclododecane-10-N-
-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-2-N-[1-O-.alpha.-D-carbonylmethyl--
mannopyranose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide,
Gd complex
[1578] 50.0 g (54.55 mmol) of the title compound of Example 21e),
6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mmol) of
lithium chloride and 34.35 g (54.55 mol) of 1,4,7-tris
(carboxylatomethyl)-10-(ca-
rboxy-3-aza-4-oxo-5-methyl-pent-5-yl)-1,4,7,10-tetraazacyclododecane,
Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while
being heated slightly. At 10.degree. C., 16.88 g (81.8 mol) of
N,N-dicyclohexylcarbodi- imide is added, and it then is stirred
overnight at room temperature. The solution is poured into 3000 ml
of acetone and stirred for 10 minutes. The precipitated solid is
filtered off and then purified by chromatography (RP-18 mobile
solvent:gradient that consists of water/ethanol/acetonitrile).
[1579] Yield: 75.9 g (91.0% of theory) of a colorless solid.
[1580] Water content: 8.6%.
[1581] Elementary analysis (relative to anhydrous substance): Cld.:
C, 35.34; H, 4.09; N, 8.24; S, 2.10; F, 21.12; Gd, 10.28. Fnd.: C,
35.28; H, 4.15; N, 8.19; S, 2.15; F, 21.03; Gd, 10.14.
EXAMPLE 109
a)
6-N-Benzyloxycarbonyl-2-N-(2,3,4,5-pentahydroxy-hexanoyl)L-lysine-1-(4--
perfluorooctylsulfonyl)-piperazine]-amide
[1582] A solution that consists of 21.45 g (120.4 mol) of
5-gluconolactone in 50 ml of tetrahydrofuran is added in drops at
50.degree. C. to a solution that consists of 100.0 g (120.4 mmol)
of the title compound of Example 21c) and 12.18 g (120.4 mmol) of
triethylamine in 500 ml of dry tetrahydrofuran. It is stirred for 3
hours at 60.degree. C. and then overnight at room temperature.
Then, 400 ml of 5% aqueous hydrochloric acid is added thereto, it
is stirred for 5 minutes at room temperature, mixed with sodium
chloride, the organic phase is separated, it is dried on magnesium
sulfate, evaporated to the dry state in a vacuum, and the residue
is chromatographed on silica gel.
[1583] (Mobile solvent:dichloromethane/ethanol=20:1).
[1584] Yield: 100.97 g (82% of theory) of a viscous oil.
[1585] Elementary analysis: Cld.: C, 37.58; H, 3.45; F, 31.58; N,
5.48; S, 3.14. Fnd.: C, 37.72; H, 3.59; F, 31.72; N, 5.42; S,
3.29.
b)
2-N-(2,3,4,5-Pentahydroxy-hexanoyl)-L-lysine-1-1[(4-perfluorooctylsulfo-
nyl)-piperazine]-amide
[1586] 100.9 g (100.0 mmol) of the title compound of Example 108a)
is dissolved in 2000 ml of ethanol, and 10.0 g of palladium
catalyst (10% Pd/C) is added thereto. It is hydrogenated for 12
hours at room temperature. Catalyst is filtered out, and the
filtrate is evaporated to the dry state in a vacuum.
[1587] Yield: 87.46 g (quantitative) of a colorless solid.
[1588] Elementary analysis: Cld.: C, 32.96; H, 3.57; N, 6.41; S,
3.67; F, 36.93. Fnd.: C, 32.91; H, 3.72; N, 6.34; S, 3.50; F,
36.78.
c)
6-N-[1,4,7-Tris(carboxylatomethyl)]-1,4,7,10-tetraazacyclododecane-10-N-
-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-2-N-[1-O-.alpha.-D-carbonylmethyl--
mannopyranose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide,
Gd complex
[1589] 50.0 g (54.55 mmol) of the title compound of Example 21e),
6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of
lithium chloride and 34.35 g (54.55 mol) of
1,4,7-tris(carboxylatomethyl)-10-(car-
boxy-3-aza-4-oxo-5-methyl-pent-5-yl)-1,4,7,10-tetraazacyclododecane,
Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while
being heated slightly. At 10.degree. C., 16.88 g (81.8 mol) of
N,N-dicyclohexylcarbodi- imide is added, and it then is stirred
overnight at room temperature. The solution is poured into 3000 ml
of acetone and stirred for 10 minutes. The precipitated solid is
filtered off and then purified by chromatography (RP-18 mobile
solvent:gradient that consists of water/ethanol/acetonitrile).
[1590] Yield: 75.9 g (91.0% of theory) of a colorless solid.
[1591] Water content: 8.6%.
[1592] Elementary analysis (relative to anhydrous substance): Cld.:
C, 35.34; H, 4.09; N, 8.24; S, 2.10; F, 21.12; Gd, 10.28. Fnd.: C,
35.28; H, 4.15; N, 8.19; S, 2.15; F, 21.03; Gd, 10.14.
EXAMPLE 110
a)
6-N-Benzyloxycarbonyl-2-N-[1-O-.alpha.-D-carbonylmethyl-(2,3,4,6-tetra--
O-benzylglucopyranose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]--
amide
[1593] 41.27 g (200.0 mmol) of N,N-dicyclohexylcarbodiimide is
added at 0.degree. C. to a solution that consists of 100.0 g (120.4
mol) of the title compound of Example 21c), 72.1 g (120.4 mol) of
1-O-.alpha.-D-carboxymethyl-2,3,4,6-tetra-O-benzyl-glucopyranose
and 13.86 g (120.4 mol) of N-hydroxysuccinimide, dissolved in 500
ml of dimethylformamide. It is stirred for 3 hours at 0.degree. C.
and then overnight at room temperature. Precipitated urea is
filtered out, the filtrate is evaporated to the dry state in a
vacuum, and it is chromatographed on silica gel.
[1594] (Mobile solvent:dichloromethane/ethanol=20:1).
[1595] Yield: 136.1 g (87% of theory) of a viscous oil.
[1596] Elementary analysis: Cld.: C, 57.32; H, 4.89; N, 4.31; F,
24.86; S, 2.47. Fnd.: C, 57.48; H, 5.04; N, 4.20; F, 24.69; S,
2.38.
b)
2-N-[1-O-.alpha.-D-Carbonylmethylglucopyranose]-L-lysine-1-[(4-perfluor-
ooctylsulfonyl)-piperazine]-amide
[1597] 130.0 g (100.0 mmol) of the title compound of Example 110a)
is dissolved in 2000 ml of ethanol, and 10.0 g of palladium
catalyst (10% Pd/C) is added thereto. It is hydrogenated for 12
hours at room temperature. Catalyst is filtered out, and the
filtrate is evaporated to the dry state in a vacuum.
