Ramot University Authority for Applied Research and Industrial

Yissum Research Development Company of the Hebrew University of Jerusalem Ltd.

Other

Tel Aviv University

Pharmos Corporation

Mordechai Sokolovsky

Yoel Kloog

Raphael Mechoulam

Amihay Freeman

Anat Biegon

Leon Goldstein

Simon Benita

Leon Golstein

Emil Pop

Jeffrey J Feigenbaum

Dexanabinol derivatives and their use as neuroprotective pharmaceutical

Pharmaceutical compositions are described for preventing neurotoxicity, crising as active ingredient the stereospecific (+) enantiomer, having (3S,4S) configuration of .DELTA..sup.6 tetrahydrocannabinol type compounds. The compositions are particularly effective in alleviating and even preventing neurotoxicity due to acute injuries to the central nervous system, including mechanical trauma, compromised or reduced blood supply as may occur in cardiac arrest or stroke, or poisonings. They are also effective in the treatment of certain chronic degenerative diseases characterized by gradual neuronal loss.

NMDA-blocking pharmaceuticals

The use of a compound of the formula: ##STR1## having the (3S,4S) configuration, and which is essentially free of the (3R,4R) enantiomer, wherein A--B designates a 1(2) or a 6(1) double bond, R designates --CH.sub.3 or --CH.sub.2 OH, R.sup.1 designates a hydrogen atom or a lower acyl group, and R.sup.2 designates (A) a straight-chained or branched C.sub.6-12 alkyl radical; or (B) a group --O--R.sup.3, in which R.sup.3 is a straight-chained or branched C.sub.5-9 alkyl radical or a straight-chained or branched alkyl radical substituted at the terminal carbon atom by a phenyl group in the manufacture of a medicament for reducing or preventing glutamate neurotoxicity. Some of the above compounds are novel, and their preparation is described. Also described is a method of treating acute injuries to the central nervous system associated with excitatory amino acid neurotoxicity, a method of treating chronic degenerative disease associated with gradual selective neuronal loss and a method of treating poisonings affecting the central nervous system by administering a pharmaceutical composition containing the above compound.

NMDA-blocking pharmaceutical compositions

The invention relates to a drug system for the treatment and alleviation of the symptoms of epilepsy; as anticonvulsant agent, and for the prevention or alleviation of brain damage due to strokes. The drug system comprises as active ingredient a compound such as MK-801, phencyclidine or as thienyl-cyclohexyl-piperidine (TCP), which is administered in such a manner that it encounters and binds to the N-methyl-D-aspartate (NMDA) receptor channels. This is in the presence of glutamate or glycine, or similarly acting amino-acid, which is either present in the patient, or which can be administered separately. The effective drug can be effectively locked in the receptor channels by means of a glutamate antagonist, such as AP-5.

Drug system

The present invention relates to novel key intermediates for the production of biologically active compounds coupled to polymers, of the general formula P--NCX.sub.2, wherein X designates a halogen atom selected from chlorine and bromine, and wherein P designates the polymer backbone of a polymer of the polyamide, polyester and ureaformaldehyde type. The invention further relates to compounds obtained by the reaction of the above compound P--NCX.sub.2 with a bifunctional or polyfunctional nucleophile. Suitable nucleophiles are hydrazides of dicarboxylic acids and amongst these there may be mentioned polyacrylamides partially substituted with acylhydrazide groups; polyfunctional amines selected from alkylamines, aralkylamines, arylamines and macromolecular compounds containing amino groups. The key intermediate PNCX.sub.2 may be coupled directly to biologically active macromolecules and amongst the preferred compounds of this type there are the various biologically active proteins and enzymes. The coupling of the biologically active macromolecules may also be effected via hydrophilic polymer moieties first grafted onto the polymer P via said dihaloisocyanide groups.

Dihaloisocyanide derivatives of polymers for coupling nucleophiles

The present invention relates to novel isocyano derivatives of linear or cross-linked, natural or synthetic macromolecules, the derivatives being of the general formula P--O--Q--NC, wherein P is the macromolecular backbone, the oxygen atom is part of the hydroxy group, Q is a group --(CH.sub.2).sub.n --wherein n is an integer of at least 3 carbon atoms, and up to about 20 carbon atoms, or Q is an aralkyl group, to a process for preparing such derivatives and to a process of linking to same biologically active proteins and to the products thus obtained.

Isonitrile derivatives of macromolecules containing hydroxyl groups

Novel substituted polyamides of the general formula ##EQU1## wherein A and B, which may be identical or different, are the hydrocarbon backbone groups of the formula --(CH.sub.2).sub.n --, where n is an integer, R.sub.2 and R.sub.3 are the residues of an aldehyde R.sub.2 --CHO or of an isocyanide R.sub.3 --N.tbd.C, where R.sub.2 and R.sub.3 are aliphatic, aromatic or heterocyclic residues of the respective aldehyde or isocyanide, or where R.sub.3 is a chromophoric moiety. R.sub.2 and R.sub.3 can be substituted, and amongst the possible substituents there may be R.sub.3 designating --(CH.sub.2).sub.n --NHCO--CHR.sub.2 --N(CO)(R.sub.4)--X, where R.sub.4 is the residue of a monocarboxylic or dicarboxylic acid and X is the lysyl residue of a protein, which may be biologically active, or the residue of a low-molecular weight compound containing a primary amine moiety. Preferred polyamides are various types of nylons. Amongst proteins chemically bound to the polyamide there may be mentioned enzymes, antibodies and peptide hormones. When R.sub.3 is a chromophoric moiety, the product is a chemically dyed polyamide. The invention relates also to a process for the production of such novel substituted polyamides.

Growing community of inventors

Tel Aviv, Israel

Mordechai Sokolovsky