Patent GB-1528370-A (GB)
Title: 1,4-diazepino(1,7-b)isoquinolines and their pharmaceutical compositions
IPC: C07D217/14
Filed: 1975-12-17
Abstract: 1528370 Octahydro-1,4-diazepino-[1,7-b]isoquinolines; their preparation and pharmaceutical compositions SANDOZ Ltd 17 Dec 1975 [20 Dec 1974] 51576/75 Heading C2C The invention comprises compounds of Formula I wherein R 1  is H or C 1-5  alkyl; R 2  is a group of Formula Ia in which n is 0 or an integer from 1 to 3, R 5  and R 6  are independently H, C 1-4  alkyl, C 1-4  alkoxy, Cl, Br, F or together form a 3,4-methylenedioxy group and R 7  is H or when R 5  and R 6  are both C 1-4  alkoxy may also be C 1-4  alkoxy; R 3  is in the 9- or 10-position and is H, C 1-4  alkyl, C 1-4  alkoxy, F, Cl or Br and R 4  is in the 9- or 10- position and is H or C 1-4  alkoxy which may be prepared by reducing a compound of Formula II wherein R 2 , R 3  and R 4  are as defined above and either (a) X is  Y is or -CH 2 - and Z is the same or R 1  defined above, or (b) X and Y are both -CH 2 - and Z is formyl or alkanoyl of 2-6 carbon atoms or C 2-5  alkoxycarbomyl. 3 - Amino - 4 - phenylbutyric acid ethyl ester is prepared from γ-phenylacetoacetic acid ethyl ester and is reacted with p-anisoyl chloride to give 3 - p - methoxybenzamido - 4 - phenylbutyric acid ethyl ester which is in turn converted to 3,4 - dihydro - 1 - p - methoxyphenyl - 3- isoquinolinylacetic acid ethyl ester by reaction with POCl 3 . This product is hydrogenated to obtain cis - 1 - p - methoxyphenyl - 1,2,3,4- tetrahydro - 3 - isoquinolinylacetic acid ethyl ester which on reaction with KCN and paraformaldehyde gives cis-2-cyanomethyl-1-p-methoxyphenyl - 1,2,3,4 - tetrahydro - 3 - isoquinolinylacetic acid ethyl ester. This ester is hydrogenated to give cis-2-(2-aminoethyl)-1-p-methoxyphenyl- 1,2,3,4 - tetrahydro - 3 - isoquinolinylacetic acid ethyl ester which is cyclized to obtain (7RS, 12aRS) - 1,4,5,7,12,12a - hexahydro - 7 - pmethoxyphenyl - 1,4 - diazepino[1,7-b]isoquinolin- 2(3H)-one which in turn alkylated with methyl iodide to obtain (7RS,12aRS) - 1,4,5,7,12,12ahexahydro - 7 - p - methoxyphenyl - 3 - methyl- 1,4 - diazepino[1,7 - b]isoquinolin - 2(3H)- one. Cis - 1 - phenyl - 1,2,3,4 - tetrahydro - 3 - isoquinolinylacetic acid ethyl ester was prepared by the same method as above replacing p-anisoyl chloride by benzoyl chloride and is reacted with bromoacetylchloride to form cis - 2 - bromoacetyl - 1 - phenyl - 1,2,3,4 - tetrahydro - 3- isoquinolinylacetic acid ethyl ester which is in turn reacted with methylamine to obtain (7RS,12aRS) - 3 - methyl - 7 - phenyl - 1,7,12,12atetrahydro - 1,4 - diazepino[1,7-b]isoquinolin- 2,5(3H,4H)-dione. (7RS,12aRS) - 1,4,5,7,12,12a - hexahydro - 7- phenyl - 1,4 - diazepino[1,7 - b] - isoquinolin- 2(3H) - one is prepared by the method described above and reduced to obtain (7RS,12aRS) - 1,2,3,4,5,7,12,12a - octahydro - 7- phenyl - 1,4 - diazepino[1,7 - b]isoquinoline which is in turn reacted with acetyl chloride to obtain (7RS,12aRS) - 3 - acetyl - 1,2,3,4,5,7,12, 12a - octahydro - 7 - phenyl - 1,4 - diazopino [1,7-b]isoquinoline. (7RS,12aRS) - 1,2,3,4,5,7,12,12a - octahydro- 7 - phenyl - 1,4 - diazepino[1,7-b]isoquinoline - 3- carboxylic acid ethyl ester is prepared by reaction of (7RS,12aRS) - 1,2,3,4,5,7,12,12a - octahydro- 7 - phenyl - 1,4 - diazepino[1,7-b]isoquinoline with ethyl chloroformate. Pharmaceutical compositions having sleep producing and prolonging, locomotor depressant and antiaggressive activity comprise a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier or diluent.