Israel Institute for Biological Research

Technion Research & Development Foundation Ltd

State of Israel, Represented by the Prime Minister's Office, Israel

State of Israel, Represented by Prime Minister's Office, Israel

Ishai Karton

Abraham Fisher

Eliahu Heldman

Aharon Levy

Yona Grunfeld

A pharmaceutical composition is disclosed comprising (-)-cis-2-methylspiro(1,3-oxathiolan-5,3')quinuclidine, and/or the pharmaceutically compatible acid addition salts thereof, together with at least one of physostigmine, tetrahydroaminoacridine, choline, lecithin, piracetam, aniracetam, pramiracetam, oxiracetam, 4-aminopyridine, 3,4-diaminopyridine, somatostatin, pirenzepine, N-methylatropine, N-butylscopolamine, scopolamine, clonidine, quanfamicine and Nerve Growth Factor. Also disclosed is a method for treating senile dementia of Alzheimer's type, which comprises coadministering to a patient in need thereof an effective dose of the spiro compound together with at least one other compound selected from those listed above.

Pharmaceutical composition comprising a spiro oxathiolon/quinuclidine

The invention relates to novel compounds (I) for treating diseases of the central and peripheral nervous system: ##STR1## including enantiomers, racemates and acid addition and quaternary salts thereof, wherein one of X and Y is O and the other of X and Y is N; Q is (CH.sub.2).sub.n or C(CH.sub.3).sub.2 where n is 1, 2 or 3 and the bridge --Q-- is attached at one end to position 1 and at the other end to position 4 or 5, and R.degree. is hydrogen, methyl or hydroxyl; in the moiety ##STR2## the line connecting Z and Y signifies a double bond when X--Z is O--C--R and Y is N, and a single bond when X--Z is N.dbd.C--R and Y is O; Z is C--R wherein R is selected from hydrogen, NH.sub.2, NH-R' (R'=C.sub.1-6 -alkyl), N(R').sub.2, R', C.sub.2-6 -alkenyl, C.sub.2-6 -alkynyl, C.sub.3-7 -cycloalkyl, R' substituted by hydroxy or by 1-6 halogen atoms, R'O-C.sub.1-6 -alkyl, carboxy-C.sub.1-6 -alkyl, R'OCO-C.sub.1-6 -alkyl, amino-C.sub.1-6 -alkyl, R''NH-C.sub.1-6 -alkyl, (R').sub.2 N-C.sub.1-6 -alkyl, 2-oxo-pyrrolidin-1-ylmethyl, aryl, diarylmethylol, and R' substituted by one or two aryl groups, wherein aryl denotes phenyl optionally substituted by 1-3 halogens, R', R'O and(or) CF.sub.3. Also claimed are compounds wherein the line connecting Z and Y signifies the absence of a bond, X is O, Z is H and Y is NH.sub.2, NO.sub.2 or N.sub.3.

Spiro nitrogen-bridged heterocyclic compounds

The invention thus provides a process for obtaining the preferential replacement by isotopes, of at least one of the hydrogen atoms selected from the group consisting of those attached to the .alpha.- or .alpha.'-carbon atoms in a compound containing the structural moiety (I) ##STR1## which comprises the steps of oxidizing the compound to the corresponding sulfoxide or sulfone which contains the corresponding structural moiety (II) ##STR2## wherein in the sulfoxide n is 1 and in the sulfone n is 2, effecting the isotopic replacement by a known method of said at least one hydrogen atom, and reducing the resultant isotope-labelled sulfoxide or sulfone to the correspondingly labelled compound containing the structural moiety (I).

Process for labelling sulfur-containing compounds

The present invention accordingly provides in one aspect, novel spiro-oxathiolane/quinuclidine compounds corresponding with the schematic structural formula (I) ##STR1## and geometrical isomers, enantiomers, diastereoisomers, racemates and acid addition salts thereof, wherein one of Y and Z is 0 and the other is S(.dbd.O).sub.n ; n is 0, 1 or 2; R' and R' are each selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, C.sub.3-7 cycloalkyl, aryl, diarylmethylol, and alkyl substituted by at least one aryl group, provided that at least R' and R' is other than hydrogen; and each X is hydrogen, or when Y is 0 and Z is S(.dbd.O).sub.n simultaneously, then each X may also be selected from the group consisting of deuterium and tritium, and provided further that when each X is hydrogen, Y is 0 and Z is S simultaneously, then at least one of R' and R' is selected from the group consisting of alkenyl, alkynyl, cyclopropyl, cyclobutyl, cycloheptyl, hydroxyalkyl and aminoalkyl.

Oxathiolanes

Quinuclidine derivatives having the general formula (I) ##STR1## and geometrical isomers, enantiomers, diastereoisomers, racemates and/or acid addition salts thereof, wherein Z represents the group &gt;CR.sup.1 R.sup.2 or two hydrogen atoms; and R.sup.1 and R.sup.2, which may be identical or different, are each alkyl, cyclopentyl, cyclohexyl, aryl, or diarylmethylol, or alkyl which is substituted by one or more aryl groups, or one of R.sup.1 and R.sup.2 may be hydrogen.

Growing community of inventors

Nes Ziona, Israel

Ishai Karton