Note: Descriptions are shown in the official language in which they were submitted.
`~ ~07~171
~O91/10~5 PCT/EP91/00126
1 --
Chelants
The present invention relates to certain novel
chelating agents, in particular polyamines, and to their
uses, especially their medical uses.
The medical use of chelating agents is well
established, for example as stabilizers for
pharmaceutical preparations, as antidotes for poisonous
heavy metal species and as diagnostic agents for the
administration of metal species (e.g. ions or atoms) for
diagnostic techniques such as X-ray, magnetic resonance
imaging (MRI) or ultrasound imaging or scintigraphy.
Polyamine chela~ing agents, for example aminopoly-
(carboxylic acid or carboxylic acid derivative)
(hereinafter APCA) chelating agents and their metal
chelates, are well known and are described for example
in US-A-2407645(Bersworth), US-A-2387735 (Bersworth),
EP-A-71564 (Schering), EP-A-130934 (Schering),
EP-A-165728 (Nycomed AS), DE-A-2918842 (Rexolin
Chemicals AB), DE-A-3401052 (Schering), EP-A-258616
(Sal~tar), DE-A-3633245 (Schering), EP-A-263059
(Schering), EP-A-277088 (Schering) and DE-A-3633243
(IDF)-
Thus, for example, EP-A-71564 describes
paramagnetic metal chelates, for which the chelating
agents are nitrilotriacetic acid (NTA),
N,N,N',N'-ethylenediamine-tetraacetic acid (EDTA),
N-hydroxyethyl-N,N',N~-ethylenediaminetriacetic acid
(HEDTA), N,N,N',N",~"- diethylenetriaminepentaacetic
acid (DTPA) and N-hydroxyethyl-iminodiacetic acid, as
being suitable as contrast agents for MRI, contrast
being achieved by the effect of the magnetic field of
the paramagnetic species (e.g. Gd(III)) with the
chelating agents serving to reduce the toxicity and to
assist administration of tha~ paramagnetic species.
Amongst the particular metal chelates disclosed by
.-, . . , - ,., : .
- ,., :., ~. ,
- , . ' '' ' . . `
:, . ; .,
2 0 7 ~ -I r~
W091/10~5 PCT/EP91/00126
2 --
EP-A-71564 was Gd DTPA, the use of which as an MRI
contrast agent has recently received much attention.
The Gd(III) chelate of 1,4,7,10-
tetraazacyclododecanetetraacetic acid (DOTA) referred to
in DE-A-3401052 (Scherlng) and in US-A-4639365
(University or Texas) and of l-hydroxypropyl-4,7,10-
triscarboxymethyl-1,4,7,10-tetraazacyclododecane (HP-
DO3A) have also recently received attention in this
regard.
To improve stability, water solubility and
selectivity, relative to the APCA chelating agents
described in E?-A-71564, Schering, in EP-A-130934, have
p~oposed the partial substitution for the N-attached
carboxvalkyl groups of alkyl, alkoxyalkyl,
alkoxycarbonylalkyl or alkylaminocarbonylalkyl groups,
where any amide nitrogens may themselves carry
polyhydroxyalkyl groups. More recently, to improve
compatibility, stability, solubility and selectivity, in
EP-A-250358 Schering have proposed a narrow range of
compounds having a DTPA-like structure including a
bridging alkylene chain.
In the field of hepatobiliary MRI cont~rast agents,
where lipophilicity rather than hydrophilicity is
desired, Nycomed in EP-A-165728, have proposed the use
of paramagnetic chelates of certain anilide
group-containing iminodiacetic acids and Lauffer in
WO-A-86/06605 has suggested the use of paramagnetic
chelates of triaza and tetraaza macrocycles which have
fused aryl group on one of the alkylene chains linking
the ring nitrogens but are otherwise unsubstituted.
Nycomed, in EP-A-299795, suggest that the toxicity
of certain APCA chelating agents and their chelates may
be reduced by introducing at least one hydrophilic
moiety as a substituent on one or more of the alkylene
bridges between the amine nitrogens.
,.
..
"
.
207~7~
~O91/10~5 PCT/EP91/00126
3 --
stability selectivity and there is thus a general and
continuing need for such polyamine chelatiny agents
which form metal chelates of reduced toxicity, impro~ed
stability or improved water solubility or having
improved biodistribution characteristics.
We now propose a novel class of polyamine chelating
agents which incorporate within their structure at least
one 5- or 6-membered heterocyclic ring.
Thus viewed from one aspect the present invention
provides a compound of formula I
Rl(CR2R )n[X(CR2R )n]~R~ (I)
(wherein each X independently represents an oxygen or
sulphur atom or a group of formula NA, or
(CR2R )nX(CR R )n represents a group of formula
-( CR2R3 ) n-l \
E~\J
R 4
-(CR2R3)n-
E represents COH, NR2, O or S;
each A independently represents a hydrogen atom or a
group 'CR2R3)pY, (CR R3)nN[(CR2R3)pY]2 or
.-
''
2074171
WO91/10~5 PCT/EPg1/00126
- 4 -
'
- ( C 2 R 3 )
R ~
where two (CR2R3)nY groups on different nitrogens,
preferably in adjacent groups, may together represent a
group -(CR2R )n~;
each Y independently rePresents a group COZ, SO2Z, POZ2,
CON(OH)R , CH2SR , CS2R or CSZ; 2
each Z independently represents a group OR or NR2R2;
each G is a 3 or 4 membered chain of carbon atoms and
optionally a nitrogen, oxygen or sulphur atom; each J is
a 2 or 3 membered chain of carbon atoms and optionally a
nitrogen, oxygen or sulphur atom; each n is an integer
of 2 to 4, preferably 2 or 3 or in a group (CR2R3)n
attached to a moiety Rl which represents a hydrogen atom
or a group R4 n may also be zero or 1;
m is an integer of 3 to 8, preferably 3 to 6;
p is an integer of 1 to 3, preferably 1;
each Rl represents a hydrogen atom or a group R4 or
together both groups Rl represent a carbon-carbon bond;
each R2 independently represents a hydrogen atom or a
C18 alkyl group optionally mono- or poly-substituted by
hydroxyl or C18 alkoxy groups or NR2R2 may together
represent a nitrogen-attached S to 7 membered saturated
heterocyclic ring optionally containing as a further
ring heteroatom a nitrogen, oxygen or sulphur atom and
optionally substituted by a group R4;
each R3 independently represents a hydrogen atom or a
Cl8 alkyl or C13 alkoxy group optionally mono or poly
substituted by hydroxy or C1 8 alkoxy groups; and
each R4 independently represents a hydrogen atom, a
.. . .
: ~ , . -: . '
2 G 7 ~ 171
r
VO91/10~5 PCT/EP9t/00126
halogen atom, a hydroxyl group, an optionally monv- or
poly-hydroxylated C18 alkyl, Cl~ alkoxy, (C18 alkoxy)-C
alkyl or poly(Cl8 alkoxy)-C18 alkyl group, a sulphonate
group or a group (CR2R3)pY or two groups R~ on the same
ring represent a (CR R3)n l [X(CR R )n]m l (CR R )n l
group in which case the said ring may be saturated; with
the provisos that at least 2 Y groups, preferably at
least 3, are present, that where both groups Rl ~ogether
form a bond, m is 4 or 5, all n are 2, one X is
2,6-pyridindiyl and the remainder are NCH2COOR2, then a~
least one R2, R3 or R4 is other than hydrogen, and that
either at least one X group comprises an aromatic
heterocyclic group or both Rl groups together represen'
a bond and two (CR2R3)pY groups together represent a
i -(CR2R3)n~ group or both Rl groups represent a bond, m
is 6 or greater and two X groups separated by at least
two other X groups are oxygen or sulphur atoms, and
preferably that where m is 3 or 4, all n are 2, one X is
4-substituted-2,6-pyridindiyl, 2,5-furandiyl, 2,5-
pyrroldiyl, 2,5-thiophendiyl or l-hydroxy-2,6-phenylene
and the remainder are NCH2 COOR2 or NH then at least one
R2, R3 or R4 is other than hydrogen) or a chelate comple~:
or salt thereof.
In the compounds of the invention, alkyl or
alkylene ~ieties in groups Rl to R4, unless otherwise
stated, mG~ be straight chained or branched and
preferably contain from l to 6 and most preferably l to
4, carbon atoms. Where substituents may themselves
optionally be substituted by hydroxyl or alkoxy groups,
this may be monosubstitution or polysubstitution and, in
the case of polysubstitution, alkoxy or hvdroxyl
substituents may be carried by alkoxy substituen-s.
Where, as is particularly preferred, the compounds
of the invention incorporate one or more hydrophilic
to R4 groups, these are preferably straight-chained or
branched moieties having a carbon atom content of from l
to 8, especially preferably l to 6, carbon atoms. The
;; ..
' ~
:. : . .
2~7~171
WO91/10~5 PCT/EP91/00126
hydrophilic groups may be alkoxy, polyalkoxy,
hydroxyalkoxy, hydroxypolyalkoxy, polyhydroxyalkoxy,
polyhydroxylated polyalkoxy, hydroxyalkyl,
polyhydroxyalkyl, alkoxyalkyl, polyalkoxyalkyl,
hydro~ylated al~oxyal~yl, polyhydroxylated alkoxyalkyl,
hydroxylated polyalkoxyalkyl, or polyhydroxylated
polyalkoxyalXyl groups. More preferably however they
will be monohydroxyalkyl or polyhydroxyalkyl groups.
The hydrophilic groups serve to increase the
hydrophilici~y and reduce the lipophilicity of the metal
chelates formed with the chelating agents of the
invention and it is preferred that the co~pounds of
formula I should contain at least l, conveniently from l
to 4, and preferably l, 2 or 3 such hydrophilic groups.
