Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-08-12
1999-10-12
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 63, A61K 31645, C07D22122
Patent
active
059655690
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE ART
The present invention relates to some new polycyclic aminopyridine compounds and to their pharmaceutically acceptable salts which are inhibitors of the enzyme acetylcholinesterase, with therapeutic benefit in the treatment of memory dysfunctions such as senile dementia or Alzheimer's disease in which medicaments capable of increasing the level of the neurotransmitter acetylcholine in the central nervous system are indicated.
PRIOR ART
Hershenson et al., J. Med. Chem. 29, 1125-1130 (1986), reported that the acetylcholine level is decreased in the brain of patients with Alzheimer's disease and have studied the benefit of physostigmine, which is an inhibitor of the enzyme acetylcholinesterase, in the treatment of the said patients.
W. K. Summers et al., Clin. Toxicol., 16, 269 (1980), reported that the known acetylcholinesterase inhibitor called tacrine, 9-amino-1,2,3,4-tetrahydroacridine, of formula ##STR2## administered intravenously in combination with lecithin, proves useful in the treatment of Alzheimer's disease although it has the drawback of its high toxicity.
Subsequently, G. M. Shutske et al., J. Med. Chem. 32, 1805-1813 (1989), described 9-amino-1,2,3,4-tetrahydro-1-acridinol derivatives which also display acetylcholinesterase-inhibiting activity, and the Patents or published Patent Applications U.S. Pat. No. 4,546,104, EP-A-0268871, U.S. Pat. No. 4,735,953, U.S. Pat. No. 4,753,950, U.S. Pat. No. 4,762,841, EP-A-394950 and JP-A-03002166 describe other compounds related to the abovementioned chemical structures which also display acetylcholinesterase-inhibiting activity.
For their part, the authors of the present invention have described, in Patent Application WO 93/13100, a process for obtaining bispyridine derivatives with acetylcholinesterase-inhibiting activity.
Another known inhibitor of the abovementioned enzyme is the product called huperzine A, of formula ##STR3##
In any case, the need remains for alternative new compounds which are more effective as acetylcholinesterase inhibitors, and which permit an ever more effective and safe treatment of such serious and socially damaging diseases as Alzheimer's disease.
The authors of the present invention have discovered a group of new polycyclic aminopyridines, some of which compounds prove much more effective than tacrine in their acetylcholinesterase-inhibiting action.
SUBJECT OF THE INVENTION
The subject of the present invention is new polycyclic aminopyridine compounds and their pharmaceutically acceptable salts with high inhibitory efficacy against the enzyme acetylcholinesterase.
Another subject of the present invention is the use of the new polycyclic aminopyridine compounds and their pharmaceutically acceptable salts in the preparation of medicaments against memory disorders such as senile dementia or Alzheimer's disease, as well as the pharmaceutical compositions containing them.
Yet another subject of the present invention is a process for obtaining the abovementioned new compounds.
DESCRIPTION OF THE INVENTION
The new aminopyridine compounds which are the subject of the present invention correspond to the general formula (I): ##STR4## in which R can be hydrogen, alkyl, aralkyl or acyl;
R.sub.1 and R.sub.2 can be, independently, hydrogen, alkyl, aralkyl, alkoxy, alkoxycarbonyl, amino or amino substituted with one or two alkyl, aralkyl or acyl groups;
m and n can adopt the values 1, 2 or 3;
X and Y can be, independently, a bond between two carbons, an oxygen or sulphur atom, a group N--R.sub.3 or an alkylene or alkenylene bridge containing from 1 to 5 carbon atoms and which can contain one or more substituents R.sub.4. When X is an alkenylene group, the latter can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring system, it being possible for the ring to be substituted with one or more groups R.sub.5 ; for example, X can be an ortho-phenylene group; ##STR5## p, q and r having a value equal to or greater than one and R.sub.6 and R.sub.7 being substituents which can individually be hydrogen, ha
REFERENCES:
patent: 4695573 (1987-09-01), Shutske et al.
patent: 5104880 (1992-04-01), Kozikowski
patent: 5106979 (1992-04-01), Kozikowski et al.
Wyngaarden, J.B. et al, Cecil Textbook of Medicine, 19th edition, W.B. Saunders Co., 1992, pp. 2075-2079.
Aquado, F., et al., "Synthesis and evoluation of tacrine-related compounds for the treatment of Alzheimer's desease"European Journal of Medical Chemistry, vol. 29, 1994, pp. 205-221.
Badia Sancho Albert
Banos Diez Josep Eladi
Camps Garcia Pelayo
Contreras Lascorz Joan
El Achab Rachid
Aulakh Charanjit S.
Medichem S.A.
Rotman Alan L.
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