[1598] Yield: 9.17 g (quantitative) of a colorless solid.
[1599] Elementary analysis: Cld.: C, 34.07; H, 3.63; N, 6.11; S,
3.50; F, 35.24. Fnd.: C, 33.92; H, 3.71; N, 6.02; S, 3.42; F,
35.33.
c)
6-N-[1,4,7-Tris(carboxylatomethyl)]-1,4,7,10-tetraazacyclododecane-10-N-
-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-2-N-[1-O-.alpha.-D-carbonylmethyl--
glucopyranose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide,
Gd complex
[1600] 50.0 g (54.55 mmol) of the title compound of Example 110b),
6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of
lithium chloride and 34.35 g (54.55 mol) of
1,4,7-tris(carboxylatomethyl)-10-(car-
boxy-3-aza-4-oxo-5-methyl-pent-5-yl)-1,4,7,10-tetraazacyclododecane,
Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while
being heated slightly. At 10.degree. C., 16.88 g (81.8 mol) of
N,N-dicyclohexylcarbodi- imide is added and then stirred overnight
at room temperature. The solution is poured into 3000 ml of acetone
and stirred for 10 minutes. The precipitated solid is filtered off
and then purified by chromatography (RP-18 mobile solvent:gradient
that consists of water/ethanol/acetonitrile).
[1601] Yield: 75.9 g (91.0% of theory) of a colorless solid.
[1602] Water content: 8.6%
[1603] Elementary analysis (relative to anhydrous substance): Cld.:
C, 35.34; H, 4.09; N, 8.24; S, 2.10; F, 21.12; Gd, 10.28. Fnd.: C,
35.26; H, 4.18; N, 8.14; S, 2.158; F, 21.01; Gd, 10.13.
EXAMPLE 111
a)
6-N-Benzyloxycarbonyl-2-N-[1-O-.alpha.-D-carbonylmethyl-(2,3,4,6-tetra--
O-benzyl-galactopyranose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazin-
e]-amide
[1604] 20.64 g (100.0 mmol) of N,N-dicyclohexylcarbodiimide is
added at 0.degree. C. to a solution that consists of 50.0 g (60.2
mol) of the title compound of Example 21c), 36.05 g (60.2 mmol) of
1-O-.alpha.-D-carboxymethyl-2,3,4,6-tetra-O-benzyl-galactopyranose
and 6.93 g (60.2 mmol) of N-hydroxysuccinimide, dissolved in 500 ml
of dimethylformamide. It is stirred for 3 hours at 0.degree. C. and
then overnight at room temperature. Precipitated urea is filtered
out, the filtrate is evaporated to the dry state in a vacuum, and
it is chromatographed on silica gel.
[1605] (Mobile solvent:dichloromethane/ethanol=20:1).
[1606] Yield: 68.1 g (87% of theory) of a viscous oil.
[1607] Elementary analysis: Cld.: C, 57.32; H, 4.89; N, 4.31; F,
24.86; S, 2.47. Fnd.: C, 57.47; H, 5.50; N, 4.19; F, 24.72; S,
2.29.
b)
2-N-[1-O-.alpha.-D-Carbonylmethyl-galactopyranose]-L-lysine-1-[(4-perfl-
uorooctylsulfonyl)-piperazine]-amide
[1608] 65.0 g (50.0 mmol) of the title compound of Example 111a) is
dissolved in 1000 ml of ethanol, and 5.0 g of palladium catalyst
(10% Pd/C) is added. It is hydrogenated for 12 hours at room
temperature. Catalyst is filtered out, and the filtrate is
evaporated to the dry state in a vacuum.
[1609] Yield: 45.85 g (quantitative) of a colorless solid.
[1610] Elementary analysis: Cld.: C, 34.07; H, 3.63; N, 6.11; S,
3.50; F, 35.24. Fnd.: C, 33.93; H, 3.74; N, 6.01; S, 3.39; F,
35.05.
c)
6-N-[1,4,7-Tris(carboxylatomethyl)]-1,4,7,10-tetraazacyclododecane-10-N-
-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-2-N-[1-O-.alpha.-D-carbonylmethyl--
galactopyranose]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide,
Gd complex
[1611] 50.0 g (54.55 mmol) of the title compound of Example 111b),
6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of
lithium chloride and 34.35 g (54.55 mol) of
1,4,7-tris(carboxylatomethyl)-10-(car-
boxy-3-aza-4-oxo-5-methyl-pent-5-yl)-1,4,7,10-tetraazacyclododecane,
Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while
being heated slightly. At 10.degree. C., 16.88 g (81.8 mol) of
N,N-dicyclohexylcarbodi- imide is added, and it then is stirred
overnight at room temperature. The solution is poured into 3000 ml
of acetone and stirred for 10 minutes. The precipitated solid is
filtered off and then purified by chromatography (RP-18 mobile
solvent:gradient that consists of water/ethanol/acetonitrile).
[1612] Yield: 37.95 g (91.0% of theory) of a colorless solid.
[1613] Water content: 8.6%.
[1614] Elementary analysis (relative to anhydrous substance): Cld.:
C, 35.34; H, 4.09; N, 8.24; S, 2.10; F, 21.12; Gd, 10.28. Fnd.: C,
35.22; H, 4.17; N, 8.18; S, 2.19; F, 20.91; Gd, 10.12.
EXAMPLE 112
a) N-Trifluoroacetyl-L-glutamic acid-mono-benzyl ester
[1615] 100 g (421.5 mmol) of L-glutamic acid-mono-benzyl ester is
dissolved in a mixture that consists of 1000 ml of trifluoroacetic
acid ethyl ester/500 ml of ethanol, and it is stirred for 24 hours
at room temperature. It is evaporated to the dry state, and the
residue is crystallized from diisopropyl ether.
[1616] Yield: 140.47 g (96% of theory) of a colorless, crystalline
powder.
[1617] Elementary analysis: Cld.: C, 50.46; H, 4.23; F, 17.10; N,
4.20. Fnd.: C, 51.35; H, 4.18; F, 17.03; N, 4.28.
b) 2-N-Trifluoroacetyl-L-glutamic
acid-mono-benzylester-5-N-(methyl)-N-(2,-
3,4,5,6-pentahydroxyhexyl)-amide
[1618] 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is added at
0.degree. C. to a solution that consists of 24.9 g (24.08 mmol) of
the title compound of Example 112a, 2.times.g (24.08 mmol) of
N-methylglucamine and 2.77 g (24.08 mmol) of N-hydroxysuccinimide,
dissolved in 150 ml of dimethylformamide. It is stirred for 3 hours
at 0.degree. C., then overnight at room temperature. Precipitated
urea is filtered out, the filtrate is evaporated to the dry state
in a vacuum and chromatographed on silica gel (mobile
solvent:dichloromethane/ethanol=20:- 1).
