New pyrrole alkaloid daminin and its derivatives, are intracellular calcium ion concentration reducing neuroprotective agents useful for treating neurodegenerative diseases, e.g. Alzheimer's disease

摘要

New pyrrole alkaloids (I) consist of the parent compound 1-(2-(pyrrol-3-ylcarbonyloxy)-ethyl)-pyridinium-3-carboxylate (designated daminin) and its derivatives. Pyrrole alkaloids of formula (I) are new. R 1- R 11, X : H, optionally substituted 1-18C alkyl (including cycloalkyl), alkenyl, optionally substituted aryl (including heteroaryl), optionally substituted benzyl, acyl (e.g. CHO, COMe, COCCl 3, fumaryl, maleyl, succinyl, COPh or branched, heteroatom-containing or aryl-substituted acyl), OH, SH, alkoxy (including cycloalkoxy, e.g. 1-4C alkoxy), alkylthio (e.g. SMe or SEt), substituted sulfonyl (e.g. SO 3H, SO 2Me, SO 2CF 3, SO 2C 6H 4Me or SO 2C 6H 4CH 2Br), nitrogen substituent (e.g. NH 2, NHR, NRR', NC or NO 2), halo, CN or hetero-substituent; R, R' : alkyl or aryl; provided that (i) if R 6is different from R 7, R 4is different from R 5or R 1- R 3or R 8- R 11are sterically hindered aryl groups, then (I) may be centro- or axially chiral, and all stereoisomers and racemic mixtures are included, (ii) two or more substituent groups may be linked to form aromatic, heteroaromatic or saturated rings and (iii) agelongin of formula (I; X = O -; R 2= Br; R 1, R 3- R 11= H) is excluded. Independent claims are included for the preparation of (I). [Image] ACTIVITY : Neuroprotective; cerebroprotective; nootropic; neuroleptic; antiparkinsonian. MECHANISM OF ACTION : Reduction of intracellular calcium ion concentration. Daminin (Ia) reduced the increase in intracellular calcium ion concentration in cultured neurones caused by the N-methyl-D-asparate (NMDA) agonist L-glutamate. Pre-incubation of neurones with (Ia) at a concentation of 0.5, 1.0 or 3.0 mu g/ml for 5 minutes before incubation with L-glutamate caused dose-dependent inhibition of the L-glutamate-induced increase in the intracellular calcium ion concentration, the degree of inhibition being almost 100% using (Ia) at 3.0 mu g/ml.