As hydrophilic groups, the compounds of the invention
may thus include for example hydroxymethyl,
;/ 2-hydroxyethyl, l,2-dihydroxyethyl, 3-hydroxypropyl,
2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl,
l-(hydroxymethyl)-2-hydroxy-ethyl, methoxymethyl,
ethoxymethyl, 2-hydroxyethoxymethyl,
methoxyethoxymethyl, (2-hydroxy-ethoxy)ethyl, etc,
groups.
Particularly preferred compounds of formula I
according to the invention include those of monocyclic
structure containing at least 6 ring heteroatoms, those
of fused bicyclic structure containing at least two ring
heteroatoms in the smaller ring, and those of fused
tricyclic or higher polycyclic structure.
In the compounds of the invention, the aromatic
groups comprised by X groups preferably are pyridine,
pyra~ine, pyrrole, furan, phenol, pyrimidine or
thiophene rings, especially pyridine rings. Where in a
group X, E is COH, e.g. where X comprises a phenol
group, it is especially preferred that an electron
withdrawing R4 substituent (e.g. a lower alkyl or
halogen such as chlorine or methyl) should be present on
the ring, preferably at the para position to the
.. . .
2~7~171
,V091/10~ PCT/EP91/00126
hydroxyl group. "N"-membered aromatic rings attach~d to
the linear or cyclic skeleton of the molecule at the 2
and/or "N-l" positions are especially preferred.
Moreover in the compounds according to the lnven~ion,
adjacent X groups preferably do not both comprise such
aromatic groups. Where the chelants of the invention
contain fused saturated heterocyclic rings these
preferably are piperazine, or l,4-diazaci~cloheplan_
rings, especially piperazin-l,4-diyl groups.
Particularly preferably one, two or three X groups
; should comprise such aromatic groups, the remaining
groups, or all but one remaining X group being
N(CR2R3)pY groups. It is especially preferred tha_
groups X comprising no ionizing group Y should be
non-adjacent particularly that they should adopt opposed
positions in macrocyclic chelants, e.g. as the 1st and
5th X groups in an 8 X ring. Particularly preferred
compounds of formula I include those of formulae Ib and
Ic
IR2R3c~ (IbJ
2R3)n
' J m-2
~CR2R3)n_1NlCR2R3)n~X(CR2R3)n)m 4NICR2R3)
R~ ) R~
,
:
SUBSTITUTE SI~EET
..
: , ~ . . .
2~74~7~
WO91/10~5 PCT/EP91/00126
and in particular those of formulae Id to Il.
R~
R~
A A~' (Id)
N
R~ R~
(è
R ' ~ N A ' A ' N R 2
R
~J4
J~ R'
1~ 1 A '
R2--NA '
R l~h \~ j~ 2
R4
R ~ R 2 R
--N N ~ ' N A ~ N
.
.' ~' ', , ; ''.'' ` ' '
";: ' '~
2~7~
WO 91/1064; PCI/EP91/00126
_ g _
ICR2R3 )
(CR2 R3 Jn ~ ( I h )
( CR2 R3)n '~;~
m-2
~CR2R3 )n
N` N
. / (CR2R3)n \
~ ~ ( li) ,
~v ~[72~R3~m v 3
~R~
( N~ A'~A~t ( Ij)
(R2~N~L R2)
(R~N~R2)z
NA' A'N
(R2~
SUBSTITUTE SltEET
' -
207~
WO91/10~ PCTtEP91/00126
-- 10 --
R ~A~'
( R 2~i N ~,~R 2)
`X~ A~
NA' ,, A'N
( R2~N~:~,
R2 R2
(11)
R2~X ~R2
R2 R2
(where A' is CHR2Y or hydrogen, z is 1 or 2, t is 1 or
2, v is 0,1,2,3 or 4 and x2 is o or S).
Where a group NR22 in a compound according to the
invention is a nitrogen attached heterocyclic ring, it
~ will conveniently be of formula
'A R4
~ CHR 4 )q
- N W
R4 R~
~V~S~ S 8
"~ "
... . ..
2~7~17~
~091/10~5 PCT/EP91/00126
r
where q is o,l or 2, and W is CHR4, NR4, O or S, where q
is zero W preferably being CHR4. Particularly
preferably such groups are of formula
~1
--U C --!l O
/ y
--OH
~ or --~ rOY
In the compounds of formula I, the groups Y
preferably r~present carboxylic acid or amide groups,
for example groups of formula COOH, CONH2,
CONCHR4CHR4W(CHR4)qCHR4, CONHR2 or CONR22 (where R2 is
an alkyl or mono or poly hydroxyalkyl group, for example
a Cl 6 alkyl group optionally carrying l, 2, 3 or 4
hydroxyl groups). Particularly preferably, in the case
where Rl are not bonds terminal X groups will comprise
an aromatic heterocyclic group.
Where Y is a carboxyl group, the compounds of
formula I can conveniently form salts or chelates in
which Y represents -COOM (wherein M is a monovalent
cation or a fraction of a polyvalent cation, for example
an ammonium or substituted ammonium ion or a metal ion,
for example an alkali metal or alkaline earth metal
ion). Particularly preferably, M is a cation deriving
from an organic base, for example meglumine or lysine.
In such salts or chelates one or more (but not
necessarily all) of the carboxyl groups are transformed
into COOM groups.
It is particularly preferred that the number of the
ion-forming groups Y in the compounds of formula I be
chosen to equal the valency of the metal species to be
chelated by the compound formula I. Thus, for example,
where Gd(III) is to be chelated, the compound of formula
I (or salt thereof) preferably contains three or six
.
2074-1~1 , .
WO91/10~5 PCT/EP91/00126
- 12 -
ion-forming Y groups, for exa~ple -COOH (or -COOM). ~In
this way, the metal chelate will be formed as a neutral
species, a form preferred since the osmolalities in
: concentrated solutions of such compounds are low and
since their toxicities relative to their ionic analogues
are significantly reduced.
Compounds of formula I in whish 211 the Y groups
are -COOH groups or salts or amiaes oî such cGmpounds
are especially preferred since compositions containing
metal chelates of such compounds can readil~ be
s~erilized, for example by au'ocl~vin~.
Included amongst the par.ic~larly pre_êrrêd
compounds according to the inven~ion are those of
formulae Ib to Ii wherein each R2 represents a hydrogen
atom or a mono- or poly-hydroxylated alkyl group, Y
represents a group of formula COZ and Z represents a
hydroxyl group or a group NHR ) and metal chelates and
salt thereof.
Especially preferred compounds according to the
invention include those of the following formulae Im to
Iw
~\~o~
NR ~N (Im)
R~ ~ O
~R ?` N ~
~R R~N (In)
R
, t ,. c . ` !
207~171
, .
iVO 91/10645 PC~r/EP91/00126
- 13 -
R~ ~ (Io)
R~ ¦
~ ;
~ ~ ~ (Ip)
N NR~ NR~ NR6 N
(/~ N N ~\) r
R ~ ~ ~ (Iq)
(Ir)
, ~R'' ~ ,
~J
(Is)
N~
'. , `' ,' . .
2074171 -~
WO 91/1064~ PC~/EP91/00126
-- 14 --
--~,b~ (It)
I`l R~ R ~1
~ N ~
NRb R~ ~1
R~
~-- ~0~
(Iu)
r_~lR R~ ~
' N ~J
R'~
~
Nrf~ ~ ~N
.3 ~ R3O
~X~ x~ (Iv)
R30
n OH
R~ k~
~ ----;~ tIW)
~ ~ J
. (where R30 is (CH2)2 or (CH2)3, each r is l or 2, t is l or
~ 2, R is hydrogen or methyl, and R is a carboxymethyl
s~ group or derivative thereof, e.g. CH2COOH,
CH2CON(CH~)CH2CHOHCH2OH, or CH2CONHR (where R
represents CH~, CH2CHOHCH2OH or CH(CH2OH)2 or a group
-CH2CONCH2CHR W(CHR )qCH2 where W represents an oxygen
-
2~417~
. '
~091/10~S PCT/EP91/00126
- 15 -
atom or a group CH2 or CHOH, q is 0 or l and R4" is
hydrogen or where q is l and W is oxygen each R4 may
also represent a Cl 4 hydroxyalkyl group) and the metal
chelates and the salts thereof.
Particularly preferred compounds according to the
invention include those of formulae Ij to Io wherein R6
is CH2COOH and the chelates, e.g. with Gd3+, and salts
thereof.
Viewed from a further aspect, the invention also
provides a process for the preparation of the compounds
of the invention, said process comprising one or more o^
the following steps:
(a) reacting a compound of formula II
Rl (CR2 R3 )n[X (CR2 R3 )n]mRl (II)
(where Rl to R3 are as defined for Rl to R3 or are
protected Rl to R groups, and X' is a group X or a
protected group X with the proviso that at least one X
group is of formula NH or (CR2 R )pNH2) with a compound
of formula III
LV-(cR2 R3 ) ~Y' (III)
(where Y' is a group Y or a protected group Y, R2 and
R are as hereinbefore defined and Lv is a leaving
group for example a halogen atom, e.g. bromine or
chlorine or a tosylate group) and if necessary
subse~uently removing any protecting groups used; and
(b) converting a compound of formula I into a chelate
complex or salt thereof.
The compounds of formula II are known from tne
literature or may be prepared in a number of ways using
207~71
WO91/lO~S PCT/EP91/00126
.
- 16 -
techniques known from the literature or analogous tG~
literature described techniques. Thus for example such
compounds may be prepared by condensing mono or
bifunctional heterocyclic compounds of formula IVa or
IVb
/~ `~ ~ R~ c)
Rl ( CR~ R ) n-l
(CR R
~(C 2' 3, ~ N (CR R )n_lCoR3 (IVb)
(where R2 , R3 and R4 are as defined for R2 to R4 or
are protected R2 to R4 groups and R12 is hydrogen, an
amine protecting group or a group (CR R )n 1 CoR3 )
with a linking molecule of formula V
H[X"(CR2 R3 )n]iX"H (V)
(where i is 1 to 5, R2 and R3 are as hereinbefore
defined, mid-chain X" groups, if any are groups X' and
end of chain X" groups are oxygen, sulphur or ring
nitrogen atoms or, preferably, NH groups) followed if
necessary by removal of any protecting groups and if
necessary by reduction.
