Gadolinium complex tetramides and use in medical imaging

Details Gadolinium complex tetramides and use in medical imaging Gadolinium complex tetramides and use in medical imaging

2001-11-21

2004-12-07

Hartley, Michael G. (Department: 1616)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

Magnetic imaging agent

C540S474000

Reexamination Certificate

active

06827927

ABSTRACT:

The present invention relates to tetramides which are derived from the pair of RRRR/SSSS enantiomers of tetra(&agr;-carboxyethyl)gadoterate, represented by the formulae
It is disclosed in EP 0 661 279 that the amides of formula II
in which R is a bulky hydrophilic group with a molecular mass or greater than 200, exhibit a longitudinal relativity r
1
which is markedly superior to those of the chelates not carrying the bulky side group (CH
2
)
2
CONHR and can be used as contrast agents in magnetic resonance diagnostic imaging.
WO 97/01359 relates to the products of formula II in which R is a group of formula
Application EP 98 403108 of Dec. 9, 1998 relates to the products of formula II in which R is the following group
It is known that the relaxivity r
1
of a gadolinium chelate is a complex function of various more or less independent factors, including the electronic correlation time, rotation correlation time and water exchange time, which factors depend in particular on the spatial structure of the chelating agent around the paramagnetic cation, so that 2 stereoisomers can have substantially different relaxivities.
Furthermore, it is essential for the specific characteristics of a pharmaceutical product to be reproducible in terms of effectiveness and of toxicity between successive manufacturing batches and it can be difficult to ensure such reproducibility in the presence of numerous stereoisomers because of their substantial differences in chemical reactivity and in physical properties.
It was thus desirable to find a process which makes it possible, at the industrial stage under acceptable economic conditions, to obtain a mixture of stereoisomers of the amides of formula II in exactly defined proportions and thus to isolate, with good yields, one of the possible racemic compounds which does not comprise the other stereoisomers and which exhibits an advantageous relaxivity r
1
in the range of the fields currently used clinically, namely between 0.5 and 1.5 tesla.
The racemic compounds according to the invention are represented by the formula III
in which R is a phenyl group or (C
1
-C
8
) alkyl group which are substituted or interrupted by one or more groups selected from phenyl, alkyl, oxy, amino or amido groups, which may or may not be substituted by alkyl, it being possible for the phenyl groups to be substituted by OH, Br, Cl, I, (C
1
-C
8
)alkyl, (C
1
-C
8
)alkyleneoxy, NO
2
; NR
x
R
y
, NR
x
COR
y
, CONR
x
R
y
or COOR
x
, R
x
and R
y
being (C
1
-C
8
)alkyl or H,
and it being possible for the linear or branched or cyclic alkyl groups to be hydroxylated,
and the salts of these acids with inorganic or organic bases, such as NaOH, KOH, N-methylglucamine, tris-(hydroxymethyl)aminomethane, lysine or diethanolamine.
Preference is given, among these, to the compounds in which
R is a group of formula
 in which X is Br or I, R
1
is H, (C
1
-C
3
)alkyl or (C
2
-C
8
)mono- or polyhydroxyalkyl and R
2
is (C
2
-C
8
)mono- or polyhydroxyalkyl, or else R
1
is H and R
2
is a group of formula
X being as defined above and R′
1
and R′
2
taking any one of the meanings given for R
1
and R
2
, with the exception of A, it being understood that —CO—NR
1
R
2
or —CO—NR′
1
R′
2
comprise at least two hydroxyl groups, and those in which R is a group
in which a is 1 or 2,
Z is a bond, CH
2
, CH
2
CONH or (CH
2
)
2
NHCO,
Z′ is a bond, O, S, NQ, CH
2
, CO, CO—NQ, NQ—CO, NQ—CO—NQ or CO—NQ—CH
2
—CONQ,
Z″ is CO—NQ, NQ—CO, CO—NQ—CH
2
—CO—NQ or NQ—CO—CH
2
—NQ—CQ, with Q being H or an optionally hydroxylated (C
1
-C4) alkyl group,
R
1
, R
2
, R
3
, R
4
and R
5
, independently of one another, are selected from H, Br, Cl, I, CO—NQ
1
Q
2
or N(Q
1
)—CO—Q
2
, and Q
1
and Q
2
, which are identical or different, are selected from optionally hydroxylated (C
2
-C
6
) alkyl groups optionally interrupted by an oxygen atom, so that Q
