Patent GB-1071757-A (GB)
Title: 5,6-dihydro-11,h-pyrido-[2,3-d] [1,5]-benzodiazepines
IPC: A61K31/55
Filed: 1965-02-26
Abstract: Compounds of the formula <FORM:1071757/C2/1> wherein R represents a straight or branched chain alkyl group containing 1 to 4 carbon atoms which may, if desired, be substituted by an alkoxy group containing 1 to 4 carbon atoms, a halogen atom, a dialkylamino group the alkyl groups of which each contain 1 to 4 carbon atoms or by the residue of a cyclic secondary aliphatic amine through its nitrogen atom (the ring of which cyclic secondary amine may be interrupted by an oxygen atom or by a further nitrogen atom and/or be substituted with at least one alkyl group containing 1 to 4 carbon atoms); an alkenyl group containing 2 to 4 carbon atoms; a cycloalkyl group or an aralkyl group (the aromatic ring of which may be substituted, if desired, by at least one halogen atom or alkyl or alkoxy group containing 1 to 4 carbon atoms); R1 and R2, which may be the same or different, represent hydrogen or halogen atoms or alkyl or alkoxy groups containing 1 to 4 carbon atoms and Z represents a carbonyl or methylene group and acid addition salts thereof and preparation thereof:  (a) when Z represents a carbonyl or a methylene group by reacting a compound of the formula <FORM:1071757/C2/2> wherein R1 and R2 have the agove significance; either as an alkali metal derivative thereof, when Z is a carbonyl group; or as the free base in the presence of an acid binding agent, when Z is a methylene group; with a compound of the formula R.X wherein R has the above significance and X is a reactive acid residue such as a halogen atom or the residue of a sulphuric or aromatic sulphonic acid at an elevated temperature by refluxing in a suitable solvent, or (b) when Z represents a methylene group by reducing a compound of the first general formula above with a reducing agent capable of converting a carbonyl group to a methylene group, such as lithium aluminium hydride in an inert solvent, an alkali metal in absolute alcohol or hydrogen and copper oxide/chromium oxide in an inert solvent.  5,6 - Dihydro - 11H - pyrido[2,3-b][1,5]-benzodiazepine and 6-methyl-, 6-ethyl-, 6-benzyl-, 6-(dimethylaminoethyl)-, 6-(dimethylaminopropyl)- and 6-(morpholinoethyl)-substituted derivatives thereof; 8(or 9)-chloro-5,6-dihydro - 11H - pyrido[2,3-b][1,5]benzodiazepine and 6 - methyl-, 6 - ethyl-, 6 - (dimethylaminoethyl)-, 6 - (dimethylaminopropyl)-, 6-(piperidinylethyl)-and 6 - (41 - methylpiperazinylpropyl)-substituted derivatives thereof; 8(or 9) - methyl - 5,6 -dihydro - 11H - pyrido-[2,3-b][1,5] benzodiazepine and 6-methyl, 6-ethyl-, 6-benzyl-, 6-(p-chlorobenzyl)-, 6-(dimethylaminoethyl)-, 6-(dimethylaminopropyl)-, 6-(morpholinoethyl)-, 6-(piperidinylethyl)- and 6 - (41 - methylpiperazinylpropyl) - substituted derivatives thereof and, finally, 8,9-dimethyl-5,6 - dihydro - 11H - pyrido[2,3-b][1,5]benzodiazepine and 6-methyl-, 6-ethyl-, 6-dimethylaminoethyl)-, 6 - (dimethylaminopropyl)-, 6-morpholinoethyl)-, 6-(piperidinylethyl)- and 6-(41 - methylpiperazinylpropyl) - derivatives thereof are prepared by reduction of appropriately substituted 5 - oxo - 5,6 - dihydro-11H - pyrido[2,3-b][1,5]benzodiazepine derivatives which are, themselves, obtained by alkylating suitable 5 - oxo - 5,6 - dihydro - 11H -pyrido[2,3-b][1,5]-benzodiazepines in the 6-position. 6 - Benzyl-, 6 - allyl-, 6 - (piperidinylethyl)- and 6 - (41 8 methylpiperazinopropyl)-substituted 5,6-dihydro-11H-pyrido[2,3-b][1,5]-benzodiazepine, 6-allyl-8(or 9)-methyl-5,6-dihydro - 11H - pyrido[2,3-b][1,5]benzodiazepine and 6 - allyl - 8,9 - dimethyl - 5,6 - dihydro-11H - pyrido[2,3-b][1,5]benzodiazepine are obtained by alkylating the appropriate 5,6-dihydro - 11H - pyrido[2,3-b][1,5]benzodiazepine in the 6-position.  In addition, 6-isobutyl-, 6-(methoxyethyl)-, 6-(chloroethyl)-, 6-(p - chlorobenzyl)-, 6 - (p - methoxybenzyl)-, 6 - allyl-, 6 - (methylpiperazinylpropyl)-, 6-(piperidinylethyl)-, 6 - allyl - 8(or 9) - chloro-, 6 - allyl - 8(or 9) - methyl-, 6 - (piperidinylethyl) - 8(or 9) - methyl-, 6 - allyl - 8,9 - dimethyl- and 6 - methallyl - 8,9 - dimethyl-substituted derivatives of 5-oxo-5,6-dihydro-11H - pyrido - [2,3-b][1,5] - benzodiazepine are also mentioned.ALSO:Pharmaceutical compositions with analgesic, sedative, antiphlogistic and anti-emetic activity as well as, in specified cases, antipyretic, histaminolytic, antireserpine and anti-tussive activity in the form of tablets, coated tablets, capsules, ampoules or suppositories suitable for enteral, parenteral or rectal administration comprise at least one compound of the formula:  <FORM:1071757/A5-A6/1> wherein R represents a straight or branched chain alkyl group containing 1 to 4 carbon atoms which may, if desired, be substituted by an alkoxy group containing 1 to 4 carbon atoms, a halogen atom, a dialkylamino group the alkyl groups of which each contain 1 to 4 carbon atoms or by the residue of a cyclic secondary aliphatic amine through its nitrogen atom (the ring of which cyclic secondary amine may be interrupted by an oxygen atom or by a further nitrogen atom and/or be substituted with at least one alkyl group containing 1 to 4 carbon atoms); an alkenyl group containing 2 to 4 carbon atoms; a cycloalkyl group or an aralykyl group (the aromatic ring of which may be substituted, if desired, by at least one halogen atom or alkyl or alkoxy group containing 1 to 4 carbon atoms; R1 and R2, which may be the same or different, represent hydrogen or halogen atoms or alkyl or alkoxy groups containing 1 to 4 carbon atoms and Z represents a carbonyl or methylene group or non-toxic physiologically acceptable acid addition salts thereof in association with a pharmaceutical carrier or excipient.  Such compositions may also contain other active ingredients of a similar or comparable nature for example sedatives such as phenyl ethyle barbituric acid or codeine salts.