Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-03-03
1996-07-23
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544663, C07D26502, A61K 31535
Patent
active
055389686
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/EP92/01762 filed Aug. 9, 1992.
The present invention relates to geneserine derivatives, a process for the preparation thereof and pharmaceutical compositions containing them.
The compounds of the invention have the following general formula I: ##STR2## wherein R is a straight or branched C.sub.2 -C.sub.20 alkyl group, a C.sub.3 -C.sub.7 cycloalkyl group, a phenyl or benzyl group, optionally substituted with C.sub.1 -C.sub.4 alkyl groups, halogen atoms, C.sub.1 -C.sub.4 alkoxy groups.
Preferably R is an alkyl group having 4 to 12 carbon atoms, most preferably 6 to 8 carbon atoms.
Compound I, in which R is an n-heptyl group, is particularly preferred.
The invention also comprise s the salts of compounds I with pharmaceutically acceptable acids, particularly hydrochloric, sulfuric, tartaric, succinic, maleic, citric, methanesulfonic, fumaric, acetic, lactic, salicylic acids.
The compounds of formula I and the pharmaceutically acceptable salts thereof have inhibiting activity against cholinesterase and they can usefully be administered to patients suffering from Alzheimer disease or from various other conditions deriving from a neurologic deficiency.
Alzheimer disease is a form of progressive dementia clinically characterized by loss of memory and impairment of the intellective activities.
The importance of the cholinergic system in Alzheimer disease is well known and the loss of the cholinergic function has been found to be related to both the presence of neuropathologic lesions and a severe loss of the cognitive functions.
On the basis of such evidences, one of the most studied therapeutical approaches is the cholino-mimetic one, intended to improve and increase the cholinergic activity.
The most promising results were obtained using cholinesterase inhibitors, particularly physostigmine and tacrine.
EP-A-0154864 and EP-A-0298202 disclose physostigmine derivatives characterized by an increased lipophilia, due to the presence of long-chain alkyl or aryl residues on the carbamoyl group which is typical of this class of alkaloids.
Geneserine, even though it has been known for many years as an anticholinergic agent and used in therapy as a gastrointestinal antispastic, has never been the object of studies in order to verify its capability to restore the cholinergic function at the level of central nervous system.
Now it has been found that geneserine derivatives of formula I have pharmacological properties which are particularly interesting and advantageous compared with the prior art compounds.
Compounds of formula I can be prepared by oxidizing compounds of formula II ##STR3## wherein R is as defined above.
The oxidation is preferably carried out by means of organic peracids or peroxides, such as m-chloroperbenzoic acid, monoperphthalic acid, peracetic acid, hydrogen peroxide, in inert solvents such as halogenated hydrocarbons, aromatic hydrocarbons, dimethylformamide, dimethylsulfoxide.
The preparation of compounds of formula II from physostigmine is known from EP-A-0154864 and EP-A-0298202, cited above.
Alternatively, compounds I can be obtained starting from geneserine by hydrolysis of the methylaminocarbonyloxy group and subsequent O-acylation with reagents capable of introducing the desired function ##STR4## wherein R is as defined above.
Examples of acylating reagent s which can conveniently be used for this purpose comprise alkylisocyanates of formula R-NCO, wherein R is as in formula I, or in alternative substituted imidazolureas of formula III ##STR5## which can be prepared from carbonyldiimidazole and amines of formula RNH.sub.2, wherein R is as defined above.
Hydrolysis of geneserine can be carried out analogously to that of physostigmine, by reaction with alkali alkoxides, whereas the O-acylation with the substituted imidazolureas is carried out in a strictly anhydrous medium, in the presence of metal sodium.
The resulting compounds I can then be salified with organic or inorganic non-toxic acids, according to the conventional techniques. Compounds I, for the envisaged therapeut
REFERENCES:
Robinson et al, Journal of Pharmacy and Pharmacology, 1968, 20S, 213S-217S.
Ligny et al, Chemical Abstracts 90: 162,308, abstract of French Patent FR 2 374 908 issued Jul. 1978.
Shishido et al, Journal of chemical Society, Perkin Trans., 1(11), Nov. 1987, 2491-2495.
Robinson et al., Journal of the Chemical society, Section C: Organic Chemistry, No. 15, 2077-2078, 1970.
Chiesi Paolo
Del Canale Maurizio
Ghidini Eleonora
Servadio Vittorino
Chiesi Farmaceutici S.p.A.
Grumbling Matthew V.
Shah Mukund J.
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