Imidazoles for the treatment of age-related cognitive disorders and alzheimer

This invention relates to the use of a compound of formula ##STR1## wherein X is --CH.sub.2 -- or ##STR2## R.sub.1 is H, C.sub.1-5 -alkyl or benzyl, which can be substituted of unsubstituted; R.sub.2 is H, C.sub.1-4 -alkyl, C.sub.1-4 -alkenyl, OH, or C.sub.1-3 -alkoxy; R.sub.3 is H, CH.sub.3, C.sub.2 CH.sub.3, OCH.sub.3, or Hal; R.sub.4 H, CH.sub.3, C.sub.2 CH.sub.3, OCH.sub.3, or Hal, and Hal is halogen, provided that when R.sub.2 is OH or C.sub.1-3 -alkoxy then X cannot be CO or a non-toxic pharmaceutically acceptable salt thereof for the use in the treatment of age related memory impairment or cognitive disorders, particularly Alzheimer's Disease.

This invention relates to the use of a group of certain .alpha..sub.2 
-receptor antagonists for the treatment of age related memory impairment 
and other cognitive disorders, particularly Alzheimer's Disease. 
The active compounds of the invention are imidazole derivatives which are 
potent and selective .alpha..sub.2 -receptor antagonists and have the 
general formula: 
##STR3## 
wherein X is --CH.sub.2 -- or 
##STR4## 
R.sub.1 is H, C.sub.1-5 -alkyl or benzyl, which can be substituted or 
unsubstituted 
R.sub.2 is H, C.sub.1-4 -alkyl, C.sub.1-4 -alkenyl, OH or C.sub.1-3 -alkoxy 
R.sub.3 is H, CH.sub.3, CH.sub.2 C.sub.3, OCH.sub.3 or Hal 
R.sub.4 is H, CH.sub.3, CH.sub.2 C.sub.3, OCH.sub.3 or Hal, and Hal is 
halogen, such as F, Cl, Br or I, 
provided that when R.sub.2 is OH or C.sub.1-3 -alkoxy then X cannot be CO, 
and their non-toxic, pharmaceutically acceptable salts. 
The compounds of the formula (I) form acid addition salts with both organic 
and inorganic acids. They can thus form many pharmaceutically usable acid 
addition salts, as for instance, chlorides, bromides, sulfates, nitrates, 
phosphates, sulfonates, formates, tartrates, maleates, citrates, 
benzoates, salicylates, ascorbates and the like. 
Certain members of the above compounds have been earlier disclosed e.g. in 
EP 183492 and EP 247764 as selective .alpha..sub.2 -antagonists valuable 
as antagonists to veterinary sedatives and analgetics.

