Imidazo(1,2-a)pyridines as peripheral benzodiazepine...

Details Imidazo(1,2-a)pyridines as peripheral benzodiazepine... Imidazo(1,2-a)pyridines as peripheral benzodiazepine...

2001-01-03

2002-04-30

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C546S121000

Reexamination Certificate

active

06379649

ABSTRACT:

TECHNICAL FIELD
The present invention relates to radiolabelled imidazo[1,2-a]pyridines and related compounds which bind to peripheral benzodiazepine receptors and are useful for imaging such receptors and providing therapeutic treatment including radiotherapy.
BACKGROUND OF THE INVENTION
The peripheral benzodiazepine receptors, which are also commonly referred to as the mitochondrial benzodiazepine receptors or &ohgr;-3-receptors, are distinct from the central benzodiazepine receptors in their pharmacology, subcellular location and structural requirements. Peripheral benzodiazepine receptors are predominantly found in the peripheral organs such as kidney, heart, adrenal cortex, testis, ovaries, plasma (platelets) as well as in the glial cells and olfactory bulbs in the brain. It has also been reported that peripheral benzodiazepine receptor density is higher in tumours, such as glioma, ovarian and colon carcinoma, than in corresponding normal tissue. Recently high concentration of peripheral benzodiazepine receptors has been reported in Dunning rat prostate tumours compared to the normal ventral or dorsolateral prostate.
The peripheral benzodiazepine receptors appear to be associated (but not exclusively) with the outer mitochondrial membrane in many tissues where they are modulated by hormones and drugs and reflect the effects of emotional stress, and hypertension. Peripheral benzodiazepine receptors in the brain have been investigated for use as markers of neurodegeneration including Huntington's disease, Alzheimer's disease, anxiety, stress, emotional disturbances, cognitive impairment, stroke, and cerebral ischemia. Several classes of ligands have been shown to exhibit high affinity binding to the peripheral benzodiazepine receptor, the most widely investigated being the benzodiazepine Ro 5-4864 (7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one) and the isoquinoline PK-11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide). Labelled with
11
C,
18
F and
123
I, these ligands have been used to map peripheral benzodiazepine receptors in the human heart and brain. Enhanced uptake of [
3
H]PK-11195 has been reported in a variety of tumour cells including breast, ovarian, prostate, adrenal, brain and colon. Radiolabelling with suitable levels of radioactive iodine may be used firstly to diagnose these tumours (using radiolabels such as
123
I or
131
I) and subsequently to treat them with therapeutic doses (for instance using
123
I,
125
I or
131
I). Furthermore, recent work has also revealed the existence of several binding domains which differ in affinity for isoquinoline and benzodiazepine ligands at different organs and species.
Various 2-aryl substituted imidazo[1,2-a]pyridines having anxiolytic, hypnotic, anticonvulsant, analgesic and other properties have been reported (Almirante L. et al.,
J. Med. Chem.
12 122-126 (1969); Langer S. Z. et al.,
Pharmacol. Biochem, Behav.
29 763-766 (1988); Langer S. Z. et al.,
Pharmacopsychiatry
23 103-107 (1990); Bourguignon, J-J., “Endogenous and Synthetic Ligands of Mitochondrial Benzodiazepine Receptors: Structure Affinity Relationships” in Giesen-Grouse. E. ed.
Peripheral Benzodiazapine Receptors
, Academic Press, London (1993)). For example
123
I labelled 6-methyl-2-(4′-iodophenyl)imidazo[1,2-a]pyridine-3-(N,N-dimethyl)acetamide has been reported as a potential tracer for the study of the peripheral benzodiazepine receptor using SPECT (Katsifis A. et al.,
J. Lab. Comp. Radiopharm.
40 620-622 (1997)).
However, the compounds which have been described previously typically exhibit strong binding to the central benzodiazepine receptors, even if they also bind to peripheral benzodiazepine receptors (see for example Anzini M. et al.,
J. Med. Chem.
39 4275-4284 (1996) and Trapani G. et al.
J. Med. Chem.
