Note: Descriptions are shown in the official language in which they were submitted.
CA 02362703 2001-08-22
WO 00/56723 PCT/EP00/02285
Perfluoroalkylamides, Their Production and Their Use in Diagnosis
The invention relates to the subject that is characterized
in the claims, i.e., macrocyclic perfluoroalkylamides, their
production and their use in diagnosis.
In nuclear magnetic resonance, the element fluorine is
second in importance to the element hydrogen.
1. Fluorine has a high sensitivity of 83% of that of
hydrogen.
2. Fluorine has only one NMR-active isotope.
3. Fluorine has a resonance frequency that is similar to
hydrogen -- fluorine and hydrogen can be measured with
the same system.
4. Fluorine is biologically inert.
5. Fluorine does not occur in biological material
(exception: teeth) and can therefore be used as a probe
or contrast medium against a background that is free of
interfering signals.
The effect of these properties is that fluorine occupies a
broad space in diagnostic patent literature with nuclear magnetic
resonance as a basis: fluorine-19-imaging, functional diagnosis,
spectroscopy.
2
US Patent 4,639,364 (Mallinckrodt) thus proposes
trifluoromethanesulfonamides as contrast media for fluorine-19-
imaging:
CF3SOZNH2
CF3SOZNH-CHZ- (CHOH) 4-CHzOH
German Patent DE 4203254 (Max-Planck-Gesellschaft), in which
an aniline derivative is proposed, also relates to fluorine-19-
imaging:
CFCF /~ ~~~,--NHCOCH~ I
i; ,,\
CF;
Fluorine-19-imaging is the subject of application WO
93/07907 (Mallinckrodt), in which phenyl derivatives are also
claimed as contrast media:
HO OH
O
CFA CFA HO O CFs
CF
HO C ~- ~ COZH N
~ ~~ _
CFA CFA HO CFA ~ H
O
HO OH
Compounds of considerably simpler structure are also claimed
for fluorine-19-imaging. Thus, Patent US 4,586,511 (Children's
Hospital Medical Center) mentions perfluorooctyl bromide
CF3 (CFZ) 7-Br
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3
European Patent EP 307863 (Air Products) mentions perfluoro-15-
crown-ether
F F F F
F p O F
F F
F F
F O O F
F O F
F
F F
F F F
and U.S. Patent US 4,558,279 (University of Cincinnati,
Children's Hospital Research Foundation) mentions perfluorocarbon
compounds, such as perfluorocyclononane or -octane,
perfluorinated ethers such as tetrahydrofuran
F F F
~F
F~O~F
or diethers such as perfluoro-propyleneglycol-diether
CFA CFA
F~O-CFZCFzCFi O--~F
C~F~ CFA
The compounds that are mentioned in Application WO 94/22368
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4
(Molecular Biosystems), e.g.,
0-CO-(CHZ)s R
CH3(CH2)7-CH=CH-(CH2)7-CO - O
O-CO-(CHZ)s R
~ Fs
-CF3
~CF, , which as
R=
CFA
CFA
CFy
fluorine-containing radicals have the perfluoro-1H,1H-neopentyl
group, are also used for fluorine-19-imaging.
U.S. Patent US 5,362,478 (VIVORX) indicates another
structural type with expanded diagnostic use, in which the
fluorocarbon/polymer shell combination is claimed for imaging
purposes. Perfluorononane and human serum albumin are mentioned.
This combination proves suitable, moreover, for using the
fluorine atom as a probe for local temperature measurement and
for determining the partial oxygen pressure.
Perfluorocarbons are also claimed in US Patent 4,586,511 for
oxygen determination.
In German Patent DE 4008179 (Schering), fluorine-containing
benzenesulfonamides are claimed as pH probes.
~CF~
F /~---~\ NHSOZCH'CHZCO~H
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For NMR diagnosis, compounds that contain iodine and
fluorine atoms are also claimed as contrast-enhancing agents in
WO 94/05335 and WO 94/22368 (both molecular biosystems):
I
CHz-CH-COzH
I Et
I
NHCOCF~
t
1 ~ ~ (CH -CO
z)s z C(CF3)a
HZN 1 OCO-(CHz)~
I -
I ~ ~ (CHz)s-COz C(CF3)~
HzN
The fluorine-paramagnetic metal ion combination is also
claimed for fluorine-19-imaging, specifically for open-chain
complexes in WO 94/22368 (Molecular Biosystems) with, e.g..
COz.
HZC -HNOC ~ N ~ N \/~ N ~ CONH -CH
z
~CO '
z C Oz'
i
C(CF~)~ C(CF~)~ Gd3+
C(CF~)~ C(CF~)~
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6
and in EP 292 306 (TERUMO Kabushiki Kaisha) with, e.g..
R
I
N
O<C~N~/ ~N~CO:~
Gd'+
~OzC~ ~CO
z
F
_ R= -CHzCF~ . -CHz / \ C(CF3)~ , -CH / \ F
z
CFA F F
cF,
~cF, . --cH r v
-CHzCHz N z
CF3
CFA
CFA
but also for cyclic compounds, as they are mentioned in EP 628
316 (TERUMO Kabushiki Kaisha)
~0 C ~ ~ ~
z N N COz~ OzC ~ ~ ~
COz.
Gd3~
~N N~
~ l-J ~
coZ- R
coZ~ . _ _
R_- w I
CFA CFA
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7
c~,
i v
CFA
-CHz ' ~ ~ CFA ~ CHZCH~-N CF ~
.. CFA
CF,
The fluorine atom-rare earth metal combination is also
claimed for NMR-spectroscopic temperature measurements in DE
4317588 (Schering):
O:C~\ /~\ /~1C0;.
N N
Cn3+
OH
N N I
CFA
COz
Ln: Rare earths: La, Pr, Dy, Eu
While no interactions between the two nuclei occur in
compounds that contain the elements fluorine and iodine,
intensive interaction does occur in compounds that contain
fluorine and paramagnetic centers (radicals, metal ions), which
are expressed in a shortening of the relaxation time of the
fluorine nucleus. The extent of this effect depends on the
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8
number of unpaired electrons of the metal ion (Gd3+ ~ Mnz+ > Fe3+
Cu2+) and on the removal between the paramagnetic ion and the ~9F
atom.
The more unpaired electrons of the metal ion are present and
the closer they are brought to the fluorine, the greater the
shortening of the relaxation time of the fluorine nucleus.
The shortening of the relaxation time as a function of the
distance from the paramagnetic ion becomes apparent in all nuclei
with an uneven spin number, thus also in the case of protons, and
gadolinium compounds are therefore widely used as contrast media
in nuclear spin tomography (Magnevist~R~, Prohance~R~, Omniscan~R~,
Dotarem~R~) .
In ~H-MR imaging ('H-MRI) , however, relaxation time T' or TZ
of the protons, i.e., mainly the protons of water and not the
relaxation time of the fluorine nuclei, is measured and used for
imaging. The quantitative measurement for the shortening of the
relaxation time is relaxivity [L/mmol-s]. Complexes of
paramagnetic ions are successfully used for shortening the
relaxation times. In the following table, the relaxivity of some
commercial preparations is indicated:
T~-Relaxivity in T~-Relaxivity in
Water [L/mmmol-s, Plasma [L/mmol~s, _
39C, 0.47 T] 39C, 0.47 T] _
MAGNEVIST~R~ 3 . 8 4 . 8
DOTAREM~R~ 3 . 5 4 . 3
OMNISCAN~R~ 3 . 8 4 . 4
PRO HANCE~R~ 3.7 4.9
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In these compounds, only interactions between protons and
the gadolinium ion occur. For these contrast media in water, a
relaxivity of about 4 [L/mmol~s] is thus observed.
Both fluorine compounds for fluorine-19-imaging, in which
the shortened relaxation time of the fluorine nucleus is used,
and non-fluorine-containing compounds, in which the relaxation
time of the protons of water is measured, are thus used
successfully for MR imaging.
In the introduction of a perfluorocarbon-containing radical
into a paramagnetic contrast medium, i.e., in the combination of
properties that were previously known as suitable only for
fluorine-imaging compounds, the relaxivity that relates to the
protons of water also increases rapidly, surprisingly enough,
with compounds that were used for proton imaging. It now reaches
values of 10-50 [L/mmol-s] in comparison to values between 3.5
and 3.8 [L/mmol~s] as they were already cited for some commercial
products in the table above.