The compounds of formula II may also be prepared by
activating starting compounds of formula V, e.g. by
tosylation, and condensing the product with a mono or
bifunctional heterocyclic compound of formulae VI or VII
2~171
. .~
~091/10~5 PCT/EP91/00126
- 17 -
,((~R4' (VI)
R13 2' 3'
Lv
2'R3'
R13 N~ ~N-(CR2 R3 )n Lv (VII)
(CR R )n
(where Rl3 is hydrogen, an amine protecting group or a
group (CR2 R3 )nLv), followed by removal of the tosyl
and other protecting groups.
Thus for e~ample linear or cyclic compounds of
~ formula II can be prepared using the following reaction
; schemes.
(A)
2CH2CH2NH2 E~h--
O O
b~ ~Y
. ~' N~ (b) NaBH4 ~NH HN~
~J~ J
SUBSTITUTF SI~EET
, ~ .
207417~ -
W O 91tlO643 PC~r/EP91/00126
- 18 -
(Bl) .
H "~,,H +NH2CH2CH2NH2 ( a) CaCl2
O O
b) NaBH~ /~
Ethanol ~NH HN~
NH HN
~ N ~J
(B2)
`1 + /~ CH3CN
~ ` N~bNH2 NH NH2
O O Ambient temperature
., .
[~N N~ N~5~
. NH HN ~ , ~ Na~H
['IN~I~ ~ `~N' Ethano~
NH HN
NH HN
(NH HN)
~ .
SUBSTlTUT' S~EET
.. .. ~ . . ..
~07~71
.
1064~ - 19 - PCr/EP91/00126
~C)
~H 2 2 2 2~H2NH2 R2 P~
N NH NH NH N
(D~
~ (d)TsCl
NH2 NH NH2 EthanolTsNH NTs NHTs
Wat~r
NaOH
(e) K2C03 + ~ _
K NTs NTs NTs K
DMF
Ambient temperature ( VIII )
If) DMF ,~,
,~ (VIII) , ~ 2l~ hours~ ~l! N~
N temperature NTs TsN
Br Br ~ ~N~
(9) HBr/HOAc rH HN s
Phenol
(E)
i~ ~h) DMF
~N N~, (VII)
OTs TsO
G~ (IX) Q
~N N~ (9) ~N N~
NTs TsN ~ NH HN
~N~
Ts H
'
SUBSTITUTE SHEET
.:
2074171
WO91/10~ PCT/EP91/00126
- 20 -
(IX)+ Na+-NTs TsN~Na+ (h)
Q 1~
~N N~ ( 9) N N~
LNTS TSNJ [~NH HNJ
\ - \J
;
(G)
R~R16 ~ N~N~ CaCl2/Ethanol
O NH2 H2N
' (X)
~N~ NaBH4 ~N~
R~ R16
R16= H orCH3 z= 1 or2
Compounds of formula II containing a
( CR2R3 ) n
-N ~ ~ N-
( CR2R3 ) n ~
group may be prepared by condensing a linear compound
having active groups at each end with a compound of
formula
~ ( CR2R3 ) n
HN HN
( CR2R3 ) n
SUBSTITUTE S!tEET
2~171
.~091/10~ PCT/EP91/00126
- 21 -
for example as follows
(H)
~ BocOBoc ~/ \~
NH2 NH NH2NH Nl INH
Boc Boc Boc
1) NaH 1 XI)
( Xl) ., MsON N N OMs
2)C~b~ Boc Boc Boc
0 ~ XII)
3) ~lsC [
H N ,NH ~N~
~XII) Boc--N N-Boc
(XIII) Boc
N~N
IXIII) ~NH3
(XIV)
The active linear compound of formula XII may of course
be prepared by other routes, e.g.
SVE3ST1TU~E SH~:ET
207~171
WO91/10~ PCT/EP91/00126
- 22 -
~BocOBoc ~ MsCl ~_~
H2N OH BocNH OH BocNH OMs
t~ i~ A MsCl
HO NH OH HO N OH
IXV) XII)
MsO N OMs
Base
Boc NaH
Compounds of formula II containing a
( CR2R3 ) n \
-N N-
~ (CR2R3~ /
group can also be prepared by condensing the
corresponding compound in which one of these (CR2R3)
bridges is missing and the nitrogens carry hydrogens
instead with a compound of formula LV-tcR2 R3 )nLv, for
example as follows
~ F~
~NH HN) Br(CH2~2Br ~N N~
NH HN NH HN
\J
This is described for example in J.Chem. Soc. Chem.
Commun. 1982,277.
In the reactions mentioned above, a starting
material containing more than one heterocyclic ring may
of course be used in place of the compound of formulae
IVa,IVb,V,VI and VII.
SUBSTITUTE S~ET
2~ 171
~ `
~091/10~5 PCT/EP91/00126
- 23 -
This is exemplified by the following scheme:
Gf,~_ hb,
0\~ oH
~ /~
~~ H J~ ~
^~ OH O~ OH
rS C~ ~ ~o~, 'S~ ~
f ~ f~ N ~~ '
GTs OTs
' I \ ~L,
~r, N~
rS
~Ts
T~ ~ J
3 11N--
~. Nl~
~ '
Combinations and extensions of these procedures may
be used to prepare further compounds of formula II, e.g.
by condensing a compound of formula VIIIB
H~X"(CR2 R3 )n]m lX"H (VIIIB)
with a compound of formula IX
Lv-(CR2 R3 )n-X'-(CR R )n-Lv (IX)
or a compound of formula IXB
Ts-[X"(CR2 R3 )n]m lX" Ts (IXB)
207~171
WO91/10645 PCT/EP91/00126
- 24 -
with a compound of formula XI
Lv-(CR2 R3 )n-Lv ~XI)
followed by removal of the tosyl groups.
This may be illustrated by the reaction schemes:
(
~X) I TsC~ /E~o
~011 /H,
. ~ ~`JaH ( ~ Nrs TsN ~ )~
x 1 ~ )
' r~ c~ r----~r~o~s
, (x~
~rST~
T5
, ~ 9 )
HN
(~)
~-0 0
(XII)__ ~
T' N )~ ( N~l Hl`l )-
\~/ ~ _ I
2~7~17~
,091/10~; - 25 - P~r/EP91/00126
The precursors of formula II for dimeric
macrocyclic chelants - i.e. compounds wherein two R4
groups on a cyclic X group together represent a group
( CR2R3 ) n. 1 [ X ( CR2R3 ) n ~ m- 1 ( CR2R3 ) n 1 ~ C an be prepared for
example by a condensation equivalent to those o~ the
schemes above usln~ a tetrafunctional precursor for the
cyclic X group and bifunctional co-reagents. It may be
desirable to utili2e aromatic tetrafunctional precursors
and subsequently to reduce the product, e.g. by high
pressure catalytlc hydrogenation. Thus compounds of
formula II may be prepared ~y the following scheme:
IL~
~ ~ H2/Pd-C H2N~N~NH2
NC N CN Ethanol H2N N NH2
OCH~ CHO
N Boc ,~ ~Nl~J NaBH~
high dilution or 200 mol% template M2 ~NJ~ or H2/Pd-C
( M2+= Cd2+ Ba2+, Pb2+ etc )~ Methanol N N
or ethanol as solvent ~NH~
.
` ~NH~ ~NI~\>
NH H~ NH HN
~¢~ reduction ~NH~
NH HN NH H N
<~NH~ ~,NH
Further reaction schemes for the production of
compounds of formula II will be evident to the skilled
chemist from the literature, e.g. Tabushi et al. Tetr.
~1 IP~C'`lTl ~Tr .CUF~
.
;.
2~7~71
W091/10~5 PCT/EP9l/00126
. - 26 -
Lett. 4339 (1976) and 1049 (1977), Richmann et al. JACS
96: 2268 (1974), Nelson, Pure and Applied Chemistry 52:
461-476 (1980). Moi et al. JACS 110: 6266 (1988), ~
EP-A-287465 (Guerbet), Stetter et al. Tetrahedron ~:
767 (1981), EP- A-232751 (Squibb), J. Chem. Soc. Commun.
277 (1982). Hancock et al. JACS 110: 2788-2794 (1988),
Smith et al. JACS 111: 7437-7443 (1989) and the
references listed therein.
To introduce a (CR2R )pY group onto a compound of
formula II using the precedure of step (a) may be
effected in an aqueous, preferably basic, medium, for
example by using a halocarboxylic acid Hal(CR2 R3 )p-
COOH or a metal, e.g. Li, salt thereof (where Hal is
~romine or chlorine) followed by amidation or
esterification of the carboxyl group.
The introduction of (CR2R3)pY moiety other than a
carboxylic acid residue may for example be performed as
follows:
a) To introduce a phosphonic acid moiety, the general
method for synthesis of alpha-aminophosphonic acids
described by K.Moedritzer et al. in J.Org.Chem 31: 1603
(1966) may be used.
R17NH CH2O R NCHzPO3H2
______~
H3PO3
(XVII) (XVIII)
(of formula II) (of formula I)
(where R17NCH2Y is a compound o. formula I).
: : :
.. ; :-.
,~091/10~5 PCT/EP91/00126
- 27 -
b) To introduce a hydroxamic acid moiety, the general
method for transformation of an activated acid
derivative into hydroxamic acid described by
P.N.Turowski et al. in Inor~. Chem. 27: 474 (1988) may
be used.
