Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-11-30
1995-07-18
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514396, 514400, A61K 31415
Patent
active
054341779
DESCRIPTION:
BRIEF SUMMARY
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 halogen, such as F, Cl, Br or I, 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
Young adult (3 months) and aged (26 months) female Kuo:Wistar rats were used.
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.
The animals were anesthetized with chloral hydrate (350 mg/kg) and placed in a stereotaxic frame with the inc
REFERENCES:
patent: 4738979 (1988-04-01), Calderon et al.
patent: 5204364 (1993-04-01), Carganico et al.
CA: 115(23) 247997(a)-Servio et al (1991).
CA: 116(23) 228130s-Servio et al (1982).
CA: 117(1) 738 F-Servio et al (1992).
European Journal of Pharmacology, vol. 183, No. 3, 1990 Neiminen S. A. et al: "Effects of atipamezole, an alpha-2 antagonist, on memory retrieval in the rat", pp. 933-934.
Airaksinen Mauno M.
Lammintausta Risto A. S.
MacDonald Ewen
Miettinen Riitta A.
Nieminen Sakari A.
Cintins Marianne M.
Criares T. J.
Orion-yhtyma Oy
LandOfFree
Imidazoles for the treatment of age-related cognitive disorders does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Imidazoles for the treatment of age-related cognitive disorders , we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Imidazoles for the treatment of age-related cognitive disorders will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2419135