Perfluoroalkyl-containing metal complexes are known from DE
196 03 033.1. The compounds of this invention are distinguished,
however, by better properties, such as, for example, higher lymph
node accumulation in three successive lymph node stations, better
elimination, greater compatibility (which is especially
advantageous for i.v. lymphography) and very good local
compatibility in the case of interstitial administration. This
opens up the possibility of adding the compounds at higher doses.
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The MRI contrast media are used mainly for the visualization
of malignant tumors.
Malignant tumors metastasize in clusters in regional lymph
nodes, whereby multiple lymph node stations may also be involved.
Thus, lymph node metastases are found in about 50-69% of all
patients with malignant tumors (Elke, Lymphographie
[Lymphography], in: Frommhold, Stender, Thurn (Eds.),
Radiologische Diagnostik in Klinik and Praxis [Radiological
Diagnosis in Clinical Studies and Practice], Volume IV, Thieme
Verlag Stuttgart, 7th Edition, 434-496, 1984)). The diagnosis of
a metastatic attack of lymph nodes is of great importance with
respect to the therapy and prognosis of malignant diseases. With
modern imaging methods (CT, US and MRI), lymphogenous metastasis
sites of malignant tumors are detected only inadequately, since
in most cases, only the size of the lymph node can be used as a
diagnostic criterion. Thus, small metastases in non-enlarged
lymph nodes (< 2 cm) cannot be distinguished from lymph node
hyperplasias without a malignant attack (Steinkamp et al.,
Sonographie and Kernspintomographie: Differential Diagnostik von
reaktiver Lymphknoten-vergroi3erung and Lymphknotenmetastasen am
Hals [Sonography and Nuclear Spin Tomography: Differential
Diagnosis of Reactive Lymph Node Enlargement and Lymph Node
Metastases on the Neck], Radiol. Diagn. 33: 158, 1992).
It would be desirable if lymph nodes with metastatic attack
and hyperplastic lymph nodes can be distinguished with use of
specific contrast media.
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Direct x-ray lymphography (injection of an oily contrast
medium suspension into a prepared lymph vessel) is known as an
invasive method that is used only infrequently and that can
visualize only small lymphatic drainage stations.
Fluorescence-labeled dextrans are also used experimentally
in animal experiments to be able to observe lymphatic drainage
after their interstitial administration. All commonly used
markers for the visualization of lymph tracts and lymph nodes
after interstitial/intracutaneous administration have in common
the fact that they are substances with a particulate nature
("particulates," e.g., emulsions and nanocrystal suspensions) or
large polymers (see above, WO 90/14846). Based on their
inadequate local and systemic compatibility as well as their
small lymphatic passageway, which causes inadequate diagnostic
efficiency, however, the previously described preparations prove
to be still not optimally suitable for indirect lymphography.
Since the visualization of lymph nodes is of central
importance for early detection of the metastatic attack in cancer
patients, there is a great need for lymph-specific contrast
medium preparations for diagnosis of corresponding changes of the
lymphatic system.
The highest possible contrast medium concentration and high
stability are just as desirable as the diagnostically relevant,
most uniform possible lymphatic concentration over several lymph
stations. The burden on the overall organism should be kept low
by quick and complete excretion of the contrast medium. A quick
start-up, if possible as early as within a few hours after the
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administration of contrast media, is important for the
radiological practice. Good compatibility is necessary.
The object of the invention is achieved by the macrocyclic
perfluoroalkyl compounds of general formula I
A
K-N-L-RF
in which
K means a complexing agent or a metal complex of general
formula II
'COOR'
~NI ~ RZ R~ O
N~N~U
N
COOR'~ NJ O
~COOR'
c«~
whereby
R~ stands for a hydrogen atom or a metal ion
equivalent of atomic numbers 21-29, 31, 32, 37-39,
42-44, 49 or 57-83,
RZ and R3 stand for a hydrogen atom, a C~-C7 alkyl
group, a benzyl group, a phenyl group, -CHZOH or
-CH2-OCH3, and
U stands for radical L, whereby L and U,
independently of one another, can be the same or
different,
A means a hydrogen atom, a straight-chain or branched C
C3o alkyl group, which optionally is interrupted by 1-
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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 OR4 groups, with R4 in the
meaning of a hydrogen atom or a C~-C~ alkyl radical, or
_L_RF.
L means a straight-chain or branched C~-C3o alkylene
group, which optionally is interrupted by 1-10 oxygen
atoms, 1-5 -NH-CO groups, 1-5 -CO-NH groups, by a
phenylene group that is optionally substituted by a
COON group, 1-3 sulfur atoms, 1-2 -N(B~)-SOZ groups,
and/or 1-2 -SOZ-N (B' ) groups with B~ in the meaning of
A, and/or optionally is substituted with radical RF,
and
RF means a straight-chain or branched perfluorinated alkyl
radical of formula C~FZ~X,
whereby 4 s n s 20, and
X stands for a terminal fluorine atom, chlorine
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.
The new perfluoroalkyl-containing compounds of general
formula I of claim 1 according to the invention comprise both
complexing agents and metal complexes. Compounds of general
formula I in which the metal ion equivalent that is bonded in
macrocycle K is absent are referred to as complexing agents, and
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compounds with a metal ion equivalent that is bonded in
macrocycle K are referred to as metal complexes.
As metal ion equivalents, and depending on the desired use
of the compounds according to the invention, the following metals
are suitable:
1. When used in NMR diagnosis and x-ray diagnosis:
complexes with the ions of elements with atomic numbers
21-29, 39, 42, 44 and 57-83;
2. When used in radiodiagnosis and radiotherapy:
complexes with the radioisotopes of elements with
atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64,
70, 75 and 77.
The ions of elements with atomic numbers 21-29, 39, 42, 44
and 57-83 are preferred.
Gadolinium is especially preferred.
Alkyl groups RZ, R3, R4 can be straight-chain or branched.
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 by way of
example.
Hydrogen and C~-C4 alkyl groups, especially preferably
hydrogen and the methyl group, are preferred for Rz, R3 and R4.
The benzyl group and phenyl group R2, A and B' can be
substituted in the phenyl ring. As a substituent, the COON group
is suitable.
If the compound of formula I contains radicals L and U at
the same time, L and U can be different from one another.
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The Ci-C3o alkylene groups U can be straight-chain or
branched. Methylene, ethylene, propylene, isopropylene, n-
butylene, 1-methylpropylene, 2-methylpropylene, n-pentylene, 1-
methylbutylene, 2-methylbutylene, 3-methyl-butylene, 1,2-
dimethylpropylene can be mentioned by way of example.
For U in the meaning of alkylene, C~-Coo alkylene groups are
preferred; C~-C4 alkylene groups are especially preferred.
The C~-C3o alkyl groups A can be straight-chain or branched.
Methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-
methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-
methylbutyl, 1,2-dimethylpropyl, n-hexyl can be mentioned by way
of example.
The C~-C3o alkyl groups A can be interrupted by 1-15 oxygen
atoms and/or substituted with 1-10 hydroxy groups, 1-5 alkoxy
groups or 1-2 COON groups, such as, e.g.,
C2H4-0-CH3, C3H6-O-CH3,
CZH4-O- (C2H4-O) t-CZH4-OH, CZH4-0- (CZH4-O) t-C2H4-OCH3 With t = 0 t0
13,
CZH40H, C3H60H, C4H80H, C5H~o0H, C6H~ZOH, C~i~40H, as well as
their branched isomers,
CH ( OH ) CHZOH ,
CH ( OH ) CH ( OH ) CH20H , CHZ [ CH ( OH ) ] ~CH20H , wi t h a = 1-10
CH [ CH2 ( OH ) ] CH ( OH ) CH20H ,
CZH4CH ( OH ) CHZOH ,
(CHZ) SCOOH with s = 1 to 15,
CZH4-O- (CZH4-O) t-CHZCOOH with t = 0 to 13,
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CzH4-0- (C2H4-O) t-CZH4-C~Fz~X with t = 0 to 13 , n = 4 to 20 and X
- a fluorine, chlorine, bromine or iodine atom.
Preferred meanings of A are hydrogen, C~-Coo alkyl,
CZH4-O-CH3, C3H6-O-CH3.
CZH4-0- (CZH4-0) X-CzH4-OH, CZH4-O- (CZH4-O) x-CzH4-OCH3 With X = 0 t0
5,
CZH40H , C3H60H ,
CHZ [CH (OH) ] yCHZOH, with y = 1-6~
CH [CHZ (OH) ] CH (OH) CH20H,
(CHZ)wCOOH with w = 1 to 10,
CZH4-O- (C2H4-0) x-CHZCOOH with x = 0 to 5,
CZH4-O- (CzH4-0) x-CZH4-CpFZPX with x = 0 to 5, p = 4 to 15, and X
a fluorine atom.