~o //o
1~0h11R2 /~
R ~ ~ ~ --- ~ R ~ R O H
~ C O G 1~
(where RlN(CH2COOH)CH2Y is a compound of formula I).
c) To introduce a sulfonic acid moiety, s-~nthesis may
be performed by alkylation of an amino function for
example with iodomethanesulfonic acid
R17NH ICH2S02H Rl NCH2S02H
(XVII) (XXI)
Amide derivatives of formula I may produced from
the oligo acids by methods analogous to those of
EP-A-250358 or of EP-A-299795. Furthermore hydrophilic
substituents on the skeleton of the linear or cyclic
chelants of formula I may be introduced by methods
`~
.
..
2~7 ~7 1 ~t~
WO91/10~5 PCT/EP91/00126
- 28 -
analogous to those of EP-A-299795.
Chelants of formula I may be used as the basis for
bifunctional chelants or for polychelant compounds, that
is compounds containing several independant chelant
; groups, by substituting for one Y or Rl to R4 group a
bond or linkage to a macromolecule or polymer, e.g. a
tissue specific biomolecule or a backbone polymer such
as polylysine or polyethyleneimine which may carry
several chelant groups and may itself be attached to a
macromolecule to produce a bifunctional-polychelant.
Such macromolecular derivatives of the compounds of
formula I and the metal chelates and salts thereof form
a further as?ect o~ the present invention.
The lin~age o_ a compound of formula I to a
macromolecule or bac~bone polymer may be effected by any
of the conventional methods such as the carbodiimide
method, the mixed anhydride procedure of Krejcarek et
al. (see Biochemical and Biophysical Research
Communications 77: 581 (1977)), the cyclic anhydride
method of Hnatowich et al. (see Science 220: 613 (1983)
and elsewhere), the backbone conjugation techniques of
Meares et al. (see Anal. Biochem. 142: 68 (1984) and
elsewhere) and Schering (see EP-A-331616 for example)
and by the use of linker molecules as described for
example by Nycomed in W0-A-89/06979.
Salt and chelate formation may be performed in a
conventional manner.
The chelating agents of the formula I (as defined
above but with the deletion of the second proviso) are
particularly suitable for use in detoxification or in
the formation of metal chelates, chelates which may be
used for example in or as contrast agents for in vivo or
in vitro magnetic resonance (MR), X-ray or ultrasound
diagnostics (e.g. MR imaging and MR spectroscopy), or
scintigraphy or in or as therapeutic agents for
radiotherapy, and such uses of these metal chelates
form a further aspect of the present invention.
' . ~. . . .
~'74~7~
. .
WO91/10~ PCT/EP91/00126
- 29 -
Salts or chelate complexes of the compounds of the
invention containing a heavy metal atom or ion are
particularly useful in diagnostic imaging or therap~.
Especially preferred are salts or complexes with metals
of atomic numbers 20-32,42-~4,49 and 57 to 83,
especially Gd, Dy and Yb. For use as an MR-diagnostics
contrast agent, the chelated metal species is
particularly suitably a paramagnetic species, the metal
conveniently being a transition metal or a lanthanide,
- preferably having an atomic number of 21-29, 42, 44 or
57-71. Metal chelates in which the metal species is Eu,
Gd, Dy, Ho, cr, Mn or Fe are especially preferred and
Gd3 , Mn2 and Dy3 are particularly preferred.
Chelates of ions Ot these m~als s?ecifically listed
above with chelants of formula I (defined as above with
the exclusion of the second proviso) or their salts with
physiologically tolerable counterions are particularly
useful for the diagnostic imaging procedures mentioned
herein and they and their use are deemed to fall within
the scope of the invention and references to chelates of
compounds of formula I herein are consequently to be
taken to include such chelates.
For use as contrast agents in MRI, the paramagnetic
' metal species is conveniently non-radioactive as
radioactivity is a characteristic which is neither
required nor desirable for MR-diagnostics contrast
agents. For use as X-ray or ultrasound contrast agents,
the chelated metal species is preferably a heavy metal
species, for example a non-radioactive metal with an
atomic number greater than 37, preferably greater than
50, e.g. Dy
For use in scintigraphy and radiotherapy, the
; chelated metal species must of course be radioactive and
` any conventional complexable radioactive metal isotope,
;i such as 99mTc or lllIn for example, may be used. For
radiotherapy, the chelating agent may be in the form of
a metal chelate with for example l53Sm, 67Cu or 90Y~
i
.'' ~ - ~
.
207~
W091/10~ PCTtEP9l/00126
~ - 30 -
For use in detoxification of heavy metals, the
chelating agent must be in weak complex or salt form
with a physiologically acceptable counterion, e.g.
sodium, calcium, ammonium, zinc or meglumine, e.g. as
the sodium salt of the chelate of the compound of
formula I with zinc or calcium.
Where the metal chelate carries an overall char~e,
such as is the case with the prior art Gd DTPA, it will
conveniently be used in the form of a salt with a
physiologically acceptable counterion, for example an
ammonium, su~stituted ammonium, alkali metal or alkallne
earth metal (e.g. calcium) cation or an anion deriving
from an inor~anic or organic acid. In this regard,
meglumine salts are particulzrly preferred.
Viewed rrom a further aspect, the present invention
provides a diagnostic or therapeutic composition
comprising a metal chelate, whereof the chelating entity
is the residue of a compound of formula I according to
the present invention, together with at least one
pharmaceutical or veterinary carrier or excipient, or
adapted for formulation therewith or for inclusion in a
pharmaceutical formulation for human or veterinary use.
Viewed from another aspect, the present invention
provides a detoxification agent comprising a chelating
agent according to the invention in the form of a weak
complex or salt with a physiologically acceptable
counterion, together with at least one pharmaceutical or
veterinary carrier or excipient, or adapted for
formulation therewith or for inclusion in a
pharmaceutical formulation for human or veterinary use.
The diagnostic and therapeutic agents of the
present invention may be formulated with conventional
pharmaceutical or veterinary ~ormulation aids, for
example stablizers, antioxidants, osmolality adjusting
agents, buffers, pH adjusting agents, etc. and may ~e in
a form suitable for parenteral or enteral
administration, for example injection or infusion or
"~ ' . :.;, : , ,
. 20~171
~091/10~ PCT/EP91/00126
~ - 31 -
administration directly into a body cavity having an
external escape duct, for example the gastrointestinal
tract, the bladder or the uterus. Thus the compositlon;
of the present invention may be in conventional
pharmaceutical administration forms such as tablets,
capsules, powders, solutions, suspensions, dispersions,
syrups, suppositories, etc; however, solutions,
suspensions and dispersions in physiologically
acceptable carrier media, for example water for
injections, will generally be preferred.
The compounds according to the invention may
therefore ~e formulated for administration using
physiologically acceptable carriers or excipients in a
manner fully within the skill OI the 2-_. For example,
the compounds, optionally with the addition of
pharmaceutically acceptable excipients, may be suspended
or dissolved in an aqueous medium, with the resulting
solution or suspension then being sterilized. Suitable
additives include, for example, physiologically
biocompatible buffers (as for example, tromethamine
hydrochloride), additions (e.g., O.Ol to lO mole
percent) of chelants (such as, for example, DTPA,
DTPA-bisamide or non-complexed chelants of formula I) or
calcium chelate complexes (as for example calcium D-'A,
CaNaDTPA-bisamide, calcium salts or chelates of chelants
of formula I), or, optionally, additions (e.g., l to 50
mole percent) of calcium of sodium salts (for example,
calcium chloride, calcium ascor~ate, calcium gluconate
or calcium lactate combined with metal chelate complexes
of chelants formula I and the like).
If the compound~ are to be formulated in suspension
form, e.g., in water or physiological saline for oral
administration, a small amount of soluble chelate may -e
mixed with one or more of the inactive ingredients
traditionally present in oral solutions and/or
surfactants and/or aromatics for flavouring.
.
207~171
", . ..
WO91~10~ PCT/EP91/00126
- 32 -
For MRI and for X-ray imaging of some portions of
the body the most preferred mode for administering metal
chelates as contrast agents is parentral, e.g.,
intravenous administration. Parenterally administrable
forms, e.g., intravenous solutions, should be sterile
and free from physiologically unacceptable agents, and
should have low os~olality to minimize irritation or
other adverse effects upon administration, and thus the
contrast medium should preferably be isotonic or
slightly hypertonic. Suitable vehicles include aqueous
vehicles customarily used for administering parenteral
solutions such as Sodium Chloride Injection, Ringer's
Injection, Dextrose Injection, Dextrose and Sodium
Chloride InJe_tior., Lactated Rin~er's Injection and
other solutions such as are described in Remington's
Pharmaceutical Sciences, 15th ed., Easton: Mack
Publishing Co., pages. 1405-1412 and 1461-1487 (1975)
and The Nati~nal Formulary XIV, 14th ed. Washington:
American Pharmaceutical Association (1975). The
solutions can contain preservatives, antimicrobial
agents, buffers and antioxidants conventionally used for
parenteral solutions, excipients and other additives
which are compatible with the chelates and which will
not interfere with the manufacture, storage or use of
products.
Where the diagnostic or therapeutic agent comprises
a chelate or salt of a toxic metal species, e.g. a
heavy metal ion, it may be desirable to include within
the formulation a slight excess of the chelating agent,
e.g. as discussed by Schering in ~E-A-3640708, or more
preferably a slight excess of the calcium salt of such a
chelating agent. For MR-diagnostic examination, the
diagnostic agent of the present invention, if in
solution, suspension or dispersion form, will generally
contain the metal chelate at concentration in the range
1 micromole to 1.5 mole per litre, preferably 0.1 to
700mM. The diagnostic agent may however be supplied in a
: ' '
' , .' '
,.~ : . ''
~7~t'71
~091/10~; PCT/EP91/00126
- 33 -
more concentrated form for dilution prior to
administration. The diagnostic agent of the invention
may conveniently be administered in amounts of from ~10 3
to 3 mmol of the metal species per kilogram of body
weight, e.g. about 1 mmol Dy/kg bodyweight.
