Tropane derivatives useable in particular for in vivo...

Details Tropane derivatives useable in particular for in vivo... Tropane derivatives useable in particular for in vivo...

1998-11-10

2001-01-30

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C514S186000, C546S010000, C546S132000

Reexamination Certificate

active

06180083

ABSTRACT:

TECHNICAL FIELD
The present invention relates to tropane derivatives which may be radioiodinated and used as iodinated radioligands for SPECT visualization (Single Photon Emission Computed Tomography) of dopamine transporters at the level of the central nervous system.
Dopamine is a neurotransmitter which is synthetized at the presynaptic neurone where it is stored. When the neurone is stimulated, dopamine is released in the synaptic gap where it diffuses. One part interacts with the receptors of the postsynaptic neurone. This interaction produces intracellular biochemical reactions which, among others, lead to propagating the nerve signal. The major part is received by the presynaptic neurone via a transporter. Inhibition of dopamine transport, by cocaine derivatives in particular, leads to an increase in dopamine level at the postsynaptic terminal of the neurone. Anomalies in dopaminergic neurotransmission are involved in neurodegenerative and psychiatric disorders such as Parkinson's and Alzheimer's disease and schizophrenia. Given the important part played by the dopamine transporter in regulating neurotransmission, the development of radioligands emitting gamma rays able to fix themselves onto the dopamine transporter with strong affinity and selectivity is necessary for visualizing this transporter for the purpose of early diagnosis of these diseases and the assessment of :
density changes in dopamine transporters over the course of the disease, and
follow-up of patient treatment
STATE OF THE PRIOR ART
For this purpose, several types of ligands have been studied, such as the derivatives of GBR having the formula:
As an example of such derivatives, the following compounds can be cited which meet the above formula :
GBR 12935:X═X═H; Y═—(CH
2
)
3
— Kd=5.5 nM (Andersen 1987)
GBR 12783:X═X′H: Y═—CH
2
—CH═CH— Kd=1.6 nM (Bonnet and Constantin 1986)
These types of compounds have very good in vitro affinity for the dopamine transporter. Nonetheless, in vitro competition studies with an Nonetheless, in vitro competition studies with an iodinated analogue of GBR 12783 (Foulon 1992) have shown a substantial loss in the affinity for the dopamine transporter. Also, brain biodistribution studies in rats have shown considerable non-specific fixation.
More recently, the use of iodinated analogues of cocaine has been suggested which all have the basic structure of tropane, shown below:
in which X, R and Z may be various substituents.
Compounds of this type are described in documents WO-A-92/02260
(1)
, WO-A-93/09814
(2)
, WO-A-93/18033
(3)
, WO-A-94/04146
(4)
, WO-A-95/11901
(5)
, J. of Med. Chem., 1992, Vol 35, n°6, pages 969-981
(6)
, J. Med. Chem., 1994, 37, pages 1535-1542
(7)
, J. Med. Chem., 1995, 38, pages
379-388(8)
and J. Med. Chem., 1996, 39, pages 543-548
(9)
.
Among these tropane derivatives, a distinction can be made between a first family of compounds in which X of the above formula represents CH
3
and Z represents a phenyl group which may or may not be substituted, and a second family of compounds in which the may be substituted by an iodine atom and Z represents a substituted phenyl group.
Among these derivatives, those of the first family in which Z represents a phenyl group substituted by an iodine atom, have undergone particular development, for example compound RTI 55 or &bgr;-CIT described in WO-A-92/02260
(1)
. However, this compound has the disadvantage of not having sufficient selectivity for dopamine transporters since it also fixes itself to serotonin transporters. Therefore, to visualize the dopamine transporter system, it is necessary to wait sufficient time until the non-specific fixation of this derivative on the serotonin transporters is eliminated .
The derivatives of the second family such as iodoaltropane (X=iodopropenyl, Z=parafluorophenyl) described in WO-A-95/11901