If the compound of general formula I contains two radicals
L-RF, these radicals can be different from one another.
For radicals L, there can be mentioned by way of example,
whereby a stands for the bond to the nitrogen atom and f3 stands
for the bond to radical RF:
a-(CH2)k-ø mit k = 1 - 15
a-CH2-CH2-(O-CH2-CH2-)r-~ mit r = 1 - 6
a-CH2-(O-CH2-CH2-)r--ø mit r = 1 - 6
a-C H 2-N H-C O-ø
a-C H 2-C H 2-N H-S 02-ø
a-CH2-NH-CO-CH2-N(CH2COOH)-S02-ø
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a-CH 2-N H-C O-C H2-N (C ZH O)-S02-ø
a-C H 2-N H-C O-C H 2-N ( C 1 O H21 )-S02-ø
a-C H2-N H-C O-C H 2-N (Cg H 13)-SO~-ø
a-CH2-NH-CO-(CH2)10-N(C2H5)-S02-ø
a-C H2-N H-C O-C H2-N (-C H2-CSHS)-S02-ø
a-CH2-NH-CO-CH2-N(-CH2-CH2-OH)S02-~
a-CH2-NHCO-(CH2)10-S-CH2CH2-ø
-._a-CH2NHCOCH2-0-CH2CH2-ø
a-CH2-CH2NHCOCH2-O-CH2CH2-ø
a-CHZ-(CHZ CHZ O)~ (CHZ),NHCO-CHZ-O-CH~CHZ ø mit r = 1-6
a-CH2NHC0(CH2)10-O-CHZCH2-ø
a-CHZCH2NHC0(CH2) 10-O-CHZCH2-ø
a-CH2-CgH4-O-CHZCH2-ø wobei die Phenylengruppe 1,4 oder 1.3 verknupft ist
a-CH2-O-CH2-C(CH2-OCH2CH2-CgFl3)2-CH2-OCH2-CH2-ø
a-CH2-NHCOCH2CHZCON-CH2CHZNHCOCH2N(C2H~)S02CgF17ø
a-CHZ CH~NHCOCHZN(CzHS)-SOZ-ø
a-C H2-O-C H2-CH (O C 10 HZ ~ )-C HZ-0-C H2C H2-ø
a-(CH2NHC0)4-CH20-CM2CH2-ø
a-(CH2NHC0)3-CHZO ,CH2CH2-ø
a-CH2-OCHZC{CH20H)2-CHZ-O-CH2CH2-ø
a
-O- -CHz O-
-ø
COOH
a-CH2NHCOCHZN(CgH~).-S02-ø
a-N HCO-C H2-CH 2-ø
a-NHCO-CH2-O-CH2CH2-ø
a-N H-C O-ø
a-NH-CO-CH2-N(CH2COOH)-S02-ø
a-NH-C Q-C H 2-N ( C 2 H ~ )-S 02-ø
a-N H-C O-C H2-N (C 10H21 )-S02-ø -
a-N H-CO-C H2-N (CgH 13)-S 02-ø
a-N H-CO-(CH 2) 10-N (C2M ~)-S02-(3
a-N H-C O-C H 2-N (-C H 2-C g H 5 )-S 02-ø
a-N H-C O-C H 2-N (-C H 2-C H 2-O H) S 02-ø
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a-NH-CO-CH2-ø
a-CH2-O-C6H4-0-CH2-CH2-ø
a-C H2-CgH4-0-CH 2-C H2-ø
a-N(C2H~)-S02-ø
a-N(CgH~)-S02-ø
a-N(C 1 OH21 )-S02-ø
a-N (C6H 13)-S02-ø
a-N(C2H~OH)-S02-[i
a-N(CH2COOH)-S02-ø
a-N(CH2CgH~)-S02-ø
a-N-[CH(CH20H)2)-S02-p
a-N-[CH(CH20H)CH(OH)(CH20H)]-S02-ø
[Key: ]
mit = with
wobei die Phenylengruppe 1,4 oder 1,3 verkniipft ist = whereby
phenylene group 1,4 or 1,3 is linked
Preferred are:
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a-CH2-O-CH2C,ri2-ø .
a-CH2-CH2-(0-CH2-CH2-)y-~ mit y = 1 - 6
a-CH2-{O-CH2-CH2-)y-ø mit y = 1 - 6
a-CH2-CH2-NH-S02-ø Bsp. 10
a-CH2NHCOCH2-0-CH2CH2-ø
a-CH2-CH2NHCOCH2-O-CHZCH2-ø
a-CHZ {CHZ-CHz-O)y (CH~,NHCO-CHz-0-CHZCH~-ø mit y = 1-6
a-CH2NHC0(CH2)10-O-CHZCH2-ø
a-CHZCH2NHC0(CH2)10-O-CH2CH2-ø
a-C H2-O-C H2-C H (OC 1 OH21 )-C H2-O-C H2 C H2-ø
a-CH2-O-C6H4-O-CH2-CH2-ø
a-CH2-C6H4-O-CH2-CH2-ø
[Key:)
mit = with
Quite especially preferred according to the invention are
radicals L of the compounds that are mentioned in the examples of
the description of this invention.
U is considered to stand for the above-cited radicals for L,
and the radicals that are identified as preferred and especially
preferred, as well as the radicals that are cited above for the
meaning of alkylene and that are optionally preferred and
especially preferred, provided that no a-position nitrogen atom
and no terminal (f3-position) SOZ group or CO group need be
present.
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Preferred radicals B' are hydrogen, straight-chain or
branched C~-Coo alkyl radicals, which are optionally interrupted
by 1-5 oxygen atoms, and/or are optionally substituted with 1-5
hydroxy groups, 1-2 COOH groups, a phenyl group that is
optionally substituted by a COOH group, a benzyl group and/or 1-5
OR4 groups, with R4 in the meaning of a hydrogen atom or a Ci-C3
alkyl radical.
Preferred radicals RF are straight-chain or branched
perfluorinated alkyl radicals of formula CPFZpX, whereby 4 is
equal to or less than p and p is equal to or less than 15, and X
stands for a terminal fluorine atom.
The production of the compounds of general formula I
according to the invention
K-N-L-RF
1
A
with
K in the meaning of a complexing agent or a metal complex of
general formula II
COOK'
R' Ra O
/~ N~U
N N II
COOR'~~N~ O
~COOR' ~~ _
can be carried out according to the following processes:
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Process A.
The carboxylic acid of formula III already contains metal
ion equivalent R':
co~R' cod'
R= R' o R= R' , O
N~U~oH ~L~ f ~ ~~N~u~NiL~s
N ~ -EHN R CO R I0' I
CO=R ~N~ 0 q i ~N J A
'C
(111) (~~ (
Carboxylic acid III that is optionally activated in situ
with R' in the meaning of a metal ion equivalent is reacted with
an amine IV in a coupling reaction to form an amide I.
This process for the production of metal complex carboxylic
acid amides is known from DE 196 52 386.
The mixture of metal complex carboxylic acid III that is
used in the coupling reaction, which optionally contains existing
carboxy groups and/or hydroxy groups in protected form, and at
least one solubilizing substance in an amount of up to 5,
preferably 0.5-2 molar equivalents relative to the metal complex
carboxylic acid, can be produced both in an upstream reaction
stage and (e. g., by concentration by evaporation, freeze-drying
or spray-drying of an aqueous or water-miscible solution of the __
components or by precipitation with an organic solvent from such
a solution) are isolated and then are reacted in DMSO with a
dehydrating reagent and optionally a coupling adjuvant and are
formed in situ optionally by adding solubilizing substances) to
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the DMSO suspension from the metal complex carboxylic acid,
dehdyrating reagent and optionally a coupling adjuvant.
The reaction solution that is produced according to one of
these processes is kept for pretreatment (acid activation) for 1
to 24, preferably 3 to 12 hours at temperatures of 0 to 50°C,
preferably at room temperature.
Then, an amine of general formula Iv
RvN~L.RF
i
A (I~
in which radicals R3, L, RF and A have the above-indicated
meanings, is added without solvent or dissolved, for example, in
dimethyl sulfoxide, alcohols, such as, e.g., methanol, ethanol,
isopropanol or mixtures thereof, formamide, dimethylformamide,
water or mixtures of the indicated solvents, preferably in
dimethyl sulfoxide, in water or in solvents that are mixed with
water. For amide coupling, the reaction solution that is thus
obtained is kept at temperatures of 0 to 70°C, preferably 30 to
60°C, for 1 to 48, preferably 8 to 24 hours.