For X-ray examination, the dose of the contrast
agent should generally be higher and for scintigraphic
examination the dose should generally ~e lower than for
MR examination. For radiotherapy and detoxification,
conventional dosages may be used.
Viewed from a further aspect, the present invention
provides a method of generating enhanced images of the
human or non-human animal body, whlch method comprises
administering to said body a diagnos~ic agen~ accordin~
to the present invention and generating an X-ray, MR,
ultrasound or scintigraphic image of at least a part
said body.
Viewed from a further aspect, the present invention
provides a method of radiotherapy practised on the human
or non-human animal body, which method comprises
administering to said body a chelate of a radioactive
metal species with a chelating agent accorqing to the
invention.
Viewed from a further aspect, the present invention
provides a method of heavy metal detoxification
practised on the human or non-human animal body, which
method comprises administering to said body a chelating
agent according to the invention in the form of a weak
complex or salt with a physiologically acceptable
counterion.
Viewed from a yet further aspect, the present
invention also provides the use of the compounds,
especially the metal chelates, according to the
invention for the manufacture of diagnostic or
therapeutic agents for use in methods of image
generationl detoxification or radiotherapy practised on
the human or non-human animal body.
' ' ~' .
'
::
, . .
207 ~
f "~,
WO91/lO~S PCT/EP9t/00126
- 34 -
Viewed from a still further aspect, the present
invention provldes a process ~or the preparation of the
metal chelates o~ the invention which process comprises
admixing in a solvent a compound of formula I or a salt
(e.g. the sodium salt) or chelate therecf together with
an at least sparingly soluble compound of said metal,
for example a chloride, oxide, acetate or carbonate.
Viewed from a yet still further aspect, the present
invention provides a process for the preparation of the
diagnostic or therapeutic agent of the present
invention, which comprises admixing a metal chelate
according to the invention, or a physiologically
accept2ble salt thereof, together wilh at least one
pharmaceutical or veterinary carrie- or excipien~.
Viewed from a yet still rurther aspect, the present
invention provides a process for the preparation of the
detoxification agent of the invention, which comprises
admixing a chelating agent according to the invention in
the form of a weak complex or salt with a
physiologically acceptable counterion, together with at
least one pharmaceutical or veterinary carrier or
excipient.
The disclosures of all of the documents mentioned
herein are incorporated by reference.
The present invention will now be illustrated
further by the following non-limiting Examples. All
ratios and percentages given herein are by weight and
all temperatures are in degrees Celsius unless otherwise
indicated.
,
:, ' , :: - '
~O91/10~5 PCT/EP91/00126
- 35 -
Exam~le 1
[l8]N6H8o4(Py)2
~q
~N~
HOOC--N N rCOOH
~N N~
HOOC--I~,N~ COOH
~J
~ (a)
Ca2~ ~2 Cl-.3H20
.. , 1~1
~Ca[18~N6H4(PY)2]Cl2 3H20
i
To a stired solution of 2,6-diformyl-pyridine (1.306 g,
9.662 mmol) and calcium chloride dihydrate (0.71 g, 4.83
mmol) in 80 mL of methanol was added ethylenediamine
(0.646 mL, 9.662 mmol). The solut on was refluxed for 3
hours, stirred at ambient temperature for 15 hours, and
stripped to dryness. The resulting solid was taken up
in lO mL of ethanol, and ethyl acetate added until
precipitation ceased, giving 2.214 g (94%) of the title
SUBSTITUTE SH1~ET
.
, ~ '
,
. .
.. . .
2074171 ~s~
WO9l/10~5 PCT/EP9l/00126
- 36 -
product as the trihydrate.
lH NMR(MeOD): ~ 3.9(s, 8H), 7.85-8.23(m, 6H), 8.67(s,
4H).
(b)
[l8]N6H8(PY)2
~1
~ ' H ~
J
NH HN
~,~J
To a stirred solution of [Ca~18]N6H~(py)2]C12.3H2O
(500mg, 0.93 mmol) in 50 ml of ethanol at ambient
temperature was added sodiu~ borohydride (0.2184 mg,
5.58 mmol). The mixture was refluxed for 3 hours,
stirred at ambient temperature overnight, stripped to
dryness, and diluted with 100 mL of water. The water
layer was extracted with methylene chloride (2 x 250 mL)
and the combined organic layers dried over K2CO2.
Evaporation of the solvent gave 162 mg (52%) of the
title ~roduct as a white solid.
1H NMR (MeOD) :C 2.73(s, 8H), 2.80-3.0(br s, 4H),
3.78(s, 8H), 6.90-7.60(m, 6H).
;.. , , ~, . . . .
.
. -, ;; ~ ' '' '' - ' ' ': '
r ~ 2 ~ 7 1
~091/10~5 PCT/EP91/00126
- 37 -
(c) r 181N6_8o4(py)2
[18]N6H8(py)2 (162 mg, 0.49 mmol) in 50 mL of
ethanol/water (1/1) is placed in a 100 mL three nec}
round-botto~ flask equipped with two addition funnels,
pH electrode, thermometer, and stir bar. NaOH (199 mg,
4.98 mmol) and BrCH2C02H (346 mg, 2.49 mmol) are each
dissolved in 10 mL of water and the resulting solutions
placed in the two addition funnels. The solution of
NaOH is added to the amine solution to bring the p~: to
10.5. The temperature is raised to 50C and the
BrCH2CO2H and NaOH solutions are added concurrentl~ ove~
a 24 hour period maintaining the pH at 'l during th~
addition. When the pH no longer drops, the reac~ic..
mixture is stirred at 75C for 4 hours, cooled to
ambient temperature and stripped to dyness. The solid
is taken up in 5 mL of water, the pH adjusted to 3 and
the solution applied to AG50-X8(200-400 mesh, H ) resin
and the titl~ ~roduct eluted with lN NH40H.
.: Exam~le 2
~ [18](Me)4N6H404(py)2
~N
~,ooc ¦ ¦ ~coo~
: ~N
H O O C ~ C C ^ I I
~'J
`: _
~ , ." .' .,
`
.~ '~ ' ` :'' ~' . .
20741'71
W091/10~5 PCT/EP91/00126
- 38 -
(a) [Ca[l8](Me)4N6(py)2]cl2.6H2o
C u 1 ~ ) 2 C I . 6 H ~ O
J~N~
I ~,J
To a stirred solution of 2,6-diacetyl-pyrldine (~o.o g,
0.306 mol) and calcium chloride dihydrate (22.49 g,
0.153 mol) in 600 mL of methanol was added
ethylenediamine (20.42 mL, 0.306 mol). The solution was
heated at 55-C for 3 hours and then stirred at 25C for
15 hours and stripped to dryness to leave a pale
yellow-orange solid. The addition of ethanol (200 ml)
followed by methylene chloride (200 mL) produced 60 g
(66%) of a pale yellow solid isolated as the
hexahydrate. 1H NMR (MeOD) :~ 2.56(s, 12~), 3.98(s,
8H), 8.18-8.26(m, 6H). FAB Mass Spectrum, m/z : 449
(MH -Cl), 413 (MH -2Cl).
[18](Me)4N6H4(PY)2 2H2o
1~1
,N H H 'I
` ~ H H 1
,1~,~.1
11 1
.
- ~
``
2 ~ 7 1
^'
WO91/10~5 PCT/EP91/00126
- 39 -
To a stirred solution of [Ca[18](Me)4N6(py)2]C12.6H20
(20 g, 33.9 mmol) in 600 mL of ethanol at ambient
temperature was added sodium borohydride (9.2 g, 242~
mmol). The mixture was refluxed for 6 hours, cooled to
ambient temperature, stripped to dryness and diluted
with 100 mL of water. After adjusting the pH to 10, the
water layer was extracted with methylene chloride (3 x
200 mL) and the combined organic layer dried over K2CG3.
Evaporation of the solvent gave a pale yellow solid
which was triturated with ether and collected by suction
filtration to glve 8.61 g (58%) of the title product as
the dihydrate. H NMR (CDC13) :~ 1.24-1.52 (m, 12H),
~.1-2.8 (m, 12H), 2.7-2.9 (m, 4H), 6.9-7.7 (ll~l 6H).
FAB Mass Spectrum, m/z : 383 (MH ).
(c) rl8lrMe)4--H40-(pv)2
~;
[18](Me)4N6H404(py)2.2H20 (8-00 g, 19 mmol) in 250 ml of
j ethanol/water (1/1) was placed in a 500 ml three neck
; round-bottom flask equipped with two addition funnels,
i pH electrode, thermometer, and stir bar. NaOH (7.66 g,
191 mmol) and BrCH2C02H (13.28 g, 95.6 mmol) were each
dissolved in 30 ml of water and the resulting solutions
placed in the two addition funnels. The solution of
NaOH was added to the amine solution to bring the pH to
10.5. The temperature was raised to 50C and the
BrCH2C02H and NaOH solutions were added concurrently
over a 24 hour period maintaining the pH at 11 during
the addition. When the pH no longer dropped the
reaction mixture was stirred at 75C for 4 hours, cooled
to ambient temperature and stripped to dryness. The
solid was dissolved in 30 ml of water and adjusted to pH
3 using lN NaOH. The solution was applied to AG50-X8
(200-400 mesh, H ) resin and the product eluted with lN
NH40H to yield 10.93 g of the title product as the
ammonium salt.
207~17~
W09ltlO~ PCT/EP91/00126
- 40 -
13c N~R(D20) :~ (ppm) 15.58, 48.83, 54.26, 60.97,
121.24, 137.5, 159.80, 172.52.