(5)
and in J. Nucl. Med., 1996, 37, pages 1197-1202
(10)
, and [
125
I] IPT (X=iodopropenyl, Z=p-chlorophenyl) described in document J. Med. Chem. 1994, 37, pages 1535-1542
(7)
and Synapse, 1995, 20, pages 316-324
(11)
show affinity and specificity for dopamine transporters. However, it would be of advantage to improve this affinity, this specificity and the kinetic properties of compounds of this type so as to make available more efficient radioligands with which visualization of the dopamine transporter systems can be obtained more quickly.
DISCLOSURE OF THE INVENTION
The object of the present invention is precisely new derivatives of tropane which have better properties than known compounds, in respect of fixation kinetics in the brain, affinity for dopamine transporters and specificity for these transporters compared with those for serotonin. Also, these new derivatives may be used to diagnose diseases such as Parkinson's disease.
Therefore the object of the invention is a compound with the formula:
in which:
R
1
represents I, a radioactive isotope of I or a group with the formula Sn (R
3
)3 in which R
3
is an alkyl group;
R
2
represents H ; an alkyl group in C
1
to C
6
; a phenyl group; a phenyl group substituted by a halogen atom, a methyl group or a methoxy group; a phenalkyl or phenylalkenyl group whose alkyl or alkenyl group comprises 1 to 6 carbon atoms and whose phenyl group may be substituted by a halogen atom; a cycloalkyl group in C
3
to C
8
or an alkynyl group;
X represents H, I, F, Cl, Br, —CH
3
, —OCH
3
, —C
2
H
5
, —CF
3
, —OH, —NH
2
, —NO
2
, —CN, —NCS, N
3
, —NHCOCH
3
or —OCOCH
3
; and
Y represents a hydrogen, chlorine, iodine or bromine atom, or the methyl group, provided that X does not represent F or Cl when Y represents H.
This compound is therefore a derivative of tropane in which the labeller (radioactive isotope of iodine) is fixed via a propenyl group onto the nitrogen atom of the basic tropane structure, the tropane being substituted in addition by a non-substituted phenyl group or substituted by one or two substituents.
Preferably, in formula (I) given above, R
2
represents an alkyl group, in particular the methyl group.
Again preferably, in formula (I) given above, the phenyl group is non-substituted or substituted in para position by CH
3
, I, CF
3
, C
2
H
5
or NH
2
.
According to one variant of embodiment of the invention, the phenyl group comprises two substituents of which one is a halogen. For example X represents Cl or F and Y represents CH
3
, or X represents NH
2
and Y represents Br or I.
When R
1
represents a radioactive iodine atom, the latter may be
125
I,
123
I or
131
I as these isotopes are suitable for in vivo visualization of dopamine transporters at SPECT (Single Photon Emission Computed Tomography) owing to their relatively short radioactive period.
For this study, the compounds of the invention may be used in the form of pure isomers or a mixture of isomers. However, better results are obtained when a compound with R
1
in position E is used.
R
1
may also represent the group Sn (R
3
) with R
3
being an alkyl group preferably having 1 to 8 carbon atoms, for example the n-butyl group. Such derivatives are intermediate products of interest in the preparation of iodinated and radioiodinated derivatives.
The compounds of the invention may be prepared by conventional processes such as that described by Goodman et al in J. Med. Chem., 1994, 37, pages 1535-1542. This synthesis corresponds to the reaction diagram illustrated in FIG.
1
.
Owing to their specificity and their affinity for dopamine transporters, the compounds of the invention may be used in pharmaceutical and radiopharmaceutical compositions. Such compositions comprise the compound of formula (I) described above in which R
1
represents I or a radioactive isotope of I, and R
2
, X and Y have the signification given above, and a pharmaceutically acceptable vehicle. In radiopharmaceutical compositions, R
1
represents a radioactive isotope of I.
These compositions may, in particular, be in the form of injectable solutions comprising from 10
−5
to 10
−

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