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.
CA 02362703 2001-08-22
23
The optionally still present protective groups are then
cleaved off.
The reaction product is isolated 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-butyl ether,
isopropanol or mixtures thereof. The additional purification can
be carried out by, for example, chromatography, crystallization
or ultrafiltration.
As solubilizing substances, alkali salts, alkaline-earth
salts, trialkylammonium salts, tetraalkylammonium salts, ureas,
N-hydroxyimides, hydroxyaryltriazoles, and 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
methane sulfonate, sodium methane sulfonate, 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 first five
mentioned are preferred.
CA 02362703 2001-08-22
24
As dehdyrating reagents, all agents that are known to one
skilled in the art are used. By way of example, there can be
mentioned carbodiimide and onium reagents, such as, e.g.,
dicyclohexylcarbodiimide (DCC1), 1-ethyl-3-(3-
dimethylaminopropyl)-carbodiimide-hydroxychloride (EDC),
benzotriazol-1-yloxytris(dimethylamino)-phosphonium
hexafluorophosphate (BOP) and 0-(benzotriazol-1-yl)-1,1,3,3-
tetramethyluronium hexafluorophosphate (HBTU), preferably DCC1.
In the literature, for example, the following suitable
processes are described:
~ Aktivierung von Carbonsauren. U'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).
~ Aktivierung mit Carbodiimiden [Activation with
Carbodiimides]. R. Schwyzer and H. Kappeler, Helv. 46:
1550 (1963) .
~ E. Wiinsch et al., Vol. 100: 173 (1967).
~ Aktivierung mit Carbodiimiden/Hydroxysuccinimid.
[Activation with Carbodiimides/Hydroxysuccinimide]: J.
Am. Chem. Soc. 86: 1839 (1964) as well as J. Org.
Chem. 53: 3583 (1988). Synthesis 453 (1972).
~ Anhydridmethode, 2-Ethoxy-1-ethoxycarbonyl-1,2- .
dihydrochinolin [Anhydride Methods, 2-Ethoxy-1-
ethoxycarbonyl-1,2-dihydroquinoline]: B. Belleau et
al., J. Am. Chem. Soc., 90: 1651 (1986), H. Kunz et
CA 02362703 2001-08-22
25
al., Int. J. Pept. Prot. Res., 26: 493 (1985) and J.
R. Voughn, Am. Soc. 73: 3547 (1951).
~ Imidazolid-Methode [Imidazolide Method]: B. F. Gisin,
R. B. Menifield, D. C. Tosteon, Am. Soc. 91: 2691
(1969) .
1 Saurechlorid-Methoden, Thionylchlorid [Acid Chloride
Methods, Thionyl Chloride]: Helv., 42: 1653 (1959).
1 Oxalylchlorid [Oxalyl Chloride]: J. Org. Chem., 29:
843 (1964).
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, there can be
mentioned 4-nitrophenol, N-hydroxysuccinimide, 1-
hydroxybenzotriazole, 1-hydroxy-7-aza-benzotriazole, 3,5-
dinitrophenol and pentafluorophenol. Preferred are 4-nitro-
phenol and N-hydroxysuccinimide; especially preferred in this
case is the first-mentioned reagent.
The cleavage of the protective groups is done 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° to 50°C, acid saponification with mineral acids or in the
case of, e.g., tert-butyl esters with the aid of trifluoroacetic r
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.
CA 02362703 2001-08-22
26
The production of the starting material, the compounds of
formula III,
C OZR'
R~ R' O~~
N~U~OH
N
~N
CO?R' < .N J
~ ~ COZR'
is known from DE 196 52 386.
The amines of general formula IV
RvN.L~RF
i
A
are commercially available products (Fluorochem, ABCR) or can be
obtained according to the following process from compounds of
general formula V by reaction with an amine of general formula VI
and subsequent reduction of compounds of general formula VII:
o
0 N --= R\ ~ ,~RF ~ R'~N/~~,~RF R~iL~Ra
R~O~L'~R~ t A~ ~R' ~ L A A
A
M Nt) (vit) (iv)
in which
RF, A, L and R3 have the above-mentioned meaning, and L' has
the meaning of group L, in which the a-CHZ group is
absent, and
R4 stands for hydrogen or a methyl group.
CA 02362703 2001-08-22
27
According to the process that is already described above for
the activation of carboxylic acid III that is disclosed in the
literature, acid V is activated before the reaction with amine
VI. For R4 in the meaning of a methyl group, an aminolysis is
carried out.
The compounds of general formula V are commercially
available products (Fluorochem, ABCR) or are produced as
disclosed in DE 196 03 033.
The compounds of formula VI are commercially available
products (Fluorochem, ABCR) or can be produced as described in
Houben-Weyl, Methoden der organischen Chemie, XI/2 Stickstoff-
verbindungen [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.
The compounds of general formula IV 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.
Process B:
As starting material, the carboxylic acid of formula IIIa
with R' in the meaning of hydrogen is used -- it does not contain
any metal ion equivalent R'. The carboxyl groups are protected
according to the processes that are known to one skilled in the
CA 02362703 2001-08-22
28
art, and a compound of formula IIIb is obtained, whereby R5
stands for any protective group.
COzH COZRS
w~ I ,%''' ~ R~ R' . ' ~ .. ~ _ ~~ R~ Ra O
. N . ~ I O + R5 . ~: ~ N. .~
~',,N N~N,U,~OH .-.,.~N N~"'~ 'U OH
0 COZRS ~.~~ N. ,~> O
CO~H ' N.. w
.,
CO=H ~ COZRs
(lllb)
(Illa)
As carboxyl protective groups, e.g., straight-chain or
branched C~-C6 alkyl, aryl and aralkyl groups, for example, the
methyl, ethyl, propyl, butyl, phenyl, benzyl, diphenylmethyl,
triphenylmethyl, bis(p-nitrophenyl)-methyl group as well as
trialkylsilyl groups are suitable. Preferred is the t-butyl
group.
, CO=R° ~ , CO=H
R' O ~., ~ ..~ . R= R° 0
L
N~N~V~'OH .t.HiiW Rf Y ~N . \--~N~V.~ii wRr
COiR~ ~\ ~. ~ , ~ O A _ RS C~=H .\ - .' ~ \ A
CO=Rf CO=H _
(Iilb) (f~ (fa)
CA 02362703 2001-08-22
29
The reaction of protected carboxylic acid IIIb with the
amine of formula IV and the cleavage of the protective groups is
carried out as described under process A, and in a subsequent
step, carboxylic acid Ia that is obtained 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.
If the metal complex that is obtained from process A or B
contains free COOH groups, these groups can also be present as
salts of physiologically compatible inorganic or organic bases.
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-
methylglucamine 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.
For the production of neutral complex compounds, enough of
the desired bases can be added to, for example, the acid complex
salts in aqueous solution or suspension so that the neutral point
is reached. The solution that is obtained can then be evaporated
to the dry state in a vacuum. It is frequently advantageous to
precipitate the neutral salts that are formed by adding water-
miscible solvents, such as, for example, lower alcohols
(methanol, ethanol, isopropanol, etc.), lower ketones (acetone,
etc.), polar ethers (tetrahydrofuran, dioxane, 1,2-
CA 02362703 2001-08-22
30
dimethoxyethane, etc.) and thus to obtain easily isolated and
readily purified crystallizates. It has proven especially
advantageous to add the desired bases as early as during the
complexing of the reaction mixture and thus to save a process
step.
With the compounds according to the invention, higher blood
concentrations are achieved than with extracellular contrast
media. They are dispersed after i.v. administration only into
the intravascular space, and they thus have a decisive advantage
compared to the extracellular contrast media.
Better elimination from the blood via the kidneys ensures a
small burden on the overall organism.
The compounds of this invention are distinguished by better
compatibility, higher lymph node concentration in three
successive lymph node stations (which is especially important for
i.v. lymphography). They are thus especially well suited for use
. in MRT lymphography.
The compounds according to the invention are suitable for
NMR diagnosis and x-ray diagnosis and for radiodiagnosis and
radiotherapy.
