Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-01-17
1999-02-09
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142315, 5142318, 5142355, 5142358, 5142378, 5142392, 5142395, 544 87, 544121, 544128, 544130, 544162, 544164, 544168, A61K 31535, C07D26532, C07D41300, C07D26530
Patent
active
058694846
DESCRIPTION:
BRIEF SUMMARY
PRIOR ART
Various memory disorders and particularly the senile dementia of Alzheimer kind are characterized by a reduction in some cerebral areas of the acetylcholine neurotransmitter levels. In these situations the acetylcholinesterease inhibition, enzyme hydrolizing the acetylcholine, turns out useful for therapeutic aims.
It is known that the physostigmine is a powerful natural inhibitor of the acetylcholinesterase and various clinical studies showed that it gives beneficial results in the treatment of the patients affected by mental pathologies. However the physostigmine has unfavourable pharmacokinetic characteristics and side-effects as to make not very easy its clinical use.
It is also known that eptastigmine or heptylcarbamic ester of the eseroline (EP 0154864), even if it is an acetylcholinesterase inhibitor less powerful "in vitro" than the physostigmine, has with respect to it better pharmacokinetic characteristics and reduced side-effects. Moreover other drugs, such as for example Tacrine (New Engl. J. Med., 315, 1241 (1986)), Velnacrine (U.S. Pat. No. 4,631,286), RA.sub.7 (EP 193926), E2020 (EP 296560) are in advanced clinical study for the Alzheimer's disease therapy.
They showed some efficacy but at times together with heavy side-effects too, for example Tacrine and Velnacrine induce high transaminase levels (Eur. Neuropsychopharmacol., 1(3), Abst. S-7-2 (1991)).
Then the search for new substances having activity inhibiting the acetylcholinesterase and low toxicity is more and more topical.
SUMMARY
A new class of anticholinesterase compounds which show a higher activity and side-effects lower than the known compounds and moreover have the advantage to be prepared with a simple and economical process has now been found. Moreover some of them carry on a selective activity on the AChE without modifying the BuChE.
Said class of compounds, derivatives of the phenylcarbamate, has the following general formula ##STR2## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4, equal or different, represent: hydrogen, linear or branched (C.sub.1 -C.sub.4) alkyl, cycloalkyl (C.sub.3 -C.sub.6), aryl (C.sub.1 -C.sub.4) alkyl, hydroxyl, or R.sub.1 and R.sub.2 together are --(CH.sub.2).sub.m -- wherein m is an integer number from 3 to 6 and form a cycle from 3 to 6 carbon atoms; branched alkyl (C.sub.1 -C.sub.6), aryl (C.sub.1 -C.sub.6) alkyl, acyl or the group: ##STR3## is a radical derivatived from the morpholine, piperidine, tetrahydroquinoline, tetrahydroisoquinoline, alkylpiperazine, arylpiperazine, arylalkylpiperazine, acylpiperazine, the dialkylaminoalkyl group being in para or meta position with respect to the carbamic group; alkyl; ##STR4## wherein R.sub.8 and R.sub.9, equal or different, represent: linear or branched (C.sub.1 -C.sub.4) alkyl, halogen, methoxy, nitro, trifluoromethyl; arylalkyl; -C.sub.4) alkyl, arylalkyl, methoxyethyl, methoxypropyl, methoxybenzyl; ##STR5## group is an heterocyclic group such as for example ##STR6## provided that when R.sub.3 .dbd.R.sub.4 .dbd.H, R.sub.1 and R.sub.2 cannot both be H, and when R.sub.7 is H and n is O, X cannot be methyl.
The compounds having general formula (I) may be salified with pharmacologically acceptable acids selected from the group comprising HCl, HBr, H.sub.2 SO.sub.4, H.sub.3 PO.sub.4, HClCO.sub.4, CH.sub.3 SO.sub.3 H, p-toluenesulfonic acid, citric acid, tartaric acid, maleic acid, salicylic acid, fumaric acid, succinic acid, oxalic acid, and so on.
The compounds of the present invention, due to the anticholinesterase activity may be used in human therapy for the treatment of those pathologies which benefit from an acetylcholine increase such as for example the Alzheimer's disease.
DETAILED DESCRIPTION OF THE INVENTION
The characteristics and the advantages of the phenylcarbamate derivatives for the use as anticholinesterase substances according to the present invention, and also the process for their preparation, will be mainly pointed out in the course of the following detailed description.
The compounds of the present invention have the
REFERENCES:
Podyani;Acta Pharm. Hung. (1992), 62(5), 218-24, 1992.
"Heterocycles", vol. 110, 1989, p. 673.
Davies, Robert E., et al: "Investigations on the Influence of Chemical Constitution upon Toxicity", Part III., pp. 191-196, 1947.
Chemical Abstracts Service, Registry Handbook, Number Section, 1977 Supplement, Registry Numbers 63306-25-2 through 65229-05-2.
Brufani Mario
Maiorana Stefano
Mairani Lucia
Mandelli Giacomina
Marchesini Donata
Kifle Bruck
Mediolanum Farmaceutici S.p.A.
Shah Mukund J.
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