Patent GB-1428481-A (GB)
Title: 10,11-dihydro-10,11-eteheno-5h-dibenz-b,f-azepines and 10,11- dihydro-10,11-etheno-5h-dibenzo-a,d-cycloheptenes and  derivatives thereof
IPC: C07D309/12
Filed: 1973-06-26
Abstract: 1428481 10,11 - (Etheno - elhano) - dibenz[b,f]azepines and dibenz[a,d]cycloheptenes SYNTEX CORP 26 June 1973 [11 July 1972] 30267/73 Heading C2C Novel compounds II and their salts in which X is hydrogen or chloro or both X's represent a further bond, R is hydrogen, C 1 -C 6  alkyl C 1 -C 6  alkoxy, halo, cyano, trifluoromethyl or methythio and Y is (in which R 1  to R 6  are hydrogen or C 1 -C 6  alkyl, R 7  and R 8  are hydrogen, C 1 -C 6  alkyl or NR 7 R 8  represents a heterocyclic ring with 3 to 7 ring atoms or one of R 7  R 8  is methyl and the other is -CR 9 R 10 -CO-phenyl in which R 9  and R 10  are hydrogen or C 1 -C 6  alkyl and the phenyl group is optionally substituted by halogen haloalkyl comprising up to 4 halogen atoms and 1 to 4 C atoms, C 1 -C 6  alkyl or C 1 -C 6  alkoxy) are prepared by (a) reacting a compound III in which Z is > C=O or >N-H with maleic anhydride to yield a compound IV (b) decarboxylating the product of step (a) to give a compound V (c) optionally hydrogenating the product of step (b) to give the corresponding 10, 11 ethano derivative, (d) optionally chlorinating the product of step (b) to give the 10,11-(1,2-dichloroethano) derivative, (d) treating the product of steps (b) (c) or (d) to introduce the Y substituent. Compounds II are prepared by reacting the corresponding dibenzo[a,b]cyclo-hepton-5-one with cyclopropyl magnesium bromide to give the corresponding 5-ol, the cyclopropyl moiety is decyclized to give the 5-propylidene derivative which is reacted with an amine R 7 R 8 NH. Compounds II are prepared by reducing the dibenzo[a,d]- cyclohepten-5-one to the alcohol, which is esterified with SO 2 Cl 2  to give the 5-chloride, this is reacted with a Grignard reagent in which R<SP>1</SP> is tetrahydro-2-pyranyl, tetrahydro-2-furanyl or 1-ethoxy-cyclohexanyl to form a compound of the Formula II in which Y represents R<SP>1</SP>-O-CH 2 -C#C-CH <, the R<SP>1</SP> group is hydrolysed, the alcohol reacted with methane sulphonyl chloride and this ester aminated with HNR 7 R 8 . Compounds II are prepared from the corresponding acetylene derivatives by reaction with benzyltrimethylammonium hydroxide. Compounds II are prepared analogously to the acetylene derivatives. Compounds II are prepared by reacting a dibenzo[a,d]cycloheptan - 5 - one with hydroxylamine hydrochloride and reacting the resulting oxime with sodium hydride and R 7 R 8 -CR 4 R 3 -CR 2 R 1 -Cl. Compounds II are prepared by reacting the corresponding dibenzo[b,f]azepine with allyl bromide, reacting the 5-allyl compound with diborane/water to form the 5-(3-hydroxypropyl) compound, esterifying the alcohol with methane sulphonyl chloride and reacting the ester with an amine NH-R 7 R 8 . Compounds II in which R 7  is methyl and R 8  is a phenacyl group) are prepared by reacting a compound II (NR 7 R 8  = NHCH 3 ) with an α-bromo-acetophenone. The reaction sequences may be varied in respect of hydrogenation and chlorination of the 10,11-etheno group. The propenyl and oxime derivatives of Formula I may be prepared as cis or trans isomers. Compounds II prepared are those in which R 1  to R 6  are mainly hydrogen although R 3  may be methyl, NR 7 R 8  is methylamino, dimethylamino, pyrrolidino, piperidino, hexamethylamino morpholino, piperazino (which may be N-substituted by methyl or #-hydroxyethyl) or methyl-phenacylamino in which the phenyl group is optionally substituted by methyl, methoxy, chloro, fluoro or trifluoro methyl. Compounds I and II are anti-depressants and form with an excipient a pharmaceutical composition which may be administered orally or parenterally.