The subject of the invention is therefore also the use of
the compounds according to the invention for the production of a
contrast medium for use in NMR diagnosis and x-ray diagnosis, for
radiodiagnosis and radiotherapy. r
Subjects of the invention are also pharmaceutical agents
that contain at least one physiologically compatible compound of
CA 02362703 2001-08-22
31
general formula I, optionally with the additives that are
commonly used in galenicals.
The production of the pharmaceutical agents according to the
invention is carried out in a way that is known in the art by the
complex compounds according to the invention -- optionally with
the addition of the additives that are commonly used in
galenicals -- being suspended or dissolved in aqueous medium and
then the suspension or solution optionally being sterilized.
Suitable additives are, for example, physiologically harmless
buffers (such as, for example, tromethamine), additives of
complexing agents or weak complexes (such as, for example,
diethylenetriaminepentaacetic acid or the Ca-complexes that
correspond to the metal complexes according to the invention) or
-- if necessary -- electrolytes such as, for example, sodium
chloride or -- if necessary -- antioxidants, such as, for
example, ascorbic acid.
If suspensions or solutions of the agents according to the
invention in water or physiological hydrochloric acid solution
are desired for enteral or parenteral administration or other
purposes, they are mixed with one or more adjuvant(s) that are
commonly used in galenicals [for example, methyl cellulose,
lactose, mannitol] and/or surfactants) [for example, lecithins,
Tween~R~, Myrj~R~] and/or flavoring substance (s) for taste
correction [for example, ethereal oils].
Basically, it is also possible to produce the pharmaceutical
agents according to the invention without isolating the
complexes. In any case, special care must be used to carry out
CA 02362703 2001-08-22
32
the chelation so that the complexes according to the invention
are practically free of non-complexed metal ions that have a
toxic effect.
This can be ensured, for example, with the aid of color
indicators, such as xylenol orange, by control titrations during
the production process. The invention therefore also relates to
a process for the production of the complex compounds and their
salts. As a final precaution, there remains purification of the
isolated complex.
In the in-vivo administration of the agents according to the
invention, the latter can be administered together with a
suitable vehicle, such as, for example, serum or physiological
common salt solution, and together with another protein, such as,
for example, human serum albumin (HSA).
The agents according to the invention are usually
administered parenterally, preferably i.v. They can also be
administered intravascularly or interstitially/intracutaneously
depending on whether bodily vessels or tissue are to be studied.
The pharmaceutical agents according to the invention
preferably contain 0.1 ~mol - 1 mol/1 of the complex and are
generally dosed in amounts of 0.0001 - 5 mmol/kg.
The examples below are used for a more detailed explanation
of the subject of the invention, without intending that it be
limited to these examples.
CA 02362703 2001-08-22
33
Example 1
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-(2-
methoxy)-ethyl-amide
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°C to a solution 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°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).
Yield: 30.28 g (91% of theory) of a colorless solid
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-(lH,iH,2H,2H,4H,4H,5H,5H-3-oxa)-
perfluorotridecylamine
30 g (51.79 mmol) of the title compound of Example la is
dissolved in 300 ml of tetrahydrofuran, and 31 ml of l0 M
CA 02362703 2001-08-22
CA 02362703 2001-08-22
34
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0°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 of 300
ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is
stirred for 8 hours at 40°C. It is evaporated to the dry state
in a vacuum, the residue is taken up in 30o 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).
Yield: 26.93 g (92% of theory) of a colorless solid
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
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°C in 100 ml of dimethyl sulfoxide. It is
cooled to 15°C, and 8.98 g (15.88 mmol) of the title compound of
CA 02362703 2001-08-22
Example lb is added. It is stirred for l0 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 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 of a little ethanol/water and chromatographed on silica
gel RP-18 (mobile solvent: gradient that consists of
tetrahydrofuran/acetonitrile/water).
Yield: 15.14 g (81% of theory) of a colorless, amorphous
powder
Water content: 5.7%
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-
dihydroxypropyl)-amide
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°C to a solution of 5.47 g (60 mmol) of 2,3-
dihydroxypropylamine and 6.07 g (60 mmol) of triethylamine,
36
dissolved in 200 ml of dichloromethane. It is stirred for 3
hours at 0°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).
Yield: 29.70 g (87% of theory) of a colorless solid
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-
perfluoro-tridecyl)-amine
30 g (48.8 mmol) of the title compound of Example 2a is
dissolved in 300 ml of tetrahydrofuran, and 50 ml of l0 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0°C, and 300 ml of
methanol is added in drops, and then it is evaporated to the dry
state in a vacuum. The residue is taken up in a mixture of 300
ml of ethanol/50 ml of l0% aqueous hydrochloric acid, and it is
stirred for 8 hours at 60°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
CA 02362703 2001-08-22
CA 02362703 2001-08-22
37
the residue is chromatographed on silica gel (mobile solvent:
dichloromethane/methanol = 15:1).
Yield: 24.07 g (85% of theory) of a colorless solid
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)-amide]-
1,4,7,10-tetraazacyclododecane, gadolinium complex
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°C in 100 ml of dimethyl sulfoxide. It is
cooled to 15°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 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, 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).
CA 02362703 2001-08-22
38
Yield: 16.09 g (85% of theory) of a colorless, amorphous
powder
Water content: 6.3%
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-pentyl)-amide
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°C to a solution 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°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).
Yield: 32.20 g (92% of theory) of a colorless solid
39
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-
perfluorotridecyl)-amine
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°C, and 200 ml of
methanol is added in drops, and 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°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).
Yield: 26.09 g (89% of theory) of a colorless solid
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
CA 02362703 2001-08-22
40
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
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°C in 100 ml of dimethyl sulfoxide. It is
cooled to 15°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,
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).
Yield: 16:10 g (84% of theory) of a colorless, amorphous
powder
Water content: 5.7%
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
CA 02362703 2001-08-22
CA 02362703 2001-08-22
41
Example 4
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-(2-
hydroxyethyl)-amide
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°C to a solution 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°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).
Yield: 28.90 g (89% of theory)
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
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
CA 02362703 2001-08-22
42
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0°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 l0% aqueous hydrochloric
acid, and it is stirred for 10 hours at 50°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).
Yield: 25.12 g (92% of theory) of a colorless solid
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-amide]-1,4,7,10-
tetraazacyclododecane , gadolinium complex
l0 g (15.88 mmol) of the gadolinium complex of l0-[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°C in 100 ml of dimethyl sulfoxide. It is
cooled to 15°C, and 8.75 g (15.88 mmol) of the title compound of
CA 02362703 2001-08-22
43
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,
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).
Yield: 16.81 g (91% of theory) of a colorless, amorphous
powder
Water content: 7.2%
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 H 3.82 N 7.14 F 27.58 Gd 13.41
Example 5
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid amide
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. Then, ammonia _
gas is fed into the solution at 0°C for about 2 hours. It is
stirred for 4 more hours at 0°C, then for 2 hours at room
temperature. 300 ml of 5% aqueous hydrochloric acid is added,
CA 02362703 2001-08-22
44
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).
yield: 27.85 g (93% of theory)
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
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°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/l00 ml of 10% aqueous hydrochloric
acid,,and it is stirred for 8 hours at 60°C. It is evaporated to
the dry state in a vacuum, and the residue from a little
ethanol/diethyl ether is recrystallized.
Yield: 26.75 g (95% of theory) of a colorless, crystalline
solid
45
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 C1 6.38
c) 3,6,9,12,15-Pentaoxahexadecanoic acid-N-
(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amide
14.24 g (50 mmol) of 3,6,9,12,15-pentaoxahexadecanoic acid
chloride is added in drops at 0°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°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).
Yield: 32.03 g (87% of theory) of a colorless oil
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)-perfluorotridecyl)-amine . r
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
CA 02362703 2001-08-22
CA 02362703 2001-08-22
' ~ 46
refluxed for 16 hours. It is cooled to 0°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°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).
Yield: 27.68 g (91% of theory)
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-
(iH,lH,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl]-amide}-
1,4,7,10-tetraazacyclododecane, gadolinium complex
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°C in 100 ml of dimethyl sulfoxide. It is
cooled to 15°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
CA 02362703 2001-08-22
' ~ 47
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,
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).
Yield: 18.05 g (84% of theory) of a colorless, amorphous
powder
Water content: 6.2%
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-(13-amino-4,7,13-trioxa-decyl)-amide]-1,4,7,10-
tetraazacyclododecane, gadolinium complex
g (15.88 mmol) of the gadolinium complex of l0-[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°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and
3.51 g (17 mmol) of N,N'-dicyclohexylcarbodiimide is added and
stirred for 5 hours at 15°C. To separate the urea, the solution
CA 02362703 2001-08-22
48
is filtered. 14.66 g (60 mmol) of 1,13-diamino-4,7,13-
trioxadecane 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 off and chromatographed on silica gel RP-18
(mobile solvent: gradient that consists of tetrahydrofuran/
acetonitrile/water).