[1619] Yield: 9.xx g (89% of theory) of a viscous oil.
[1620] Elementary analysis: Cld.: C, 51.43; H, 5.51; F, 13.56; N,
6.66. Fnd.: C, 51.22; H, 5.41; F, 13.40; N, 6.75.
c) N-Trifluoroacetyl-L-glutamic
acid-N-(methyl)-N-(2,3,4,5,6-pentahydroxyh- exyl)-amide
[1621] 21.9xx g (52.15 mmol) of the title compound of Example 112b
is dissolved in 500 ml of ethanol, and 3 g of palladium catalyst
(10% Pd/C) is added. It is hydrogenated at room temperature.
Catalyst is filtered out, and the filtrate is evaporated to the dry
state in a vacuum.
[1622] Yield: 43.0 g (quantitative) of a colorless solid.
[1623] Elementary analysis: Cld.: C, 40.01; H, 5.19; F, 17.26; N,
8.48. Fnd.: C, 39.84; H, 5.13; F, 17.09; N, 8.68.
d) Trifluoroacetyl-L-glutamic
acid-5-N-(methyl)-N-(2,3,4,5,6-pentahydroxyh-
exyl)-amide-[1-(4-perfluorooctylsulfonyl)-piperazine]-amidepiperazine]-ami-
de
[1624] 16.42 g (66.4 mmol) of EEDQ
(2-ethoxy-1,2-dihydroquinoline-1-carbox- ylic acid ethyl ester) is
added at 0.degree. C. to 10.96 g (33.2 mmol) of the title compound
of Example 112c and 18.87 g (33.2 mmol) of
1-perfluorooctylsulfonyl-piperazine (produced according to DE
19603033) in 80 ml of tetrahydrofuran, and it is stirred overnight
at room temperature. It is evaporated to the dry state in a vacuum
and chromatographed on silica gel (mobile
solvent:dichloromethane/methanol=20- :1).
[1625] Yield: 28.67 g (92% of theory) of a colorless solid.
[1626] Elementary analysis: Cld.: C, 39.61; H, 2.89; F, 35.66; N,
6.19; S, 3.54. Fnd.: C, 39.68; H, 2.74; F, 35.81; N, 6.13; S,
3.40.
e) L-Glutamic
acid-5-N-(methyl)-N-(2,3,4,5,6-pentahydroxyhexyl)-amide-[1-(-
4-perfluorooctylsulfonyl)-piperazine]-amide
[1627] Ammonia gas is introduced at 0.degree. C. for one hour into
a solution that consists of 28.36 g (30.22 mmol) of the title
compound of Example 112d in 200 ml of ethanol. It then is stirred
for 4 hours at 0.degree. C. It is evaporated to the dry state, and
the residue is absorptively precipitated from water. The solid is
filtered off and dried in a vacuum (50.degree. C.).
[1628] Yield: 24.19 g (95% of theory) of an amorphous solid.
[1629] Elementary analysis: Cld.: C, 41.12; H, 2.89; F, 35.66; N,
6.19; S, 3.54. Fnd.: C, 41.15; H, 2.83; F, 35.78; N, 6.28; S,
3.71.
f)
N-[1,4,7-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-(pen-
tanoyl-3-aza-4-oxo-5-methyl-5-yl)]-L-glutamic
acid-5-N-(methyl)-N-(2,3,4,5-
,6-pentahydroxyhexyl)-amide-5-[1-(4-perfluorooctylsulfonyl)-piperazine]-am-
ide, Gd complex
[1630] 20.43 g (24.25 mmol) of the title compound of Example 112e,
2.79 g (24.25 mmol) of N-hydroxysuccinimide, 2.12 g (50 mmol) of
lithium chloride and 15.27 g (24.25 mmol) of
1,4,7-tris(carboxylatomethyl)-10-[(3-
-aza-4-oxo-5-methyl-5-yl)]-pentanoic
acid]-1,4,7,10-tetraazacyclododecane, Gd complex are dissolved in
200 ml of dimethyl sulfoxide while being heated slightly. At
10.degree. C., 8.25 g (40 mmol) of N,N-dicyclohexylcarbodiimide is
added and then stirred overnight at room temperature. The solution
is poured into 3000 ml of acetone and stirred for 10 minutes. The
precipitated solid is filtered off and then purified by
chromatography (silica gel RP-18, mobile solvent:gradient that
consists of water/ethanoIacetonitrile).
[1631] Yield: 28.45 g (79% of theory) of a colorless solid.
[1632] Water content: 11.0%
[1633] Elementary analysis (relative to anhydrous substance): Cld.:
C, 34.41; H, 3.83; F, 23.13; N, 9.03; S, 2.30; Gd, 11.26. Fnd.: C,
34.34; H, 3.98; F, 23.29; N, 9.19; S, 2.15; Gd, 11.07.
EXAMPLE 113
a)
6-N-Benzyloxycarbonyl-2-N-[1-O-.alpha.-D-carbonylmethyl-(2,3,4-tri-O-be-
nzyl-glucuronic
acid-benzylester]-L-lysine-[1-(4-perfluorooctylsulfonyl)-p-
iperazine]-amide
[1634] 41.27 g (200.0 mmol) of N,N-dicyclohexylcarbodiimide is
added at 0.degree. C. to a solution that consists of 100.0 g (120.4
mol) of the title compound of Example 21c), 73.77 g (120.4 mol) of
1-O-.alpha.-D-carboxymethyl-2,3,4-tri-O-benzyl-glucuronic
acid-benzylester and 13.86 g (120.4 mol) of N-hydroxysuccinimide,
dissolved in 500 ml of dimethylformamide. It is stirred for 3 hours
at 0.degree. C. and then overnight at room temperature.
Precipitated urea is filtered out, the filtrate is evaporated to
the dry state in a vacuum and chromatographed on silica gel.
[1635] (Mobile solvent:dichloromethane/ethanol=20:1).
[1636] Yield: 147.58 g (86% of theory) of a viscous oil.
