Optical isomers of dihydro-2,3-benzodiazepine derivatives, process for their stereoselective synthesis, their use, pharmaceutical compositions containing them and the intermediates of the synthesis

摘要

Enantiomeric dihydro-2,3-benzodiazepine derivatives or their acid addition salts are new. Enantiomeric dihydro-2,3-benzodiazepine derivatives of formula (I) or their acid addition salts are new. X : a halogen or chloro atom, or alkoxy; Y 1halogen or chloro atom; X+Y 1a methylenedioxy group; R : 1-4C alkyl (preferably methyl or ethyl). The configuration of the chiral carbon atom is R or S. Independent claims are included for the following: (1) new intermediate selected from enantiomeric dihydro-2,3-benzodiazepine derivatives of formula (V); enantiomeric benzo[b]pyran derivatives of formula (XII); hydrazone derivatives of formula (XIV); racemic and enantiomeric dihydro-2,3-benzodiazepine derivatives of formula (III); racemic and enantiomeric dihydro-2,3-benzodiazepine compounds of formula (VI); diastereomeric dihydro-2,3-benzodiazepine derivatives having high stereochemical purity of formula (VII); racemic or enantiomeric dihydro-2,3-benzodiazepine compounds of formula (VIII), or their acid addition salts with their optically active acids; (2) a pharmaceutical composition comprising the enantiomeric dihydro-2,3-benzodiazepine derivatives (I) and a carrier; and (3) preparation of the dihydro-2,3-benzodiazepine derivatives (I) (preferably (R)-(-)-7-acetyl-5-(4-amino-3-methylphenyl)-8-methyl-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine; or (R)-(-)-3-acetyl-1-(4-amino-3-methylphenyl)-8-chloro-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine) of high enantiomeric purity. V 1hydrogen atom or hydroxyl; L 1hydroxyl, or alkyl- or aryl-sulfonyl; R aa substituted arylene, alkylene or alkenylene (preferably cis- or trans-alkenylene, especially cis-ethenylene); R 1T 1 (preferably hydrogen atom); R 2T 1 (preferably methyl); R 3T 1 (preferably phenyl); T 1aliphatic or branched saturated or unsaturated alkyl, aryl or aralkyl (all optionally substituted), or hydrogen atom. The hydrazone compounds (XIV) are mixtures of E and Z isomers. [Image] [Image] [Image] [Image] ACTIVITY : Cerebroprotective; Vasotropic; Neuroprotective; Vulnerary; Anticonvulsant; Neuroleptic; Cytostatic; Muscular-Gen.; Relaxant; Antiparkinsonian; Nootropic; Antiinflammatory; CNS-Gen.; Analgesic; Antiemetic; Antimigraine; Antiaddictive; Tranquilizer. MECHANISM OF ACTION : Non-competitive antagonist of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. The AMPA antagonistic efficacy of (R)-(-)-7-acetyl-5-(4-amino-3-methylphenyl)-8-methyl-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (A1) was evaluated in the chicken retina by using Spreading depression test method as described in Sheardown (1993). The compound (A1) was effective AMPA antagonist compound, because the effect of the AMPA receptor was blocked by 1.8 mu M (EC 50) value.