40 3109-3118 (1997)). Hence, the prior art compounds are not sufficiently selective for peripheral benzodiazepine receptors to be useful for diagnosis or therapy of conditions associated with a high density of those receptors. Thus there is a need for substances that bind strongly to peripheral benzodiazepine receptors but do not bind strongly to central benzodiazepine receptors.
Surprisingly, the present inventors have discovered that certain 2-(iodophenyl)-imidazo[1.2-a]pyridines having an electronegative substituent especially halogen, in the pyridine nucleus exhibit strong binding to peripheral benzodiazepine receptors and much weaker binding to central benzodiazepine receptors. Hence the compounds of the present invention have superior properties, as far as the PET and SPECT imaging of peripheral benzodiazepine receptors is concerned, compared to related substances which have been reported previously.
The compounds of the present invention, appropriately labelled, are clinically useful in SPECT and PET scanning, for example to detect those cancers which express high density of the peripheral benzodiazepine receptors and/or to detect, or non-invasively diagnose, neurodegenerative disorders. The compounds of the present invention are also useful for the treatment of disorders characterised by an abnormal density of peripheral benzodiazepine receptors, such as neurodegenerative disorders and tumours.
SUMMARY OF THE INVENTION
In a first embodiment, the invention provides a compound of formula (I)
wherein
Y is selected from F, Cl, Br, I, OH, SH, NH
2
, CN, and COOH;
Z is selected from N(R
3
)C(O)R
4
and C(O)NR
3
R
4
;
R
1
and R
2
are independently selected from (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
3
-C
6
)cycloalkyl, (C
6
-C
12
)aryl, (C
6
-C
12
)aryloxy, (C
6
-C
12
)aryl(C
1
-C
6
)alkyl, heteroaryl, heteroaryl(C
1
-C
6
)alkyl, heterocyclic, (C
2
-C
6
)alkanoyl and (C
2
-C
7
)acyl, each of which may be unsubstituted OF substituted with from 1 to 3 substituents selected from the group consisting of halogen, OH, (C
1
-C
4
)alkoxy, SH, NH
2
, (C
1
-C
4
)alkylamino, di((C
1
-C
4
)alkyl)amino, carboxy, (C
1
-C
4
)alkoxycarbonyl. (C
2
-C
4
)alkanoyl, oxo, amido, CN, CNS, SCN, CNO, OCN, and NHOH;
R
3
and R
4
are each independently hydrogen or a group selected from (C
1
-C
4
)alkyl, (C
2
-C
4
)alkenyl, (C
2
-C
4
)alkynyl, (C
3
-C
6
)cycloalkyl, (C
6
-C
12
)aryl, (C
6
-C
12
)aryl(C
1
-C
4
)alkyl, heteroaryl, heteroaryl(C
1
-C
4
)alkyl, heterocyclic, (C
1
-C
4
)alkoxycarbonyl and (C
2
-C
5
)acyl, each of which may be unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogen, OH, (C
1
-C
4
)alkoxy, SH, NH
2
, (C
1
-C
4
)alkylamino, di((C
1
-C
4
)alkyl)amino, carboxy, (C
1
-C
4
)alkoxycarbonyl, (C
1
-C
4
)alkanoyl, oxo, amido, CN, CNS, SCN, CNO, OCN, and NHOH,
or R
3
and R
4
together are (C
2
-C
7
) alkylidene which may be optionally substituted with from 1 to 3 substituents selected from the group consisting of halogen, OH, (C
1
-C
4
)alkoxy, SH, NH
2
, (C
1
-C
4
)alkylamino, di((C
1
-C
4
)alkyl)amino, carboxy, (C
1
-C
4
)alkoxycarbonyl, (C
1
-C
4
)alkanoyl, oxo, amido, CN, CNS, SCN, CNO, OCN, and NHOH;
m and n are independently 0, 1 or 2; and
p is 1.
In a second embodiment, the invention provides a compound of the first embodiment which is radiolabelled.
The invention further provides a pharmaceutical composition including a compound of the first or second embodiment together with at least one pharmaceutically acceptable carrier, diluent, excipient or adjuvant.
In a third embodiment, the invention further provides a method for diagnosis of a disorder in a mammal characterised by an abnormal density of peripheral benzodiazepine receptors, the method including the steps of:
administering to the mammal an amount of a radiolabelled compound of the second embodiment sufficient to allow a detectable image of the location of the radiolabel in the body of the mammal to be recorded;
recording a image of the distribution of the radiolabel in at least part of the body of the mammal; and
diagnosing the presence or absence of the dis

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