Yield: 12.66 g (69% of theory) of a colorless, amorphous
powder
Water content: 3.5%
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-4, 7, 10, 17-tetraoxa-14-aza-17-oxo-CZO-CZ8-hepta-
decafluoro)-heptacosyl]-amide}-1,4,7,10-
tetraazacyclododecane, gadolinium complex
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°C in 150 ml of dimethyl sulfoxide. It is cooled to 15°C, and
6.19 g (30 mmol) of N,N~-dicyclohexylcarbodiimide is added and
stirred for 5 hours at 15°C. To separate the urea, the solution
is filtered. 12.5 g (10.82 mmol) of the title compound of
CA 02362703 2001-08-22
. 49
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/
acetonitrile/water).
Yield: 13.01 g (90% of theory)
Water content: 6.7%
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-(lH,iH,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-amide]-
1,4,7,10-tetraaza-cyclododecane, gadolinium. complex
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°C in 100 ml of dimethyl sulfoxide. tt is cooled to 15°C, and
,_
3.51 g (17 mmol) of N,N'-dicyclohexylcarbodiimide is added and
stirred for 5 hours at 15°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
~CA 02362703 2001-08-22
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).
Yield: 13.86 g (78% of theory) of a colorless, amorphous
powder
Water content: 9.3%
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 8
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-
(2,3,4,5,6-pentahydroxy)-hexylamide
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 dichioromethane, 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°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/150 ml of dioxane. It is stirred for 3
hours at 0°C, then for 8 hours at room temperature. 400 ml of 5%
aqueous hydrochloric acid is added, and it is thoroughly stirred
CA 02362703 2001-08-22
~ ~ 51
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).
Yield: 30.71 g (78% of theory)
Elementary analysis:
Cld: C 31.55 H 2.94 N 2.04 F 47.13
Fnd: C 31.44 H 3.09 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-perfluorotridecyl)-amine
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°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°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
each with 400 ml of chloroform. The organic phases are dried on
magnesium sulfate, evaporated to the dry state in a vacuum, and _ r
the residue is chromatographed on silica gel (mobile solvent:
dichloromethane/methanol = 3:1).
Yield: 19.69 g (67% of theory) of a colorless solid
CA 02362703 2001-08-22
' ~ 52
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-perfluorotridecyl]-amide}-
1,4,7,10-tetraazacyclododecane, gadolinium complex
l0 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°C in 100 ml of dimethyl sulfoxide. It is
cooled to 15°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,
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).
Yield: 16.10 g (79% of theory) of a colorless, amorphous
powder
Water content: 6.3%
CA 02362703 2001-08-22
' ~ 53
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-hydroxy-1,3-dioxepan-6-yl)-amide
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°C to a solution that consists of 9.67 (60 mmol) of 5-
amino-2,2-dimethyl-1,3-dioxepan-6-of and 6.07 g (60 mmol) of
triethylamine, dissolved in 200 ml of dichloromethane. It is
stirred for 3 hours at 0°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).
Yield: 27.62 g (85% of theory)
Elementary analysis: -r
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
CA 02362703 2001-08-22
54
b) N-(1-Hydroxymethyl-2,3-dihydroxypropyl)-N-
(1H,1H,2H,2H,4H,4H,5H,5H-3-oxaperfluorotridecyl)-amine
27 g (40.58 mmol) of the title compound of Example 9a is
dissolved in 300 ml of tetrahydrofuran, and 26 ml of l0 M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 20 hours. It is cooled to 0°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°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).
Yield: 20.09 g (81% of theory) of a colorless solid
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
CA 02362703 2001-08-22
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-perfluorotridecyl]-amide)-
1,4,7,10-tetraazacyclododecane, gadolinium complex
l0 g (15.88 mmol) of the gadolinium complex of l0-[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°C in 100 ml of dimethyl sulfoxide. It is
cooled to 15°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-1,3-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,
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).
Yield: 13.40 g (69% of theory) of a colorless, amorphous
powder
Water content: 9.1
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
CA 02362703 2001-08-22
~ 56
Example 10
a) Perfluorooctylsulfonic acid-N-[(2-benzyloxycarbonylamino)-
ethyl] -amide
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°C. It is cooled to room temperature and added directly to
a silica gel column for chromatographic purification (mobile
solvent: dichloromethane/acetone = 20:1).
Yield: 42.22 g (36% of theory) of a colorless solid
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)-ethyll-amide
30 g (44.36 mmol) of the title compound of Example l0a 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.
Yield: 24.05 g (quantitative) of a colorless solid
Elementary analysis: - r.
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
CA 02362703 2001-08-22
~ 57
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
l0 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°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and
3.51 g (17 mmol) of N,N'-dicyclohexylcarbodiimide is added and
stirred for 5 hours at 15°C. To separate the urea, the solution
is filtered. 8.61 g (15.88 mmol) of the title compound of
Example lOb and 2.02 g (2~O 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).
Yield: 15.76 g (86% of theory) of a colorless, amorphous
powder
Water content: 6.5%
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
CA 02362703 2001-08-22
' ~ 58
Example 11
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-(2-
benzyloxy-carboxylamino-ethyl]-amide
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°C to a solution 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°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).
Yield: 33.30 g (83% of theory) of a colorless solid
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
CA 02362703 2001-08-22
- 59
b) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-[(2-
amino) -ethyl] -amide
30 g (42.96 mmol) of the title compound of Example lla is
dissolved in 500 ml of methanol, and 5 g of palladium catalyst
(l0% Pd/C) is added, and it is hydrogenated overnight at room
temperature. It is filtered off into the catalyst, and the
filtrate is evaporated to the dry state in a vacuum.
Yield: 24.24 g (quantitative) of a colorless solid
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- (C9-C~6-heptadecafluoro) -
hexadecyl]-amide}-1,4,7,10-tetraazacyclododecane-gadolinium
complex
l0 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°C in 100 ml of dimethyl sulfoxide. It is cooled to 15°C, and
3.51 g (17 mmol) of N,N'-dicyclohexylcarbodiimide is added, and _.
it is stirred for 5 hours at 15°C. To separate the urea, the .
solution is filtered. 8.96 g (15.88 mmol) of the title compound
of Example llb and 2.02 g (20 mmol) of triethylamine are added to
the filtrate, and it is stirred for 12 hours at room temperature.
CA 02362703 2001-08-22
~ 60
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).
Yield: 15.31 g (82% of theory) of a colorless, amorphous
powder
Water content: 6.3%
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
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°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°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
CA 02362703 2001-08-22
~ ~ 61
sulfate and evaporated to the dry state in a vacuum. The residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/acetone = 20:1).
Yield: 24.86 g (93% of theory) of a colorless solid
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)-amine
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 l2 hours. It is cooled to 0°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 l0% aqueous hydrochloric
acid, and it is stirred for 8 hours at 40°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).
Yield: 20.95 g (90% of theory ) of a colorless solid
CA 02362703 2001-08-22
' ~ 62
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-
3-oxa)-perfluoroundecyl]-amide}-1,4,7,10-
tetraazacyclododecane-gadolinium complex
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°C in 100 ml of dimethyl sulfoxide. It is
cooled to 15°C, and 8.98 g (15.88 mmol) of the title compound of
Example 12b is added. It is stirred for l0 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, 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).
Yield: 14.01 g (83% of theory) of a colorless, amorphous
powder
CA 02362703 2001-08-22
' ' 63
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-tridecyl)-amide
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°C to a solution that consists of 12.44 g (60 mmol)
of 3,6,9,12-tetraoxa-tridecylamine and 6.07 g (60 mmol) of
triethylamine, dissolved in 200 ml~of dichloromethane. It is
stirred for 3 hours at 0°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).
Yield: 31.61 g (90% of theory) of a colorless solid
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
CA 02362703 2001-08-22
64
b) N-(3,6,9,12-Tetraoxatridecyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-
oxa-perfluoroundecyl)-amine
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°C, and 200 ml of
methanol is added in drops, and 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°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).