Example 3
[12]N403(py)
H!:)OC I~C;~Or
/N N
~ '~\'
~Oi3H
a) 2 6-Di(bromomethyl~pvridine
2,6-Di(hydroxymethyl)pyridine (10.0 g; 71.8 mmol) and
hydrobromic acid (42% solution in water; lOo mi, 70
mmol) were heated under reflux for 2 hours. The
resulting solution was cooled to 0C, neutralized by
slow addition of a 40% w/w solution of sodium hydroxide
in water (87 ml), diluted with water (200 ml) and
extracted with dichloromethane (5xlOO ml). The combined
organic phases were concentrated in vacuo to yield a red
solid (about 10 g). This was chromatographed on silica
gel (170 g) and eluted with dichloromethane to yield
3.75 g (20%) of the title ~roduct.
H NMR(CDC13):~ 7.69(t, lH), 7.35(d, 2H), ~.51(s, ~H).
':: , ,` , ,: . ' .
, .
.. . . . . .
.. . ... .
- 2~7~171
~O91/10~5 PCT/EP91/00126
. - 41 -
b) [12~N4(py)(Ts)3
~,1
1'--~ N ,~A~l
1`1 T s T s N
>
\ ~ ,/
R5~_ ~ A
To ~ solution of the tritosylate of diethylenetriamine
(4.59 g; 8.113 mmol) in dimethylformamide (100 mL)
heated at llO C, was added NaH (60% dispersion: 0.75 g)
under a nitrogen atompshere. The resultant, white
suspension, and also a solution of 2,6-ditbromo-
methyl)pyridine (1.5 g; 8.113 mmol) in DMF (80 ml) at
110C were dripped separately and simultaneously into
DMF (100 mL) also maintained at 110C. After 2 1/2
hours of vigorous stirring at this temperature, the
solution was cooled and then concentrated to dryness in
vacuo. Water (150 ml) was added and the beige
precipitate collected by suction filtration.
Dichloromethane (250 mL) was added to the solid,
followed by water (200 mL), and after sha~ing the
organic phase collected via a separating funnel. The
aqueous phase was extracted with dichloromethane (2X100
mL) and the combined organic fractions dried ~MgS0~) and
concentrated in vacuo to a solid (about 5.6g).
Purification on silica gel (200 g) eluting with
2a74l7l
WO91/10~5 PCTtEP91/00126
- 42 -
chloroform/acetone (95:5) afforded the title product as
a white crystalline solid (2.43 g; 45%).
lH NMR(CDC13) :~ 7.24-7.74(m, 15H); 4.26 (s,
3.3(t, 4H); 2.71(s, 4H); 2.4(d, 9H).
Route B
2,6-Di(bromomethyl)pyridine (5.0 g; 19 mmol; 0.86 eq) in
dimethylformamide (200 ml) was dripped over a period o-
10 hours into a mixture of the tritosylate of
diethylenetriamine (12.72 g; 22 mmol) and pot2ssiu~
carbonate (7.154 g; 58 mmol~ in DMF (3,~ mLj, s~irring
a~ 25C. After stirring for 15 hours 2_ 2~c _he e~cess
potassium carbonate was removed by suc~ion filtration
and the filtrate concentrated to about 120 mL. water
(250 mL) was added and the white precipitate removed by
suction filtration and washed with water until the
ensuing filtrate was neutral pH. Excess tritosylate was
precipitated by adding chloroform to the solid residue,
the precipitate was removed by suction filtration and
the filtrate concentrated in vacuo to a white solid (16
g). This solid was chromatographed on silica gel (600
g) and eluted with chloroform to yield 12.3 g of the
title ~roduct (97% with respect to
2,6-dibromomethylpyridine; 82~ with respect to
diethylenetriamine tritosylate).
lH NMR(CDC13):~ 7.24-7.74(m, 15H); 4.26(s, 4H); 3.30(t,
4H); 2.71(s, 4H): 2.40(d, 9H).
: . . ,
: .
' ''' ' ` . ';: ' , '" - . . .
: ' , ' ' :
20~17~
,~/0 91tlO645 P~/EP91/00126
-- 43 --
(c) [12]N4(py)
~`1
NH HN
~\_ ,,N~
H
A mixture of [12]N~,(py) (Ts)3 (56-6 g; 84 mmol) and
phenol (90 g) in a solution of HBr in acetic acid (30
w/w; 1000 mL) was stirred at 80C for 48 hours. The
reaction mixture was allowed to cool and was then poured
into ice-water (1000 mL). With vigorous stirring,
diethylether (1500 mL) was added, followed by ethanol
(1500 mL). After 5 minutes, the mixture was allowed to
stand, whereupon a white precipitate began to settle.
The solid was removed by suction filtration, washed with
ethanol and dried under vacuum. The off-white solid
(about 38 g) was dissolved in water (100 mL) and pa~sed
through a bed of AG lX-8 anion-exchange resin (hydroxide
form, 560 g). The water was then removed by
roto-evaporation to yield the title product as a white
solid (15 g; 8S%).
lH NMR(D2O) :~ 7.5(t, lH); 7.0(d, 2H); 3.76(s, 4H);
2.60(s, 4H); 1.8(s, 4H).
Mass Spectrum : (M+H ) 207.3.
(d) ~12]N4O3(py~
Chloroacetic acid (24 g; 254 mmol) in water (500 ml) was
adjusted to pH 7 with NaOH solution. This was added
dropwise to a solution of [12]N4(py) (15.00 g; 727 mmol)
in water maintained at a temperature of 95C. During
2a7~7l
WO91/10~5 PCT/EP91/00126
- 44 -
the addition, the pH is maintained at pH 9-10 by the
addition of lN NaOH solution. When addition was
complete, the reaction mixture was adjusted to p~l 3
using lN HCl solution and concentrated to a solid.
Water (150 mL) was added, the pH readjusted to p~ 7 and
the sample applied to a bed of AG lX-8 anion-exchange
resin (100-200 mesh, acetate form, 1.5 L). The columr.
was eluted with an aqueous acetic acid solution to yield
10.2 g (37~) of the title ~roduct.
H NMR(D2O) :~ 7.72(t, lH); 7.2(d, 2~ .56(s, ~H);
3.78(s, 4H); 2.76(s, 4H).
-~ Exam~le 4
1 4 7 10.13-Pentaazabicvclo~11.2.21he~tadecane-
4 7.10-trislacetic acid) ([151N503(pip!) -
rN N~
- HOOC ~ ~ COOH
N N
~\~N~
, ~OOH
a) N,5~Ul~L~Q~yLlethanolamine
~, ,
To a solution of tosyl chloride (100 g, 520 mmol) in 5G
ml of dry pyridine, was added dropwise ethanolamine (15
ml, 250 mmol) in 65 ml of pyridine. The temperature was
held below 5C, and vigorous stirring was maintained
together with a steady flow of nitrogen gas. After the
addition was completed, the mixture was allowed to stir
at ambient temperature overnight. The solution was then
cooled to 5C, and 500 mL of ice-water was added slowly.
~ ' ' ,' .~` -
2074171
WO91/10~ PCT/EP91/00126
- 45 -
Precipitated solid was separated by filtration andwashed with water. Crystallization from methanol ~150
ml) gave 56.4 g (62~) of the title produc .
H NMR(CDCl3):~ 2.45(s, 3H), 2.6(s, 3H), 3.2(m, 2H),
4.l(t, 2H), 5.0(t, lH), 7.3-7.7(m, 8H).
b) N-Tosylaziridine
- To a vigorously stirred suspension of N,O-bis(tosyl)-
ethanolamine (40 g, 110 mmol) in S00 ml of toluene was
added KOH (20% solution in wàter, 140 ml) over a period
of 0.5 hour. After stirring for an additional 2 hours,
the water phase was removed, and the organic layer was
washed with water (3 x 150 ml) and dried over MgSO4.
After filtration, toluene was evaporated to give 20.1 g
(92.5%) of the title ~roduct.
H NMR(CDCl3):~ 2.4(s, 4H), 2.5(s, 3H), 7.4(d, 2H),
7.8(d, 2H).
c) N,N'-Bis(N-tosylaminoethyl)piperazine
' I~ ' .
~N N~
/
, ~ ~
N H T s T s N H
Piperazine (22.0 g, 255 mmol) and N-tosylaziridine
(105.5 g, 530 mmol) were refluxed in 650 ml of
acetonitrile for .8 hours. After the solution had been
cooled to ambient temperature, the precipitated product
was separated by filtration, washed with cold
20~ ~ 7 ~
WO91~10~ PCT/EP9t/00126
- 46 -
acetonitrile and dried in vacuo to yield 83.7 g (68%~ of
the title product.
H NMR(CDCl3):~ 2.5(s, 6H), 2-4(t~ 4H), 2.~(t~ 4H)~,
2.3(s, 8H).
d) 4 7.10-Tris(tosyl)-1 4 7.10 13-pentaazabicvclo-
r 11 . 2.2]-heptadecane
N,N'-Bis(N-tosylaminoethyl)piperazine (4.0 g, 8.7 mmol)
was dissolved in 200 ml of DMF, and Cs2CO3 (6.0 g, lo.
mmol) was added. The mixture was stirred under a
nitrogen atmosphere at 110C for 2 hours before
~,N-bis(tosyloxyethyl)amine (~.9 g, 8.6 mmol - p-epar~i
as described by Guerbet in EP-A-287465) in 80 mi of DlIF
was added dropwise over 0.5 hour. Stirring at llO'C was
maintained for an additional 3 hours. The reaction
mixture was evaporated to dryness. The resulting solid
was stirred in C~2Cl2 overnight. Undissolved material
was filtered, and the solution was evaporated to
dryness. The resulting solid was stirred in acetone for
19 hours. The precipitated product was separated by
filtration to yield 1.3 g t21~) of the title product.