[1637] Elementary analysis: Cld.: C, 52.25; H, 4.31; N, 3.93; F,
22.66; S, 2.45. Fnd.: C, 52.38; H, 4.17; N, 4.12; F, 22.78; S,
2.39.
b) 2-N-[1-O-.alpha.-D-Carbonylmethyl-glucuronic
acid]-L-lysine-1-[(4-perfl-
uorooctylsulfonyl)-piperazine]-amide
[1638] 142.52 g (100.0 mmol) of the title compound of Example 113a)
is dissolved in 2000 ml of ethanol, and 10.0 g of palladium
catalyst (10% Pd/C) is added thereto. It is hydrogenated for 12
hours at room temperature. Catalyst is filtered out, and the
filtrate is evaporated to the dry state in a vacuum.
[1639] Yield: 93.06 g (quantitative) of a colorless solid.
[1640] Elementary analysis: Cld.: C, 33.56; H, 3.36; N, 6.02; S,
3.45; F, 34.71. Fnd.: C, 33.31; H, 3.42; N, 6.04; S, 3.40; F,
35.51.
c)
6-N-[1,4,7-Tris(carboxylatomethyl)]-1,4,7,10-tetraazacyclododecane-10-N-
-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-2-N-[1-O-.alpha.-D-carbonylmethyl--
glucuronic
acid]-L-lysine-[1-(4-perfluorooctylsulfonyl)-piperazine]-amide, Gd
complex, sodium salt
[1641] 50.76 g (54.55 mmol) of the title compound of Example 113b),
6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of
lithium chloride and 34.35 g (54.55 mol) of
1,4,7-tris(carboxylatomethyl)-10-(car-
boxy-3-aza-4-oxo-5-methyl-pent-5-yl)-1,4,7,10-tetraazacyclododecane,
Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while
being heated slightly. At 10.degree. C., 16.88 g (81.8 mol) of
N,N-dicyclohexylcarbodi- imide is added, and it then is stirred
overnight at room temperature. The solution is poured into 3000 ml
of acetone, and it is stirred for 10 minutes. The precipitated
solid is filtered off and then purified by chromatography (RP-18
mobile solvent:gradient that consists of
water/ethanol/acetonitrile).
[1642] Yield: 75.149 g (88.0% of theory) of a colorless solid.
[1643] Water content: 8.6%
[1644] Elementary analysis (relative to anhydrous substance): Cld.:
C, 34.53; H, 3.80; N, 8.05; Na, 1.47; S, 2.05; F, 20.63; Gd, 10.05.
Fnd.: C, 34.38; H, 3.95; N, 8.19; Na, 1.63; S, 2.15; F, 20.83; Gd,
10.14.
EXAMPLE 114
a)
6-N-Benzyloxycarbonyl)-2-[2-(N-ethyl-N-perfluorooctylsulfonyl]-amino]-a-
cetyl-L-lysine
[1645] 49.46 g (200.0 mmol) of EEDQ
(2-ethoxy-1,2-dihydroquinoline-1-carbo- xylic acid ethyl ester) is
added at 0.degree. C. to 31.820 g (113.5 mmol) of
6-N-benzyloxycarbonyl)-L-lysine and 66.42 g (113.5 mmol) of
2-(N-ethyl-N-perfluorooctylsulfonyl)-aminoacetic acid (produced
according to DE 196 03 033) in 300 ml of tetrahydrofuran, and it is
stirred overnight at room temperature. It is evaporated to the dry
state in a vacuum and chromatographed on silica gel (mobile
solvent:dichloromethane/- methanol=20:1).
[1646] Yield: 55.79 g (58% of theory) of a colorless solid.
[1647] Elementary analysis: Cld.: C, 36.85; H, 3.09; N, 4.96; F,
38.11; S, 3.78. Fnd.: C, 36.85; H, 3.19; N, 4.87; F, 38.28; S,
3.95.
b)
6-N-Benzyloxycarbonyl-2-N-[2-(N-ethyl-N-perfluorooctylsulfonyl)-amino]--
acetyl-L-lysine-N-methyl-N-(2,3,4,5,6-pentahydroxy-hexyl)-amide
[1648] 20.64 g (100.0 mmol) of N,N-dicyclohexylcarbodiimide is
added at 0.degree. C. to a solution that consists of 51.02 g (60.2
mol) of the title compound of Example 114a), 11.75 g (60.2 mol) of
N-methyl-glucamine and 6.93 g (60.2 mol) of N-hydroxysuccinimide,
dissolved in 250 ml of dimethylformamide. It is stirred for 3 hours
at 0.degree. C. and then overnight at room temperature.
Precipitated urea is filtered out, the filtrate is evaporated to
the dry state in a vacuum, and it is chromatographed on silica
gel.
[1649] (Mobile solvent:dichloromethane/ethanol=20:1).
[1650] Yield: 53.05 g (86% of theory) of a viscous oil.
[1651] Elementary analysis: Cld.: C, 38.68; H, 4.03; N, 5.47; F,
31.52; S, 3.13. Fnd.: C, 38.49; H, 4.17; N, 5.32; F, 31.70; S,
3.29.
c)
2-N-[2-(N-Ethyl-N-perfluorooctylsulfonyl)-amino]-acetyl-L-lysine-N-meth-
yl-N-(2,3,4,5,6-pentahydroxy-hexyl)-amide
[1652] 102.48 g (100.0 mmol) of the title compound of Example 114b)
is dissolved in 2000 ml of ethanol, and 10.0 g of palladium
catalyst (10% Pd/C) is added thereto. It is hydrogenated for 12
hours at room temperature. Catalyst is filtered out, and the
filtrate is evaporated to the dry state in a vacuum.
[1653] Yield: 89.06 g (quantitative) of a colorless solid.
[1654] Elementary analysis: Cld.: C, 33.72; H, 3.96; N, 6.29; S,
3.60; F, 36.26. Fnd.: C, 33.91; H, 3.82; N, 6.14; S, 3.47; F,
36.31.
d)
6-N-[1,4,7-Tris(carboxylatomethyl)]-1,4,7,10-tetraazacyclododecane-10-N-
-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-2-N-[2-(N-ethyl-N-perfluorooctyl-s-
ulfonyl)-amino]-acetyl-L-lysine-N-methyl-N-(2,3,4,5,6-pentahydroxy-hexyl)--
amide, Gd complex
[1655] 48.58 g (54.55 mmol) of the title compound of Example 114),
6.28 g (54.55 mmol) of N-hydroxysuccinimide, 4.62 g (109.0 mol) of
lithium chloride and 34.35 g (54.55 mol) of
1,4,7-tris(carboxylatomethyl)-10-(car-
boxy-3-aza-4-oxo-5-methyl-pent-5-yl)-1,4,7,10-tetraazacyclododecane,
Gd complex, are dissolved in 400 ml of dimethyl sulfoxide while
being heated slightly. At 10.degree. C., 16.88 g (81.8 mol) of
N,N-dicyclohexylcarbodi- imide is added and then stirred overnight
at room temperature. The solution is poured into 3000 ml of acetone
and stirred for 10 minutes. The precipitated solid is filtered off
and then purified by chromatography (RP-18 mobile solvent:gradient
that consists of water/ethanol/acetonitrile).