Yield: 28.17 g (93% of theory) of a colorless solid
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
CA 02362703 2001-08-22
~ 65
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)-perfluoroundecyl]-amide}-
1,4,7,10-tetraazacyclododecane-gadolinium complex
l0 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°C in 100 ml of dimethyl sulfoxide. It is
cooled to 15°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, 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).
Yield: 16.13 g (84% of theoryl
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
CA 02362703 2001-08-22
66
Example 14
a) 2-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecyl)-amino-
acetic acid-t-butylester
6.523 g (40 mmol) of bromoacetic acid-t-butylester is added
in drops at 50°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).
Yield: 28.11 g (57°s of theory) of a colorless solid
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)-perfluorotridecyl]-amide}-
1,4,7,10-tetraazacyclododecane-gadolinium complex
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°C in 100 ml of dimethyl sulfoxide. It is
cooled to 15°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
CA 02362703 2001-08-22
' ' 67
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, 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).
Yield: 16.64 g (85% of theory)
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
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
CA 02362703 2001-08-22
68
and set at pH 7.2 with 5% aqueous sodium hydroxide solution. The
solution is filtered, and the filtrate is freeze-dried.
Yield: 10.48 g (91% of theory)
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 Na 2.00
Example 15
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-(2-
hydroxyethyl)-amide
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-butyl ester, dissolved in
20 ml of tetrahydrofuran, is added in drops, and it is stirred
for 5 hours at 50°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-propanol = 20:1).
Yield: 23.46 g (61% of theory)
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
CA 02362703 2001-08-22
~ 69
b) N-(1H,1H,2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecyl)-N-[4-t-
butyloxycarbonyl-3-oxa)-butyl]-amine
35.o 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°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 ethanoh/50 ml of 10% aqueous hydrochloric
acid, and it is stirred for 8 hours at 40°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).
Yield: 31.88 g (93% of theory)
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
CA 02362703 2001-08-22
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)-perfluorotridecyl]-amide~-
1,4,7,10-tetraazacyclododecane, gadolinium complex
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°C in 100 ml of dimethyl sulfoxide. It is
cooled to 15°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 m1 of diethyl ether, and it is stirred
for 2 hours at room temperature. The deposited precipitate is
filtered off, dissolved in a mixture that consists of a little
ethanol/water and chromatographed in silica gel RP-18 (mobile
solvent: gradient that consists of tetrahydrofuran/
acetonitrile/water).
Yield: 16.63 g (82% of theory)
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
CA 02362703 2001-08-22
' ~ 71
d) 1,4,7-Tris-(carboxylatomethyl)-10-{(3-aza-4-oxo-hexan-5-
ylic)-acid-[N-(4-carboxy-3oxa)-butyl)-N-
(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl]-amide}-
1,4,7,10-tetraazacyclododecane, gadolinium complex
12 g (9.4o mmol) of the title compound of Example 15c is
dissolved in 50 ml of trifluoroacetic acid, and it is stirred for
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.
Yield: 11.41 g (92% of theory)
Water content: 5.8%
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 __
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
CA 02362703 2001-08-22
72
residue is dissolved in 100 ml of dichloromethane, and added in
drops at 0°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°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).
Yield: 52.87 g (91% of theory)
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
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°C, and 20o 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°C. It is evaporated to
the dry state in a vacuum, the residue is taken up in 400 ml of
CA 02362703 2001-08-22
73
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).
Yield: 47.18 g (92% of theory) of a colorless solid
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-tetraazacyclododecane,
gadolinium complex
g (15.88 mmol) of the gadolinium complex of l0-[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°C in 100 ml of dimethyl sulfoxide. It is
cooled to 15°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 - 1.
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, dissolved in a mixture that consists of a little
CA 02362703 2001-08-22
~ 74
ethanol/water and chromatographed on silica gel RP-18 (mobile
solvent: gradient that consists of tetrahydrofuran/
acetonitrile/water).
Yield: 20.95 g (82% of theory)
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-pentyl)-amide
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-butylester, dissolved in
20 ml of tetrahydrofuran, is added in drops, and it is stirred
for 5 hours at 50°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-propanol = 20:1).
Yield: 19.31 g (59% of theory)
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
CA 02362703 2001-08-22
' ' 75
b) N-(3,6-Dioxa-heptyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-
perfluorotridecyl)-amine
32 g (51.34 mmol) of the title compound of Example 17a is
dissolved in 300 ml of tetrahydrofuran, and 31 ml of to M
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0°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 of 300
ml of ethanol/50 ml of 10% aqueous hydrochloric acid, and it is
stirred for 8 hours at 40°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).
Yield: 28.47 g (91% of theory)
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
CA 02362703 2001-08-22
~ ~ 76
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
g (15.88 mmol) of the gadolinium complex of l0-[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°C in 100 ml of dimethyl sulfoxide. It is
cooled to 15°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, 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).
Yield: 16.09 g (83% of theory)
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 _
CA 02362703 2001-08-22
' ~ 77
Example 18
a) 2H,2H,4H,4H,5H,5H-3-Oxa-perfluorotridecanoic acid-N-(hexyl)-
amide
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°C to a solution that consists of 6.07 g (60 mmol) of
n-hexylamine and 6.07 g (60 mmol) of triethylamine, dissolved in
200 ml of dichloromethane. It is stirred for 3 hours at 0°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).
Yield: 30.95 g (89% of theory)
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
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
CA 02362703 2001-08-22
~ 78
boranedimethyl sulfide (in tetrahydrofuran) is added. It is
refluxed for 16 hours. It is cooled to 0°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 l0% aqueous hydrochloric
acid, and it is stirred for 8 hours at 40°C. It is evaporated to
the dry state in a vacuum, and 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).
Yield: 28.16 g (93% of theory)
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-(hexyl)-N-(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-
perfluorotridecyl]-amide}-1,4,7,10-tetraazacyclododecane,
gadolinium complex
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°C in 100 ml of dimethyl sulfoxide. It is
cooled to 15°C, and 10.98 g (15.88 mmol) of the title compound of
CA 02362703 2001-08-22
' ~ 79
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, 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).
Yield: 16.29 g (84% of theory)
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.butyloxycarbonyl)-decyl]-amide
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 i.n 100 ml of dichloromethane and added in _ _
drops at 0°C to a solution that consists of 15.45 g (60 mmol) of
il-amino-undecanoic acid-t-butylester and 6.07 g (60 mmol) of
triethylamine, dissolved in 200 ml of dichloromethane. It is
CA 02362703 2001-08-22
stirred for 3 hours at 0°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).
Yield: 42.04 g (92% of theory)
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-perfluorotridecyl)-amine
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°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 m1 of ethanol/70 ml of 10% aqueous hydrochloric
acid, and it is stirred for 8 hours at 40°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
CA 02362703 2001-08-22
81
vacuum, and the residue is chromatographed on silica gel (mobile
solvent: dichloromethane/2-propanol = 20:1).
Yield: 34.84 g (91% of theory)
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-(10-t.butyloxycarbonyl)-decyl-N-
(1H,1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl]-amide}-
1,4,7,10-tetraazacyclododecane, gadolinium complex
g (15.88 mmol) of the gadolinium complex of l0-[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°C in 100 ml of dimethyl sulfoxide. It is
cooled to 15°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, 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).
CA 02362703 2001-08-22
' 82
Yield: 17.92 g (83% of theory)
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]-amide}-1,4,7,10-
tetraazacyclododecane, gadolinium complex, sodium salt
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
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.
Yield: 12.48 g (92% of theory)
Water content: 6.2%
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
CA 02362703 2001-08-22
83
Example 20
a) 15-Henzyl-3,6,9,12,15-pentaoxa-hexadecanoic acid-N-
(1H,1H,,2H,2H,4H,4H,5H,5H-3-oxa)-perfluorotridecyl)-amide
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-pentaoxahexadecanoic 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°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°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).
Yield: 44.91 g (94% of theory) of a colorless solid
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 _.
CA 02362703 2001-08-22
' ~ 84
b) N-15-Benzyl-3,6,9,12,15-pentaoxa-hexadecyl)-N-
(1H,1H,2H,2H,4H,4H,5H,5H-3oxa)-perfluorotridecyl)-amine
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°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°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).
Yield: 39.32 g (93% of theory)
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
CA 02362703 2001-08-22
~ 85
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
g (15.88 mmol) of the gadolinium complex of 10-[1-
(carboxymethylcarboamoyl)-ethyl]-1,4,7,10-tetraaazacyclododecane-
1,4,7-triacetic acid and 1.35 g (31.76 mmol) of lithium chloride
are dissolved at 60°C in 100 ml of dimethyl sulfoxide. It is
cooled to 15°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, 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).