3C NMR(CDCl3):~ 21.8, 47.8, 49.6, 50.3, 57.9, 127.6,
130.1, 136.0, 143.8.
e) 1,4,7,_10 13-Pentaazabicyclo L11.2.2lhePtadecane
HBr in acetic acid (32~ w/w, 82 ml) was added to a
mixture of phenol (4.3 g, 46 mmol) and 4,7,10-
tris(tosyl)-1,4,7,10,13-pentaazabicyclo[11.2.2]hepta-
decane (2.06 g, 3 mmol). The solution was stirred at
70'C for 24 hours. The temperature was raised to 85~C,
and stirring was continued for 5.5 hours. The solution
was allowed to cool to ambient temperature.
Precipitated solid was collected and triturated with
ether and cold ethanol. The solid was then dissolved in
water and passed down a Dowex AGI-8X column. Water was
. . . , ~
, ., " .
,~091/10~ PCT/EP91/00126
, - 47 -
removed. Drying of the solid overnight yielded 0.32 g
(50%) of the title_ roduct.
H NMR(CDCl3):~ 2.4(br s, 12H), 2.7(br s,l2H)
f) 1,4,7,10,13-Pentaazabicyclo[11.2.2lheptadcane-
4,7,10-tris(acetic acid) (rlSlN5O3(pip))
:.
Bromoacetic acid (2.57 g, 19 mmol) is disolved in water,
and LioH (0.77 g, 19 mmol) is carefully added at 5C.
This solution is added to a solution of
1,4,?,10,13-pentaazabicyclo[11.2.2]heptadecane (1.3 g,
5.4 mmol) in water (2.5 ml). The mixture is heated to
6~'C, whlle the pH is held between 9 and 10 with
addition of 4 M LioH. After 2 hours, the temperature is
increased to 80C. Stirring is maintained at this
temperature for 45 minutes following the addition of
LioH. The m .ture is then cooled to ambient temperature
and neutralized with HBr. The volume is reduced to 2
ml, and then the mixture is loaded onto a Dowex l-X8
column (acetate, 50-lO0 mesh). The material is eluted
with deionized water, then lN, 2N, 3N and 4N acetic
acid. Fractions containing product are concentrated by
rotary evaporation, and repeatedly reconcentrated with
several portions of deionized water until the title
~roduct is obtained as an acetate-free solid.
,~ .
.
,
;, ~ , .
,
207~171
WO91/10~5 PCT/EP91/00126 .
48 -
Example 5
[15]N503(py)2
H~OC ~ ~OOH
. . ._
The title compound is prepared from
2,6-di(hydroxymethyl)-pyridine, reacted with HBr to form
2-bromomethyl-6-hydroxy-methylpyridine, condensed with
2-aminomethyl-6-hydroxy-methylpyridine, then
pertosylated and cyclized with the sodium salt of
bistosyl- ethylenediamine, detosylated with HBr and
acetic acid and alkylated with chloroacetic acid (see
Scheme (I)).
Example 6
N.N"-Bisfpvrid-2-vl-methyl)-diethylenetriamlne-N.N',N"-
triacetic acid(Bis(~y)DTTA)
HOOC~ ~ ~ rCOOh
f=~l~ N N~
~N C O O H ~_
. ~ '' , '
.. .. . ..
: ' ` ' ` ' ,.,.. ' ` ~ .~, . : '
':' - ` .
. .' ~ ! , .
,'
207~71
WO91/10~5 PCT/EP91/00126
- 49 -
a) N N''-Bis(pyrid-2-yl-methYl)diethylenetriamine
Diethylenetriamine (76 g, 0.75 mol) and pyridine-2- ~
carboxaldehyde (174 g, 1.62 mol) in 2.5 L of absolute
ethanol were heated for 2 hours at 50C with stirring.
After the reaction mixture was cooled to ambient
temperature, 25 g of 10% palladium on charcoal was added
and the schiff base hydrogenated at slightly greater
than 1 atmosphere of hydrogen, over a 48-hour period.
The catalyst was removed by filtration, the filtrate
adjus~e~ to pH ~. with HC1 gas and then lowered to pH l
using 12 N HCL. The resulting precipitate was removed
by suction filtration, washed with absolute ethanol
until the washings were colourless, and recrystallized
from 95% ethanol. This hydrochloride salt was then
dissolved in 500 mL of water and neutralized with 5 N
NaOH, then raised to pH 12.5, and the free base, the
title compound, was extracted with methylene chloride (4
x 500 mL). The methylene chloride solution was dried to
give 136 g (65%) of a pale yellow oil. NMR (D2O): ~ 2.46
(s, 8H), 3.55 (s, 4H), 7.10 (m, 4H), 7.55 (t, J=12.5 Hz,
2H), 8.25 (d, J=10 Hz, 2H), 7.50 (t, J=10 Hz, 2H), 8.40
(d, J=10 Hz, 2H). (Preparation of the trihydrochloride
salt is also described in Inorg. Chem. 17: 889 (1978)).
b) N.N''-Bis(pyrid-2-yl-methyl)-N.N'.N " -tris(t-
butYlcarboxvmethvl)diethvlenetriamine
To a solution of N, N''-bis(pyrid-2-yl-
methyl)diethylenetriamine (23.6 g, 82.6 mmol) and
diisopropylethylamine (53.4 g, 0.4 mol) in 1.2 L of
methylene chloride at ambient temperature was added
dropwise t-butylbromoacetate (50 g, 0.2 mol) in 300 mL
of methylene chloride. After being stirred for 24
hours, the solution was evaporated to dryness and placed
under vacuum for 2 hours to remove excess
diisopropylethylamine. The crude solid was taken up in
' `' ' :
2~7~17:~ `
WO91/10~5 PCT/EP91/00126
5 0
1.5 L of methylene chloride, washed with 0.2 N NaOH,
water t2 x 250 mL), brine (200 mL) and dried (MgSO4).
The methylene chloride was removed, 200 mL oP ethyl ~
acetate added and this solution passed through 300 g of
silica gel in a B~chner funnel using EtOAc to elute the
product. The pure fractions (TLC: methanol:CH2Cl2 (3:7)
were combined to give 40.6 g t79.5%) of the title
compound. NMR (CDCl3) S 1.26 (s, 9H), ~ 1.31 (s, 18H),
2.62 (s, 8H), 3.12 (s, 2H), 3.17 (s, 4H), 3.78 (s, 4H),
7.02 (t, J=10 Hz, 2H), 7.35 (d, J=10 Hz, 2H).
c) N N''-Bis(pyrid-2-yl-methyl~diethYlenetriamine-
N N' N " -triacetic acid
The tris(t-butylcarboxymethyl)ester (24.89g, 0.1 mol) of
step (b) was dissolved in a solution of 600 mL of
methylene chloride containing 380 mL of trifluoroacetic
acid. The solution was stirred for 48 hours, evaporated
under reduced pressure and diluted with 50 mL of water.
This solution was applied to 200 mL of AG50-X8 (H~ form,
100-200 mesh) and after washing with water until
neutral, the product was eluted with lN NH40H. After
removal of NH40H solution, the product was taken up in 24
mL of water, and the solution was adjusted to pH 10 and
then applied to AGl-X8 (acetate, 100-200 mesh). The
column was washed with three bed volumes of water and
the product eluted with 2 N HOAc to-give 12.0 g (69%) of
the title product after several lyophilizations. NMR
(D20) ~ 3.02 (t, J=6 Hz, 4H), 3.08 (t, J=6 Hz, 4H), 3.14
(s, 4H), 3.41 (s, 2H), 4.08 (s, 4H), 7.52 tm, 4H), 8.05
(t, J=10 Hz, 4H), 8.40 (d, J=10 Hz, 2H).
: ,
..
20~4171
~O91/10~ - 51 - PCT/EP91/00126
Examp l e 7
[ 17 ] N503 (pip)
~N N
~N N
H O O C ~ C O O H
COOH
The title compound is prepared from
1,4-di(3-aminopropyl)-piperazine and
di(hydroxyethyl)~.~ine by the method of Scheme (J)
followed by alkylation with bromoacetic acid.
Exam~e &
[12]N4O2(pip)
~N N
--N N--
HOOC-- \-- ` CO
_ . _
.~ ,
: ' . ` ' ` ` '. ~ .. `' `
2~7~71
WO91/10~ PCT/EP91/00126
- - 52 -
A) The title com~ound is prepared by reaction of
1,4,7,10-tetraazacyclododecane and 1,2-dibromoethane
(according to the method of J. Chem. Soc. Chem. Commun.
227 (1982)), followed by alkylation with bromoacetic
acid.
B) The title compound is prepared by reaction of the
bis-tosylate of 1l4-di(hydroxyethyl)piperazine with the
sodium salt of bistosyl~ ethylenediamine by the method
of Scheme (F), followed by alkylation with bromoacetic
acid.
E~amF~e g
[14]N~O2(pip)
~N NJ
HOOC~ --/ ~COOH
The title c~om~ound is prepared by reaction of the sodium
salt of the bistosylate of 1,4-di(3-aminopropyl)-
piperazine with mesylated ethan-1,2-diol by the method
of scheme (K), followed by alkylation with bromoacetic
acid.
~7l7l
~: .
,~09l~l0643 PCT/EP91/00126
- 53 -
Example 10
[15~N502(py) (pip)
~ G~
~N N~
HOOC~ ~` COCH
N N
\\r/N`~/'/
~ ~,J
''
The title compound is prepared by reaction of 2,6-
diformyl-pyridine with 1,4-di(2-aminoethyl)piperazine by
~ the method of scheme (G), followed by alkylation with
:~ bromoacetic acid.
Example 11
~15](Me)2N5O2(py)(pip)
,,--N N~,
HOOC ( ~ COOH
--~N N
"~, " N~
, " ,'J
~,
,!