[1656] Yield: 73.27 g (89.4% of theory) of a colorless solid.
[1657] Water content: 8.6%
[1658] Elementary analysis (relative to anhydrous substance): Cld.:
C, 35.18; H, 4.23; N, 4.23; S, 21.3; F, 21.50; Gd, 10.47. Fnd.: C,
35.28; H, 4.15; N, 4.19; S, 2.18; F, 21.33; Gd, 10.61.
EXAMPLE 115
MRT-Visualization of Arteriosclerotic Plaque After Intravenous
Administration of Metal Complexes According to the Invention
[1659] In rabbits with genetically induced arteriosclerosis
(Watanabe rabbits), it was possible to observe a significant
enhancement in the arteriosclerotic plaque 5-60 minutes as well as
24 hours and 48 hours after intravenous administration of 25
.mu.mol of Gd/kg of body weight of the compounds according to the
invention in T.sub.1-weighted gradient-echo images (TR 11.1 ms, TE
4.3 ms, 150 flip angle .alpha.). The healthy vessel wall showed
only little or no contrast medium image and therefore also
indicated only little or no signal rise in the T1-weighted images.
Based on the contrast between the plaque with strong signals and
the healthy vessel wall with little or no signals, a diagnosis of
the arteriosclerotic vessel wall changes was possible.
[1660] The pictures in FIG. 1 show MR images of the aorta before,
as well as 24 hours and 48 hours after intravenous administration
of 25 .mu.mol of Gd/kg of body weight of metal complex XV in
Watanabe rabbits (genetically induced arteriosclerosis). The
T.sub.1-weighted gradient-echo images (1.5 T; TR: 11.1 ms, TE: 4.3
ms; NA: 2; matrix: 213*256; layer thickness: 1.0 mm) illustrate a
strong signal rise in the arteriosclerotic plaque. The localization
of the plaque, especially in aortic arches and in vascular
passages, was confirmed by means of Sudan-III-staining.
EXAMPLE 116
MRT-Visualization of Arteriosclerotic Plaque After Intravenous
Administration of Metal Complex XV in Rats, and Correlation of the
Post Mortem Image with Sudan-III-Staining
[1661] The pictures in FIG. 2a and 2b show MR images of the aorta
before as well as 35 minutes, 60 minutes and 24 hours after
intravenous administration of 10 .mu.mol of Gd/kg of body weight of
gadolinium metal complex XV in Watanabe rabbits (genetically
induced arteriosclerosis). The T.sub.1-weighted
gradient-echo-images (MPRage; 1.5T; TR: 11.1 ms, TE: 4.3 ms; NA: 2;
matrix: 213*256; layer thickness: 1.0 mm) illustrate a strong
signal rise in arteriosclerotic plaque. The localization of the
plaque, especially in aortic arches as well as in vascular
passages, was confirmed by means of Sudan-III-staining. Then, the
MR-imaging of the agar-embedded preparation was again examined with
a T.sub.1-weighted gradient-echo sequence (MPRage; 1.5 T; TR 11.1
ms, TE 4.3 ms, 15.degree. flip angle .alpha.; NA: 2; matrix:
213*256) and a spin-echo sequence (1.5 T; TR: 400 ms, TE: 15 ms;
NA: 16; matrix: 256*256) (post mortem image). In this case, there
was shown an excellent correlation of the aortic sections with
strong signal rise and stained plaque, which confirms an uptake of
the compounds according to the invention in the arteriosclerotic
plaque.
EXAMPLE 117
Infarction Visualization (MRT) After Intravenous Administration of
Metal Complex XV in Rats
[1662] The pictures in FIG. 3 show MR images of the heart (in vivo
and post mortem) 24 hours after intravenous administration of 100
.mu.mol of Gd/kg of body weight of metal complex XV in rats with
acutely induced myocardial infarction. The T.sub.1-weighted
spin-echo images (1.5 T; TR: 400 ms, TE: 6 ms; NA: 4; matrix:
128*128; layer thickness: 2.5 mm) illustrate the strong signal rise
in the infarction area. The successful induction of an acute
myocardial infarction was confirmed by means of NBT-staining.
[1663] Metal complex XV, 100 .mu.mol/kg i.v.; T1-SE, TR/TE 400/6
ms; arrow: myocardial infarction.
EXAMPLE 118
Infarction Visualization (MRT) After Intravenous Administration of
Metal Complex I in Rats
[1664] The pictures in FIG. 4 show MR images of the heart (in vivo
and post mortem) 24 hours after intravenous administration of 100
.mu.mol of Gd/kg of body weight of metal complex I in rats with
acutely induced myocardial infarction. The T.sub.1-weighted
spin-echo images (1.5 T; TR: 400 ms, TE: 6 ms; NA: 4; matrix:
128*128; layer thickness: 2.5 mm) illustrate the strong signal rise
in the infarction area. The successful induction of an acute
myocardial infarction was confirmed by means of NBT-staining.
EXAMPLE 119
Lymph Mode Visualization (MRT) After Intravenous Administration of
Metal Complex XV in VX2-Tumor-Carrying Rabbits
[1665] The pictures in FIG. 5a and 5b show MR images of iliac lymph
nodes precontrast and up to 24 hours after intravenous
administration of 200 .mu.mol of Gd/kg of body weight of metal
complex XV in rabbits with VX2-tumors implanted i.m. The
T.sub.1-weighted gradient-echo images (1.5 T; sequence: MPRange; TR
11.1 ms, TE 4.3 ms, .alpha. 15.degree.) illustrate the strong
signal rise in healthy lymph node tissue. Zones without signal rise
within the lymph node were diagnosed as metastases and confirmed
histologically (H/E-staining of the lymph node section). Later (24
hours) after contrast medium administration, however, a signal
reversal was observed, surprisingly enough. The signal rise in
healthy lymph node tissue was reduced, while the metastasis now
exhibited a considerable signal rise.
[1666] Surprisingly enough, even immediately after administration,
a considerable enhancement of the primary tumor (especially the
periphery) could be observed. Later (24 hours p.i.), this
enhancement also propagates out from the center of the tumor.