According to this invention compounds of formula (I) have been found to 
possess valuable pharmacological activities and they are thus believed to 
be useful in the treatment of age related memory impairment and their 
cognitive disorders. 
Preferably R.sub.1 is hydrogen, methyl or ethyl. If R.sub.1 is benzyl it 
may optionally be substituted by one or more substituent chosen from 
C.sub.1-4 alkyl, halogen and C.sub.1-3 alkoxy. Preferably R.sub.2 is H, 
methyl, ethyl, methoxy or ethoxy, most preferably methyl or methoxy. 
R.sub.3 and R.sub.4 are preferably H. 
Particularly valuable compounds of formula (I) are atipamezole or 
4-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole, MPV-1260 BI or 
1-methyl-4-(2-methoxymethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole and 
MPV-1705 AI or 2-ethyl-2-(1-ethyl-1H-imidazole-4-yl)-1-indanone. 
Anatomical and electrophysiological properties of noradrenergic neurons 
projecting from the locus coeruleus of the forebrain suggest that this 
system plays a role in selective attention, learning and memory. 
Dysfunction of the noradrenergic system, possibly in conjunction with 
dysfunction of the cholinergic system, may also underlie some aspects of 
age-related cognition deficits. 
Impairment in cognitive functions, induced by pharmacological (e.g. 
scopolamine) or surgical manipulation (e.g. cholinergic nucleus basalis 
lesion) or age-related, have been shown to be associated with marked 
alterations in cortical EEG-recordings (increase in slow wave activity and 
number of high voltage spindles). 
It has now been shown that the incidence of high voltage spindles is high 
in a sub-population of aged rats which shows impaired memory performance 
in the passive avoidance test. Compounds of this invention were able to 
markedly decrease the incidence of high voltage spindles in these animals. 
Pre-retention test injections of the compounds also improved passive 
avoidance performance. 
Methods 
Subjects: 
Young adult (3 months) and aged (26 months) female Kuo:Wistar rats were 
used. 
Passive avoidance 
The passive avoidance apparatus consisted of a rectangular plexiglass box, 
divided into dark and lighted compartament by a sliding guillotine door. 
The dark compartament had a metal grid floor. Rats were placed in the 
lighted side. After 60 s a door opened into the dark side. 5 s after the 
entry to the dark side a 1.0 mA shock was delivered to the rat's feet. The 
shock remained on until the rat returned to the lighted side. Training 
continued until the rat remained on the lighted side for 60 s. Mean 
latency to first enter the dark chamber and number of re-entries were 
recorded during the training trial. Testing occured 6 days later. The rat 
was put on the lighted side and the door opened 60 s later. The session 
continued until the rat entered the dark side, or for 600 s. The latency 
to enter (retention latency) was recorded. 
Neurophysiology 
The animals were anesthetized with chloral hydrate (350 mg/kg) and placed 
in a stereotaxic frame with the incisor bar set at -3.3 mm. The active 
recording electrodes (stainless steel screws 0.5 mm in diameter) were 
located on the skull at the following coordinates: ML=3.0 mm, AP=2.0 and 
-7.0 mm relative to the bregma. The reference and ground electrodes were 
located in the midline above the cerebellum. The electrodes and connected 
female pins were embedded in dental acrylic. A recovery period of 7 days 
was allowed before any recording were taken. 
The EEG values of rats were taken between 1000-1400 h. The rats were 
allowed to move freely in a plexiglass cage. Samples were obtained 
simultaneously from frontal and occipital recording sites. The incidence 
and duration of spike and wave HVSs (high voltage spindles, Aston-Jones & 
Bloom (1981a), Journal of Neuroscience, 1, 876-886) were analysed from 
polygraph charts using a ruler. The rats were recorded 15 minutes after 
saline or atipamezole (3 mg/kg s.c.) injections. In separate experiments 
MPV-1260 BI (30 mg/kg p.o.) and MPV-1705 AI (6 mg/kg p.o.) or NaCl were 
administered and EEG recordings were taken 1 and 4 hours later. 
Results 
Table 1 discloses the positive effect of atipamezole on the PA performance. 
Table 2 shows that atipamezole alleviates the EEG change (increase in the 
number of HVSs) induced by high age in rat. Table 3 shows that MPV-1260 BI 
and MPV-1705 AI have a similar effect. 
TABLE 1 
______________________________________ 
Retention of the inhibitory avoidance task. 
Values are expressed as mean .+-. S.D. 
Group Latency to enter 
______________________________________ 
YC 352 .+-. 91 
YA 401 .+-. 33 
AC 164 .+-. 231* 
AA 330 .+-. 78 
______________________________________ 
*p &lt; 0.05, Duncan's test. 
Abbreviations: 
YC = young controls (n = 10) 
YA = young atipamezole 3 mg/kg (n = 10) 
AC = aged controls (n = 10) 
AA = aged atipamezole 3 mg/kg (n = 10) 
TABLE 2 
______________________________________ 
Effect of atipamezole on the number and duration 
(s) of high voltage spindles (HVS) in aged and 
young rats. Values are expressed as mean .+-. S.D. 
Number Duration (s) 
______________________________________ 
Y 3 .+-. 3 4 .+-. 2 
A 32 .+-. 34* 
4 .+-. 4 
AA 4 .+-. 9.cndot. 
3 .+-. 6 
______________________________________ 
*p &lt; 0.05 vs young rats, Duncan's test 
.cndot.p &lt; 0.05 vs HVS values of aged rats recorded after saline 
injections, Wilcoxon signed ranks test. 
Group abbreviations: 
Y = young rats, saline injections 
A = aged rats, saline injections 
AA = aged rats, atipamezole 3 mg/kg injections 
TABLE 3 
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The effect of .alpha..sub.2 -antagonists MPV-1260 BI and 
MPV-1705 AI on the number and duration of high 
voltage spindles in aged rats. 
Compound Number Duration (s) 
______________________________________ 
Control (n = 4) 
1 h 77 4.6 
4 h 88 5.7 
MPV-1260 BI 30 mg/kg (n = 4) 
1 h 17 3.7 
4 h 63 6.2 
Mpv-1705 AI 6 mg/kg (n = 4) 
1 h 5 3.4 
4 h 35 5.6 
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Pharmaceutical compositions for use in accordance with the present 
invention may be formulated in conventional manner using one or more 
physiologically acceptable carriers or excipients. The compounds of 
formula (I) and their physiologically acceptable salts are preferrably 
formulated for oral or parenteral administration. The pre#erable dose 
range is 0.1 to 1 mg/kg/day for parenteral administration and 1 to 10 
mg/kg/day for oral administration.