~ ' , ' ' . ' ` '
,'' ~ ,. ,' ' ~ '
~0~171
WO91/10~5 PCT/EP91/00126
- 54 -
The titl Q ompound is prepared by reaction of 2,6-
diacetyl-pyridine with 1,4-di(2-aminoethyl)piperazine by
the method of scheme (G), followed by alkylation with
bromoacetic acid.
Example 12
[ l~ ] N502 (py) (pip)
N !i ~
HQQ'' ~ ,/ CQOH
The title com~ound is prepared by reaction of 2,6-
diformyl-pyridine with 1,4-di(3-aminopropyl)piperazine
by the method of scheme (G), followed by alkylation with
bromoacetic acid.
.
: ' - - .:
~ ` ~ , ' ,': : '
:: . :,. .
2 ~ ~t ~
~091/10~5 PCT/EP91/00126
Example 13
[17](Me)2N5O2(py)(pip)
~N N~
HOOC~ ~ COOH
~N NJ
:;
The title com~ound is prepared by reaction of 2,6-
diacetyl-pyridine with 1,4-di(3-aminopropyl)piperazine
by the method of scheme (G), followed by alkylation with
bromoacetic acid.
Example 14
[24]N8H86(PY)2
~q
HOOC ~ ~ COOH
. ~ ~
~N N~
N N
HOOC~ ~, N~ COOH
SU~3S~17UTE SH~:T
wo~l0l7 ~ 17 1 - 56 - PCT/EP9l/OUI26
: (a)
J
~N H H N,
~N N l ~J
Tetraimine and bisimine/bisimidazolidine
To a solution of diethylenetriamine (0.76 g, 7.40 mmol)
in 200 mL of acetonitrile at ambient temperature
diformylpyridine (1.00 g, 7.40 mmol) in 130 mL of
acetonitrile was added dropwise over 4 hours. The
solution was stirred overnight and the white precipitate
formed was removed by filtration, and washed with
acetonitrile to yield 1.21 g (81%) of the tetraimine and
bisimine/bisimidazolidine ti~l~L~ _ucts as a mixture
(about 1:1). 1H NMR (CD30D): ~ 2.5 - 3.75 (m, 17 H);
4.25 (s, 3 H); 7.25 - 7.75 (m, 6 H). FAB mass spectrum,
m/z. 405.
': : '
: ~
2~7~171
WO91~10~5 PCT/EP91/00126
. - 57 -
(b) [24]N8H8(py)2
~NH HN,
. I "i
~N H H N~
"`
~ N HH t~
,J
~'J
The tetraimine:bisimine/bisimidazolidine (3.00 g, 7.42
mmol) was added to a suspension of sodium borohydride
(1.17 g, 31 mmol) in 100 mL of ethanol. The mixture was
stirred for 1 hour at ambient temperature, refluxed for
0.5 hours, and then stirred overnight at ambient
temperature. The reaction mixture was then stripped to
dryness, 20 mL of water was added and the product was
extracted with chloroform (6 x 100 mL), and dried (MgS04)
to give 2.70 g (88% yield) of the title com~ound as a
pale yellow oil. lH NMR (CD30D): ~ 2.55 (br s, 16H,); ~
3.71 (s, 8H); 7.10 (d, J = lO Hz, 4H); ~ 7.55 (t, J = lO
Hz, 2H). .
.- ... . . ..
2n7~l~7l
WO91/10~5 PCT/EP91/00126
- 58 -
(cj [24]N8H806(PY)2
HOOC ~ l COOH
,~ t~
" HOOC ~ U COOH
H O O C~ J C O O H
~J
`:
The amine (1.34 g, 3.24 mmol) of step (b) and
diisopropylethylamine (3.55 g, 25.9 mmol) were dissolved
in 125 mL of methylene chloride and to this was added
neat t-butylbromoacetate (4.11 g, 3.40 mL, 21.06 mmol)
all at once. The reaction mixture was stirred overnight
at ambient temperature, refluxed for 0.5 hour, cooled,
and stripped to dryness. The resulting oil was taken up
in 400 mL of methylene chloride, washed with water (2 x
100 mL), brine (100 mL) and dried (MgSO4). The product
was purified by silica gel chromatography, eluting with
methamol: CH2Cl2 (5:95) to yield the hexa-t-butyl ester.
H NMR (CDCl3): 1.36 (br s, 54H); ~ 2.61 (br s, 16H);
3.20 (br s, 12H); ~ 3.75 (br s, 8H); ~ 7.15-7.25 (m,
6H). The material was taken up in 100 mL of methylene
chloride and 100 mL of trifluoroacetic acid, stirred
overnight and stripped to dryness. The resulting thic~
oil was taken up in 20 mL of water, the pH adjusted to
10.9 using SN NaOH and the solution applied to AGl-X8,
(OAc- form) resin and the product eluted with 0.1 N HOAc
to yield, after recrystallization from water, 194 mg of
the title product. 1H NMR (D20): ~ 2.90 (s, 8H); ~ 3.15
(s, 4H); ~ 3.25 (s, 8H); ~ 3.55 (s, 8H), ~ 4.35 (s, 8H);
. ' .,'~ ~', .
' ' ' ~ ,
~ ., ~ .. .. .
2~7~171
, .
WO91/10~5 PCT/EP91/00126
- 59 -
~ 7.15 (d, J = 10 Hz, 4H); ~ 7.55 (t, J = 10 Hz, 2H).
FAB mass spectrum, m/z: 761.
Example 15
rGdrl81N6Q4 (py) 21Na
5 mL of a 100 mM aqueous solution of [18jN6O4(py)2
(Example 1) and 5 mL of a 100 m~l aqueous solution of
GdC13 are mixed thoroughly and the pH is adjusted to pH
6.9 with lN NaOH to yield the title ~roduct.
Exam~le 16
rGd[181(Me)4N6H4O4(~Y)2
5 mL of a lOO mM aqueous solution of [18](Me)4N6O4(py)2
(Example 2) and 5 mL of a lO0 mM aqueous solution of
GdC13 are mixed thoroughly and the pH is adjusted to pH
6.9 with lN NaOH to yield the title ~roduct.
The Tl relaxivity in mMls1, measured in water at 10 MHz
and 37 C was 1.7.
ExamPle 17
Gd[l21N4(Py)o3
1.902 g (5 mmol) of [12]N403(py) (E~ample 3) was
dissolved in water (3 ml). Gd2O3(915 mg; 1.01 eq) was
added and the volume made up to 8 ml with water. This
was then stirred for 2 hours at 100~C. Using Xylenol
orange as an indicator, further [12]N403(py) was added
in small aliquots until a negative test result was
2~7~7:L
WO91/10~5 PCT/EP91/00126
- 60 -
achieved. A titration of excess ligand with GdC13 was
used to check for less than 0.05% ligand excess. The
solution was then diluted to 10 ml with water to pro~uce
a 350 mM solution of Gd[12]N403(py). Finally the pH was
adjusted to 6.2 ~ith lM ~1aOH.
The Tl and T2 relaxivities of the chelate, in mMlsl
measured in water at 10MHz and 37C were respectively
6.99 and 6.23.
Example ~8
Gd[151N_23(~
To a suspension of 1,4,7,10,13-pentaazabicyclo[11.2.2]-
heptadecane-4,7,10-tris(acetic acid) (1.0 g, 2.4 mmol)
(Example 4) in water (1 ml) is added Gd2O3 (0.24 g, 1.2
mmol) with stirring. The mixture is heated at 75C
overnight. Evaporation to dryness gives the title
product.
.
Example 19
(Mn r 181(Me)4_6H4O4(~y)2)Na2
The title compound is prepared analogously to that of
Example 16 by reaction of the chelant of Example 2 with
MnC12.
.
"' ' "' ' ' ~'
,
207~171
. .
WO91/10~ PCT/EP91/00126
- 61 -
Example 20
GdBis(py)DTTA
N,N"-Bis(pyrid-2-yl-methyl)diethylenetriamine~
triacetic acid (2,8719 g, 6.25 mmol) (the compound of
Example 6) and gadolinium oxide (1.1328 g, 3.125 mmol)
were combined in 15 mL of water and heated at 95C for 4
hours to provide a solution of the desired comple~.
Relaxivity (water) at 10 MHz, 37~C : R1 = 3.65 ~M1sec
and R2 = 3.57 mMl secl.
Exam~le 21
(CaBis(py)DTTA~ Na
The title com~ound is prepared analogously to that of
Example 16 by reaction of the chelant of Example 6 with
. CaC12.
Example 22
,.
Composition comprising GdBis(py)DTTA and CaNa
; Bis(py)DTTA
-- --
The compounds of Examples 20 and 21 are admixed in a
95:5 (by weight) ratio and dispersed in water for
injections to a Gd content of 400 mM.
2a7~l7l
WO91/l0~5 PCT/EP9l/00126
- 62 -
Example 23
Gdtl71N5O3(PiP~
The title chelate is prepared analogously to that of
Example 16 by reaction of the chelant of Example 7 with
GdC13.
E~am~le 24
Mn[121,~~02
The titl~ c~elate is prepared analogous'y to that o-
Example 16 by reaction of the chelanl of Example 8 with
MnC12,
,
Example 25
MnL14~N402 (pip)
The title chelate is prepared analogously to that of
Example 16 by reaction of the chelant of Example 9 with
MnC12 .
Example 26
Mn~5]N5O2(py~tpip)
The title chelate is prepared analogously to that of
Example 16 by reaction of the chelant of Example 10 with
MnC12.
..
~07 ~ 171
,. ~
WO91/10~5 PCT/EP91/00126
- 63 -
Example 2?
Mn r 151 (Me) 2N52 (t~y~ (E)ip)
The title chelate is prepared analo~o~sly to that of
Example 16 by reaction of the chelant of Example 11 ~titn
MnCl2.
.