EXAMPLE 120
Tumor Visualization (MRT) After Intravenous Administration of Metal
Complex I in VX2-Tumor-Carrying Rabbits
[1667] The pictures of FIG. 6 show MR images of an iliac lymph node
and of a primary tumor (VX2-tumor implanted i.m.) precontrast, 60
minutes and 20 hours after intravenous administration of 100
.mu.mol of Gd/kg of body weight of metal complex I in rabbits. The
T.sub.1-weighted gradient-echo images (1.5 T; sequence: MPRange; TR
11.1 ms, TE 4.3 ms, .alpha. 15.degree.) illustrate the strong
signal rise in healthy lymph node tissue.
[1668] Shortly after administration (60 minutes p.i.), a
considerable enhancement of the primary tumor (especially the
periphery) can be observed. Subsequently (20 hours p.i.), the
signal rise is also propagated in the more central region of the
tumor.
[1669] The enhancement of a pathological structure (optionally
secondary tumor or necrosis) on the contralateral side, which shows
up only in late images ("late enhancement") is especially
noteworthy.
[1670] Metal Complex X
EXAMPLE 121
Infarction Visualization (MRT) After Intravenous Administration of
the Contrast Medium in Rats
[1671] The pictures in FIG. 7 show MR images of the heart (in vivo
and post mortem) 6 hours after intravenous administration of 100
.mu.mol of Gd/kg of body weight of a polar Gd-chelate with
perfluorinated side chains (metal complex X) in rats with acutely
induced myocardial infarction. The T.sub.1-weighted, EKG-triggered
spin-echo images (1.5 T; TR (effective): 400 ms, TE: 12 ms; NA: 4;
matrix: 128*128; layer thickness: 2.5 mm) illustrate the strong
signal rise in the infarction area. The successful induction of an
acute myocardial infarction was confirmed by means of
NBT-staining.
EXAMPLE 122
Organ Distribution (Including Lymph Node Concentration) After
Intravenous Administration of the Contrast Medium in Rats
[1672] After intravenous administration of 100 .mu.mol of total
gadolinium/kg of body weight of a polar Gd-chelate with
perfluorinated side chains (metal complex X) in rats, the metal
content in various organs as well as in the lymph nodes (pooled as
mesenteric and peripheral lymph nodes) was determined 24 hours
after administration (MW, n=2).
3 Organ .mu.mol Gd/L % Dose Liver 104 2.34 Femur 3 0.01 Kidneys 150
0.65 Brain 1 0.01 Carcass 192 34.01 Blood 1 0.01 Stomach 49 0.18
Intestine 65 1.22 Spleen 54 0.07 Pancreas 6 0.02 Heart 3 0.01 Lung
18 0.05 Muscle 1 0.00 Mesenteric lymph 19 0.01 nodes Peripheral
lymph 11 0.01 nodes Total 38.58
EXAMPLE 123
Lymph Node Visualization (MRT) After Intravenous Administration of
the Contrast Medium in Rats
[1673] By way of example, the pictures in FIG. 8 show MR images of
iliac lymph nodes precontrast and up to 60 minutes after
intravenous administration of 100 .mu.mol of Gd/kg of body weight
of metal complex X in rats. The T.sub.1-weighted gradient-echo
images (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, .alpha.
15.degree.) illustrate the strong signal rise in healthy lymph node
tissue even very shortly after injection. The enhancement was thus
263% at the time of 15 minutes p.i. and 254% at the time of 60
minutes p.i.
EXAMPLE 124
Lymph Node Visualization (MRT) After Intravenous Administration of
the Contrast Medium in VX2-Tumor-Bearing Rabbits
[1674] By way of example, the pictures in FIG. 9 show MR images of
iliac lymph nodes precontrast and up to 60 minutes after
intravenous administration of 200 .mu.mol of Gd/kg of body weight
of metal complex X in rabbits with VX2-tumors implanted i.m. The
T.sub.1-weighted gradient-echo images (1.5 T; sequence: MPRange; TR
11.1 ms, TE 4.3 ms, .alpha. 15.degree.) illustrate the strong
signal rise in healthy lymph node tissue. The enhancement in the
healthy lymph node tissue was 382% at the time of 15 minutes p.i.
and 419% at the time of 60 minutes p.i. Zones without signal rise
within the lymph node were diagnosed as metastases and confirmed
histologically (H/E-staining of the lymph node section). The ratio
of signal intensities of healthy lymph node tissue to metastasis
was 3.0 at the time of 15 minutes p.i. and 3.4 at the time of 60
minutes p.i.
[1675] Surprisingly enough, even immediately after administration,
a considerable enhancement not only of the lymph nodes but also of
the primary tumor (especially the periphery) could be observed (15
minutes p.i.: 277%). Later (up to 24 hours p.i.), this enhancement
also propagates out from the center of the tumor (24 hours p.i.:
217%).
[1676] Metal Complex V
EXAMPLE 125
Infarction Visualization (MRT) After Intravenous Administration of
the Contrast Medium in Rats
[1677] The pictures in FIG. 10 show MR images of the heart (in vivo
and post mortem) 24 hours after intravenous administration of 100
.mu.mol of Gd/kg of body weight of a polar Gd-chelate with
perfluorinated side chains (metal complex V) in rats with acutely
induced myocardial infarction. The T.sub.1-weighted, EKG-triggered
spin-echo images (1.5 T; TR (effective): 400 ms, TE: 12 ms; NA: 4;
matrix: 128*128; layer thickness: 2.5 mm) illustrate the strong
signal rise in the infarction area. The successful induction of an
acute myocardial infarction was confirmed by means of
NBT-staining.
EXAMPLE 126
Organ Distribution (Including Lymph Node Concentration) After
Intravenous Administration of the Contrast Medium in Rats
[1678] After intravenous administration of 200 .mu.mol of total
gadolinium/kg of body weight of a polar Gd-chelate with
perfluorinated side chains (metal complex V) in rats, the metal
content in various organs as well as in the lymph nodes (pooled as
mesenteric and peripheral lymph nodes) was determined 24 hours
after administration (MW, n=2).
4 Organ .mu.mol Gd/L % Dose Liver 344 6.34 Femur 13 0.05 Kidneys
436 1.77 Brain 4 0.02 Carcass 268 37.93 Blood 15 0.18 Stomach 28
0.08 Intestine 113 1.56 Spleen 116 0.17 Pancreas 30 0.05 Heart 14
0.02 Lung 62 0.17 Muscle 9 0.02 Mesenteric lymph 70 0.05 nodes
Peripheral lymph 44 0.02 nodes Total 48.43
EXAMPLE 127
Lymph Node Visualization (MRT) After Intravenous Administration of
the Contrast Medium in Rats
[1679] By way of example, the pictures in FIG. 11 show MR images of
iliac lymph nodes precontrast and up to 60 minutes after
intravenous administration of 200 .mu.mol of Gd/kg of body weight
of metal complex V in rats. The T.sub.1-weighted gradient-echo
images (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, .alpha.
