Patent GB-1115604-A (GB)
Title: Dibenzocycloheptatriene derivatives and their preparation
Inventor: FOUCHE JEAN CLEMENT LOUIS
IPC: C07C65/24
Filed: 1966-06-17
Abstract: The invention comprises compounds of the Formula I, wherein X represents a halogen atom, or an alkyl, alkoxy, alkylthio, alkylsulphonyl or alkylsulphinyl radical; A represents a straight or branched, saturated, divalent aliphatic radical hydrocarbon chain in which at least 2 carbon atoms separate Z from the dibenzocyclo-heptatriene nucleus and Z represents an amino, monoalkylamino or dialkylamino group or a 1-pyrrolidinyl, 4-R-substituted-piperidino, morpholino or 4-R1-substituted-piperazino radical where R represents a hydrogen atom or a hydroxyl or hydroxyalkyl radical and R1 represents a hydrogen atom or an alkyl, hydroxyalkyl, hydroxyalkoxyalkyl, alkenyl, alkynyl, phenyl, phenylalkyl or phenylalkenyl radical in which the phenyl radicals may be substituted by one or more halogen atoms, or alkyl, alkoxy, nitro, amino, or trifluoromethyl radicals, such that all the aliphatic hydrocarbon chains in X, A, Z, R and R1 have at most 5 carbon atoms, and their acid addition and quaternary ammonium salts; their preparation by reacting a compound of H-Z with a dibenzocycloheptatriene derivative of the Formula III wherein Y represents a reactive ester residue; the preparation of compounds of the Formula I wherein X represents an alkylsulphonyl or alkylsulphinyl radical by oxidizing said compounds wherein X represents an alkylthio group and the preparation of compounds of the Formula I wherein Z represents a 4 - R11 - substituted piperazino radical, where R11 has any of the meanings given to R1 above other than a hydrogen atom or phenyl group, by reacting an ester of the formula R11Y with a dibenzocycloheptatriene derivative of the Formula XXII and if desired converting the resultant bases to acid addition or quaternary ammonium salts thereof.  <FORM:1115604/C2/1> <FORM:1115604/C2/2> <FORM:1115604/C2/3> <FORM:1115604/C2/4> <FORM:1115604/C2/5> <FORM:1115604/C2/6> <FORM:1115604/C2/7> <FORM:1115604/C2/8> <FORM:1115604/C2/9> <FORM:1115604/C2/100> <FORM:1115604/C2/111 Dibenzocycloheptatrienes of the Formula III may be prepared by standard methods from the corresponding alcohols of the Formula IV.  Hydroxyalkyl-dibenzocycloheptatriene derivatives of the Formula IV, where at least 3 carbon atoms of chain A are present between the hydroxy group and the dibenzocycloheptatriene nucleus, may be prepared by reacting a ketone of the Formula V with a Grignard reagent of the formula Hal-Mg-A1-O-B wherein Hal represents a halogen atom, A represents a C3- 5 divalent hydrocarbon radical having at least 3 carbon atoms between the Mg atom and the -OB residue and B represents a readily removable protective group to give a hydroxy ether of the Formula VII, dehydrating the latter to give an ether of the Formula VIII which may be converted into the required alcohol by known methods.  Compounds of the Formula VIII wherein X represents an alkylthio group may be oxidized to the corresponding alkylsulphonyl- and alkylsulphinyl derivatives of the Formula VIII and the latter may be converted into compounds of the Formula IV by the above process. Alcohols of the Formula IV wherein A represents a chain of the formula -CHR1-CHR2-in which R1 represents a hydrogen atom or a C1- 3 alkyl radical and R2 represents a C1- 3 alkyl radical may be prepared from ketones of the Formula V and halogenated compounds of the formula Hal-CHR1-COOR3 where Hal represents a halogen atom and R3 represents a C1- 4 alkyl radical in a Reformatsky reaction to give esters of the Formula XVII, converting the latter into the corresponding acid chlorides via the free acids, and reacting said acid chlorides with a cadmium derivative of the formula R2-Cd-R2 to give ketones of the Formula XX which may be reduced to the desired alcohols.  Dibenzocycloheptadien-11-ones of the Formula V, where X represents a halogen atom or an alkyl, alkoxy or alkyl-thio radical may be prepared by cyclizing a substituted phenyl-acetic acid of the Formula IX wherein X1 represents a halogen atom or an alkyl, alkoxy or thioalkyl radical.  Dibenzocycloheptadien-11-ones of the Formula V, where X represents an alkylsulphonyl or alkylsulphinyl radical may be prepared by oxidizing the corresponding ketone in which X represents an alkylthio radical.  Substituted phenylacetic acids of the Formula IX may be prepared from the o-benzylbenzoic acid of the Formula X by conversion to the methyl ester, reduction to the corresponding benzyl alcohol and conversion of the latter to the desired compound of the Formula IX via the chloride and nitrile. Therapeutic compositions with neuroleptic, sedative, tranquillizing, antihistaminic, anti-emetic and analgesic activity, which may take the forms of tablets, pills, powders, granules, emulsions, solutions, elixirs, syrups, suspensions, capsules, suppositories, ointments and creams for oral, parenteral and topical application, comprise at least one compound of the Formula I or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof together with a pharmaceutical carrier or coating.