1
and Q
2
together comprise from 4 to 10 OH groups, it being understood that at least 1 and at most 2 R
1
, R
2
, R
3
, R
4
and R
5
groups are amide groups.
The racemic compounds of the invention can be prepared by a method known per se by reaction of the amine RNH
2
with the pair of complexes of the enantiomeric octaacids of formula I in aqueous solution with an agent which activates carboxyl functional groups under conventional conditions for peptide condensations, as disclosed in the abovementioned patents, for mixtures of isomers.
Some of the isomers of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(2-glutaric acid), obtained by hydrolysis of the corresponding ethyl esters, separated by silica liquid chromatography and crystallization from water, have been described by Judith A. K. Howard et al. in Chem. Commun., 1381-1382 (1998).
A process which can be operated industrially has now been found which makes it possible to obtain the pair of RRRR/SSSS enantiomers starting from the mixture of the stereoisomers of the gadolinium complex of this octaacid resulting from the substitution, by a conventional method, of the nitrogen atoms of 1,4,7,10-tetraazacycladodecane. It consists in carrying out the isoomerization by simple heating in aqueous solution at acidic pH, preferably between 2 and 4.5 and better still between 2.5 and 3.5, and at a temperature of greater than 70° C., preferably of greater than 90° C. and better still at reflux of the solution, for the time needed to obtain the racemic compound of the invention, i.e. from a few hours to a few days, in particular 35 to 45 hours at reflux at approximately pH 3.
The starting mixture of the stereoisomers can be obtained by the action of the compound of formula R′OOC—CHX—(CH
2
)
2
—COOR′, in which R′=H or (C
1
-C
3
)alkyl and X is a leaving group in a nucleophilic substitution, in particular a halogen atom, preferably bromine, or a sulphonate or tosylate or triflate group, which reaction is followed by the hydrolysis of the ester functional groups, in particular by the action of an alkaline carbonate or hydroxide in an alcoholic, agueous/alcoholic or aqueous medium.
A person skilled in the art will select, during preliminary trials, the concentration of the solution, the pH, the temperature and the duration of the heating in order to carry out complete isomerization without significant decomposition, in particular according to the product and the amount treated.
It is surprising that, under these conditions, the chelate is not decomplexed and that the decomposition of the ligand is negligible and that, in addition, the pair of enantiomers which is finally isolated comprise less than 15% of the 3 pairs formed on conclusion of a conventional synthesis, which consists in hydrolysing, in basic medium, the product obtained by reaction of ethyl 2-bromoglutarate with the heterocycle and in then carrying out its complexation by the action of GdCl
3
or to Gd
2
O
3
.
Thus, according to another of its aspects, the present invention relates to a process comprising the stages consisting:
1—in keeping an aqueous solution of the mixture of the stereoisomers of the gadolinium complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(2-glutaric acid), with a pH of between 2 and 4.5, at a temperature of greater than 70° C. for a few hours to a few days, so as to obtain the racemic mixture of octaacids of formula:
2—in reacting this mixture with the amine RNH
2
, R being defined above for the Formula III, with an agent which activates the acid functional group.
The starting mixture of the stereoisomers of the gadolinium complex of 1,4,7,10-tetraazacyclododecane-4,7,10-tetra(2-glutaric acid) of formula;
can be obtained in a simple fashion by employing a process comprising the stages consisting in:
reacting 1,4,7,10-tetraazacyclododecane with a compound of formula R′OOC—CHX(CH
2
)
2
—COOR′ in which R′ is a hydrogen atom or (C
1
-C
3
)alkyl and X is a leaving is group;
conventionally hydrolysing the ester functional group of the resulting compound when R′ is other than H; and
complexing the compound thus obtained with the gadolinium ion.
M

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