15.degree.) illustrate the strong signal rise in healthy lymph node
tissue even very shortly after injection. The enhancement was thus
147% at the time of 15 minutes p.i. and 230% at the time of 60
minutes p.i.
EXAMPLE 128
Lymph Node Visualization (MRT) After Intravenous Administration of
the Contrast Medium in VX2-Tumor-Bearing Rabbits
[1680] By way of example, the pictures in FIG. 12 show MR images of
iliac lymph nodes precontrast and up to 60 minutes after
intravenous administration of 200 .mu.mol of Gd/kg of body weight
of metal complex V in rabbits with VX2-tumors implanted i.m. The
T.sub.1-weighted gradient-echo images (1.5 T; sequence: MPRange; TR
11.1 ms, TE 4.3 ms, .alpha. 15.degree.) illustrate the strong
signal rise in healthy lymph node tissue. The enhancement in the
healthy lymph node tissue was 246% at the time of 15 minutes p.i.
and 282% at the time of 60 minutes p.i. Zones without signal rise
within the lymph node were diagnosed as metastases and confirmed
histologically (H/E-staining of the lymph node section). The ratio
of signal intensities of healthy lymph node tissue to metastasis
was 2.5 at the time of 15 minutes p.i. and 1.7 at the time of 60
minutes p.i.
[1681] Surprisingly enough, even immediately after administration,
a considerable enhancement not only of the lymph nodes but also of
the primary tumor (especially the periphery) could be observed (15
minutes p.i.: 350%). Later (up to 24 hours p.i.), this enhancement
also propagates out from the center of the tumor (24 hours p.i.:
106%).
[1682] Metal Complex XIV
EXAMPLE 129
Infarction Visualization (MRT) After Intravenous Administration of
the Contrast Medium in Rats
[1683] The pictures in FIG. 13 show MR images of the heart (in vivo
and post mortem) 3 hours after intravenous administration of 100
.mu.mol of Gd/kg of body weight of a polar Gd-chelate with
perfluorinated side chains (metal complex XIV) in rats with acutely
induced myocardial infarction. The T.sub.1-weighted, EKG-triggered
spin-echo images (1.5 T; TR (effective): 400 ms, TE: 12 ms; NA: 4;
matrix: 128*128; layer thickness: 2.5 mm) illustrate the strong
signal rise in the infarction area. The successful induction of an
acute myocardial infarction was confirmed by means of
NBT-staining.
EXAMPLE 130
Organ Distribution (Including Tumor and Lymph Node Concentration)
After Intravenous Administration of the Contrast Medium in
Prostate-Cancer-Bearing Rats
[1684] After intravenous administration of 200 .mu.mol of total
gadolinium/kg of body weight of a polar Gd-chelate with
perfluorinated side chains (metal complex XIV) in rats
(Cop-inbreeding with Dunning R3327 MAT-Lu prostate cancer
i.m.-implanted 12 days earlier), the metal content in various
organs, in tumors, as well as in the lymph nodes (pooled as
mesenteric and peripheral lymph nodes) was determined 10 minutes, 1
hour and 24 hours after administration (MW.+-.SD, n=3).
5 Metallkomplex XIV Gd-Konzentration [.mu.mol/l] % Dosis 10 min
p.i. 1 h p.i. 24 h p.i. 10 min p.i. 1 h p.i. 24 h p.i. Leber 192
.+-. 12 147 .+-. 7 64 .+-. 4 2.62 .+-. 0.11 2.04 .+-. 0.15 0.96
.+-. 0.05 Milz 200 .+-. 13 123 .+-. 10 69 .+-. 5 0.13 .+-. 0.01
0.08 .+-. 0.01 0.06 .+-. 0.00 Pankreas 191 .+-. 14 139 .+-. 26 25
.+-. 1 0.35 .+-. 0.02 0.21 .+-. 0.05 0.03 .+-. 0.01 Niere 761 .+-.
60 1181 .+-. 232 338 .+-. 49 1.76 .+-. 0.14 2.84 .+-. 0.61 0.81
.+-. 0.09 Lunge 603 .+-. 30 415 .+-. 39 44 .+-. 4 1.04 .+-. 0.02
0.80 .+-. 0.06 0.09 .+-. 0.01 Herz 320 .+-. 8 190 .+-. 15 19 .+-. 0
0.32 .+-. 0.01 0.19 .+-. 0.01 0.02 .+-. 0.00 Gehirn 38 .+-. 6 22
.+-. 2 4 .+-. 4 0.10 .+-. 0.03 0.06 .+-. 0.00 0.01 .+-. 0.01
Muskel**** 93 .+-. 5 56 .+-. 3 8 .+-. 1 0.06 .+-. 0.02 0.04 .+-.
0.00 0.00 .+-. 0.00 Tumor 246 .+-. 25 266 .+-. 87 56 .+-. 4 0.25
.+-. 0.05 0.37 .+-. 0.14 0.04 .+-. 0.01 Femur 115 .+-. 3 81 .+-. 10
9 .+-. 1 0.39 .+-. 0.02 0.28 .+-. 0.03 0.03 .+-. 0.00 mes. LK 291
.+-. 29 179 .+-. 16 50 .+-. 6 0.08 .+-. 0.01 0.05 .+-. 0.01 0.02
.+-. 0.00 periph. LK 284 .+-. 19 254 .+-. 14 51 .+-. 5 0.13 .+-.
0.00 0.14 .+-. 0.02 0.02 .+-. 0.00 Magen (entleert) 244 .+-. 17 165
.+-. 21 19 .+-. 2 0.56 .+-. 0.07 0.40 .+-. 0.05 0.05 .+-. 0.00 Darm
(entleert) 242 .+-. 15 201 .+-. 32 36 .+-. 5 1.55 .+-. 0.09 1.16
.+-. 0.22 0.26 .+-. 0.04 Blut** 957 .+-. 38 575 .+-. 56 22 .+-. 1
26.73 .+-. 0.84 16.13 .+-. 1.77 0.61 .+-. 0.03 Restkorper* 419 .+-.
27 392 .+-. 25 42 .+-. 0 70.71 .+-. 2.74 64.27 .+-. 5.50 6.81 .+-.
0.16 Harn 0-24 h -- -- 619 .+-. 19 -- -- 79.86 .+-. 3.13 Faeces
0-24 h -- -- 781 .+-. 611 -- -- 6.00 .+-. 4.91 Summe der Organe***
80.06 .+-. 2.84 72.94 .+-. 5.83 9.21 .+-. 0.27 Bilanz*** 95.07 .+-.