Yield: 18.84 g (83% of theory)
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
CA 02362703 2001-08-22
. 86
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
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 into the catalyst, and the
filtrate is evaporated to the dry state in a vacuum.
Yield: 10.13 g (95% of theory)
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
In Vivo Comparison of the Compounds of Examples 4c and 5e with
Dy-DTPA
Three 350 g male (Schering-SPF) rats are used as test
animals. 0.33-0.37 ml (in each case 100 mmol/L) of the following
contrast medium solution is administered intravenously to each
animal: mixture of 1 part each of a perfluoroalkyl-containing
compound and the dysprosium-complex of (Dy-DTPA). The _.
administered dose is in each case 100 ~,mol of Gd or Dy/kg of body . _
weight. Via a catheter in the common carotid artery, blood
samples are taken at the following times: 1, 3, 5, 10, 15, 20,
30, 45, 60, 90, 120 minutes p.i. In the blood samples that are
CA 02362703 2001-08-22
obtained, in each case the concentrations of gadolinium (Gd) and
dysprosium (Dy) are measured in parallel using atomic emission
spectrometry (ICP-AES). The proportion of the injected compounds
(Gd-containing perfluoroalkyl-containing compound and Dy-
containing comparison substance) that remains in the blood space
can be compared in the same animal by the different labeling.
The a- and E-half life, the distribution volume and the total
clearance can be calculated from the blood concentrations using
special software (Topfit program). These data thus yield
information on the compounds that remain in the intravascular
space, the distribution conditions in the organism and the
elimination.
Results: At all examination times, significantly higher blood
concentrations of the perfluoroalkyl-containing compounds
(substances from Example 4c or 5e) compared with the
extracellular contrast media (Dy-DTPA) are obtained. In this
respect, see Figures 1 and 2:
Figure 1 shows the blood level (in % of the dose) of Gd
(perfluoroalkyl-containing compound of Example 5e) and Dy (Dy-
DTPA) after intravenous administration of 100 ~mol/kg of body
weight in rats in each case (n = 3).
In Table 1, pharmacokinetic parameters (plasma) of the _.
compound of Example 5e) and Dy-DTPA after intravenous _i
administration of 100 ~mol/kg of body weight in rats (n = 3) are
CA 02362703 2001-08-22
' ~ 88
indicated in each case:
5e Dy-DTPA
a-t~ min 3.77 0.75 2.19 0.59
i3-t~ min 102.29 24.48 62.59 37.47
Vd ss L/kg 0.16 0.03 0.29 0.09
Total Clearance ml/min*kg 1.22 0.05 4.24 1.52
Tab. 1
Figure 2 shows the blood level (in % of the dose) of Gd
(perfluoroalkyl-containing compound of Example 4c) and Dy (Dy-
DTPA) after intravenous administration of 100 ~,mol/kg of body
weight in rats in each case (n = 3).
4C Dy-DTPA
a-t'~ min 1.01 0.32 0.89 0.32
i3-t~ min 79.68 12.26 21.37 2.18
Vd ss L/kg 0.12 0.00 0.15 0.03
Total Clearance ml/min*kg 1.14 0.19 5.77 1.08
Tab. 2
In Table 2, the pharmacokinetic parameters (plasma) of
compound 4c) and Dy-DTPA after intravenous administration of 100
~.mol/kg of body weight in rats in each case (n = 3) are
indicated . -_
The considerably higher blood concentrations of the -
perfluoroalkyl-containing compounds (substances from Examples 4c
or 5e) indicate a significantly smaller distribution volume
CA 02362703 2001-08-22
89
compared to Dy-DTPA (see also Vd ss in Tables 1 and 2), i.e.,
these perfluoroalkyl-containing compounds are not dispersed like
Dy-DTPA in the intravascular space (vessels) and in the
extracellular space, but rather for the most part only in the
intravascular space (especially at early times). Later on, the
blood level of the perfluoroalkyl=containing compounds drops, but
the elimination times or i3-half lives are considerably shorter
than in other blood-pool agents. The total blood clearance of
the perfluoroalkyl-containing compounds is only slightly smaller
compared to Dy-DTPA, which indicates a comparatively good renal
elimination.
The perfluoroalkyl-containing compounds that are described
in Example 21 show efficient elimination from the blood (via the
kidneys), but an extracellular contrast medium such as Dy-DTPA
shows a considerably smaller distribution volume.
Example 22
Lymph Node Concentration in Guinea Pins
Different perfluoroalkyl-containing gadolinium complexes
were studied 30 and 90 minutes after subcutaneous administration
(l0 ~Cmol of total gadolinium/kg of body weight, hind paw s.c.) to
stimulated guinea pigs (complete Freund adjuvant; in each case
0.1 ml of i.m. in the right and left upper and lower arm; 2 weeks __
before the administration of test substances) with respect to _
their lymph node concentration in three successive lymph node
stations (popliteal, inguinal, iliac). In this connection, the
CA 02362703 2001-08-22
results listed below (determination of the gadolinium
concentration using ICP-AES) were obtained:
Substance Time of Gadolinium
Content in
Three
Lymph Node Successive
Lymph Node
Stations
Removal [ ~tmo 1 ]
[~ of dose/g
of tissue]
Example Popliteal Inguinal Iliac
7 30 minutes 452 ~.mol/1 181 ~Cmol/1 228 umol/1
13.1% 5.2% 6.6%
6b 30 minutes 442 mol/1 339 ~,mol/1 322 ~,mol/1
12.6% 9.6% 9.1%
5e 30 minutes 581 ~mol/1 166 ~.mol/1 111 ~.mol/1
16.9% 4.8% 3.2%
3c 90 minutes 346 ~,mol/1 184 ~mol/1 171 ~,mol/1
10.1% 5.4% 5.0%
Example 23
Lymph Node Visualization (MRT) after Interstitial Administration
of Contrast Medium
Figures 3 and 4 show MR. images of popli:teal, inguinal and
iliac lymph nodes both before (Fig. 3: Precontrast) and 15 or 30
minutes after (Fig. 4) subcutaneous administration (guinea pigs,
hind paw, interdigital space) of the substance of Example 5e
(Fig. 3: Fig. 3 and Fig. 4) or of Example 3c (Fig. 4: Fig. 5
and Fig. 6) (in each case l0 ~.mol of Gd/kg of body weight). The
T~-weighted, gradient echo images (TR 10 ms, flash outphase, TE 5
ms, a 40°) illustrate the strong signal increase in the various
lymph nodes of the injected body side (arrow) in comparison to
the non-injected body side or to the precontrast image.
CA 02362703 2001-08-22
. 91
Example 24
Retention of the Opacif~rina Metal at the Infection Site
After s.c. administration of 10 ~Cmol of total gadolinium/kg
of body weight in the guinea pig paw, the retention of metal at
the injection site was studied at different times.
Substance Gadolinium Content
Example at the Infection
Site
paw
[% of dose)
30 min. p.i. 90 min. p.i. 7 days p.i.
7 54.2% 36.8% 1.3%
6b 66.4% 26.1% 0.6%
5e 8.5% 9.4% -
3c 6.5% 4.9% 1.7%
Example 25
Oraan Distribution of the Contrast Medium After s.c.
Administration
After subcutaneous administration of l0 ~,mol of total
gadolinium/kg of body weight in the hind paw of stimulated guinea
pigs (complete Freund adjuvant; 0.1 ml i.m in the right and left
upper and lower leg in each case; 2 weeks before the test
substances are administered), the retention of the metal in the
liver as well as in the kidneys and spleen was examined 7 days
after the administration.
CA 02362703 2001-08-22
92
Substance Gadolinium Content
Example in Various Organs
[% of dose]
Liver Kidneys Spleen
7 6.2% 0.2% 0.0%
6b 1.5% 0.1% 0.0%
3c 1.3% 0.1% 0.0%
Example 26
Relaxivity of Compounds According to the Invention
Substance R1
[L/mmol*sec]
at 0.47 T and 37C
Example Water Plasma
7 18.1 21.0
6b 11.6 13.3
5e 12.4 30.3
30 14.0 21.0
lc 13.8 25.7
2c 11.8 19.6
4C 14.4 21.9
lOc 21.6 27.8
CA 02362703 2001-08-22
93
Example 27
Compatibility of Compounds According to the Invention
Substance LD 50
Example [mmol of Gd/kg of body weight]
2c 3
3c
4c 0.3
5e 15