2.41 *Blutproben sind im Restkorper enthalten **58 ml Blut/kg KGW
***Bilanz ohne Blutwerte, da diese im Restkorper enthalten ****nur
Gewebealiquot *Blood samples are contained in the remainder of the
body **58 ml Blut/kg KGW = 58 ml of blood/kg of body weight Balance
without blood values, since the latter [are] contained in the
remainder of the body Only tissue aliquot
EXAMPLE 131
Lymph Node Visualization (MRT) After Intravenous Administration of
the Contrast Medium in Guinea Pigs
[1685] By way of example, the pictures in FIG. 14 show MR images of
iliac and inguinal lymph nodes precontrast and up to 24 hours after
intravenous administration of 200 .mu.mol of Gd/kg of body weight
of metal complex XIV in guinea pigs with stimulated lymph nodes
(Freund adjuvant). The T.sub.1-weighted gradient-echo images (2.0
T; TR 10 ms, TE 5 ms, .alpha. 40.degree.) illustrate the strong
signal rise in healthy lymph node tissue even very shortly after
injection. The enhancement was 127% at the time of 60 minutes
p.i.
EXAMPLE 132
Lymph Node Visualization (MRT) After Intravenous Administration of
the Contrast Medium in VX2-t-Tumor-Bearing Rabbits
[1686] By way of example, the pictures in FIG. 15 show MR images of
iliac lymph nodes precontrast and up to 23 hours after intravenous
administration of 200 .mu.mol of Gd/kg of body weight of metal
complex XIV in rabbits with VX2-tumors implanted i.m. The
T.sub.1-weighted gradient-echo images (1.5 T; sequence: MPRange; TR
11.1 ms, TE 4.3 ms, .alpha. 15.degree.) illustrate the strong
signal rise in healthy lymph node tissue. The enhancement in the
healthy lymph node tissue was 297% at the time of 10 minutes p.i.
and 269% at the time of 60 minutes p.i. Zones without signal rise
within the lymph node were diagnosed as metastases and confirmed
histologically (H/E-staining of the lymph node section). The ratio
of signal intensities of healthy lymph node tissue to metastasis
was 5.1 at the time of 10 minutes p.i. and 1.9 at the time of 60
minutes p.i.
[1687] Surprisingly enough, even immediately after administration,
a considerable enhancement not only of the lymph nodes but also of
the primary tumor (especially the periphery) could be observed (15
minutes p.i.: 594%). Later (up to 24 hours p.i.), this enhancement
also propagates out from the center of the tumor (120 hours p.i.:
162%).
[1688] Metal Complex III
EXAMPLE 133
Infarction Visualization (MRT) After Intravenous Administration of
the Contrast Medium in Rats
[1689] The pictures in FIG. 16 show MR images of the heart (in vivo
and post mortem) 22 hours after intravenous administration of 100
.mu.mol of Gd/kg of body weight of a polar Gd-chelate with
perfluorinated side chains (metal complex III) in rats with acutely
induced myocardial infarction. The T.sub.1-weighted, EKG-triggered
spin-echo images (1.5 T; TR (effective): 400 ms, TE: 12 ms; NA: 4;
matrix: 128*128; layer thickness: 2.5 mm) illustrate the strong
signal rise in the infarction area. The successful induction of an
acute myocardial infarction was confirmed by means of
NBT-staining.
EXAMPLE 134
Organ Distribution (Including Lymph Node Concentration) After
Intravenous Administration of the Contrast Medium in Rats
[1690] After intravenous administration of 200 .mu.mol of total
gadolinium/kg of body weight of a polar Gd-chelate with
perfluorinated side chains (metal complex III) in rats, the metal
content in various organs as well as in the lymph nodes (pooled as
mesenteric and peripheral lymph nodes) was determined 24 hours
after administration (MW, n=2).
6 Organ .mu.mol Gd/L % Dose Liver 1222 26.28 Femur 76 0.32 Kidneys
489 1.97 Brain 10 0.05 Carcass 242 36.30 Blood 83 1.15 Stomach 165
0.57 Intestine 230 3.56 Spleen 464 0.89 Pancreas 203 0.48 Heart 82
0.13 Lung 338 0.96 Muscle 28 0.04 Mesenteric lymph 455 0.33 nodes
Peripheral lymph 279 0.18 nodes Total 73.20
EXAMPLE 135
Lymph Node Visualization (MRT) After Intravenous Administration of
the Contrast Medium in Rats
[1691] By way of example, the pictures in FIG. 17 show MR images of
iliac lymph nodes precontrast and up to 60 minutes after
intravenous administration of 200 .mu.mol of Gd/kg of body weight
of metal complex III in rats. The T.sub.1-weighted gradient-echo
images (1.5 T; sequence: MPRange; TR 11.1 ms, TE 4.3 ms, .alpha.
15.degree.) illustrate the strong signal rise in healthy lymph node
tissue even very shortly after injection. The enhancement was thus
320% at the time of 15 minutes p.i. and 401% at the time of 60
minutes p.i.
EXAMPLE 136
Lymph Node Visualization (MRT) After Intravenous Administration of
the Contrast Medium in VX2-Tumor-Bearing Rabbits
[1692] By way of example, the pictures in FIG. 18 show MR images of
iliac lymph nodes precontrast and up to 60 minutes after
intravenous administration of 200 .mu.mol of Gd/kg of body weight
of metal complex III in rabbits with VX2-tumors implanted i.m. The
T.sub.1-weighted gradient-echo images (1.5 T; sequence: MPRange; TR
11.1 ms, TE 4.3 ms, .alpha. 15.degree.) illustrate the strong
signal rise in healthy lymph node tissue. The enhancement in the
healthy lymph node tissue was 195% at the time of 15 minutes p.i.
and 233% at the time of 60 minutes p.i. Zones without signal rise
within the lymph node were diagnosed as metastases and confirmed
histologically (H/E-staining of the lymph node section). The ratio
of signal intensities of healthy lymph node tissue to metastasis
was 1.9 at the time of 15 minutes p.i. and 1.8 at the time of 60
minutes p.i.
[1693] Surprisingly enough, even immediately after administration,
a considerable enhancement not only of the lymph nodes but also of
the primary tumor (especially the periphery) could be observed (15
minutes p.i.: 232%).
[1694] In the foregoing and in the following examples, all
temperatures are set forth uncorrected in degrees Celsius and, all
parts and percentages are by weight, unless otherwise
indicated.
[1695] The entire disclosure of all applications, patents and
publications, cited herein and of corresponding German application
No. 100 40 380.8, filed Aug. 11, 2000 is hereby incorporated by
reference.
* * * * *