Patent GB-802902-A (GB)
Title: New basically substituted heterocyclic compounds and process for their manufacture
Filed: 1955-03-03
Abstract: <FORM:0802902/IV (b)/1> The invention comprises 11-unsubstituted dibenzo - [b : f] - thia [1] - aza - [4] - cycloheptadienes having the nucleus of the formula which are substituted in the 10-position by a group R-A-, where R is a tertiary amino group disubstituted by lower alkyl, cycloalkyl or alkylene groups or an alkylene group interrupted by a hetero atom, each of these groups containing not more than 6 carbon atoms, and A represents an alkylene residue of not more than 6 carbon atoms, and salts and quaternary ammonium compounds thereof.  The compounds may optionally contain substituents in the benzene rings, for example, halogen atoms or amino, lower alkyl or lower alkoxy groups.  The residue R-A- may suitably be a dimethylamino-, diethylamino-, pyrrolidino-, piperidino-, or morpholino-ethyl, propyl, isopropyl, butyl, isobutyl or pentyl group. The compounds are obtained by introducing the groups R-A- or the corresponding quaternary ammonium radical into the 10-position of the 10-unsubstituted compound, for example, by reacting the 10-unsubstituted dibenzothia-aza-cycloheptadiene either as the metal salt, or in the presence of a condensing agent, such as an acid-binding agent, or an excess of the amine reactant, with a reactive ester of the appropriate tertiary amino-alkanol, or a corresponding quaternary compound, such as the halide, or p-toluenesulphonate; or by effecting the above reaction with a reactive ester of an alkanol containing a substituent convertible into an amino group such as a halogen atom and subsequently treating the convertible substituent, for example, by reaction with an amine, to introduce the amino group.  The compounds are also made by reducing the oxo group in a 10-(R-A-)-11-oxo-dibenzo-[b : f]-thia - (1) - aza - [4] - cycloheptadiene - [2 : 6] by known methods for reducing an amide, for example by means of a complex metal hydride such as lithium aluminium hydride or catalytically with hydrogen in the presence of copper chromite, or electrolytically.  The compounds or their salts, e.g. hydrohalides, sulphates, nitrates, phosphates, thiocyanates, acetates, propionates, oxalates, malonates, succinates, malates, methane sulphonates, ethane sulphonates, hydroxyethane sulphonates and benzene and toluene sulphonates are used as medicaments.  Examples describe the preparation of 10 - substituted dibenzo - [b : f] - thia - [1] - aza-[4]-cycloheptadienes of the above general formula in which the 10-substituents are b -dimethylaminoethyl, b  - diethylaminoethyl, g -diethylaminopropyl, g -pyrrolidinopropyl and b -dimethylaminopropyl groups and also the 8 - chloro - 10 - (g  - dimethylaminopropyl) -, 8 - chloro - 10 - (g  - diethylaminopropyl) -, 7 - chloro - 10 - (g  - dimethylaminopropyl) -, 7 - chloro - 10 - (b  - diethylaminoethyl - and 6 - chloro - 10 - (g  - dimethylaminopropyl) compounds.  8 - Chloro - 10 - (g  - dimethylaminopropyl) - 11 - hydroxy - dibenzo - [b : f] - thia - [1] - aza - [4] - cycloheptadiene - [2 : 6] is obtained as a by-product in the reduction of the corresponding 11-keto compound with lithium aluminium hydride.  Specification 802,901 is referred to.ALSO:Preparations having an antihistaminic effect and suitable for enteral, parenteral or topical administration comprise 11-unsubstituted dibenzo - [b : f] - thia - [1] - aza - [4] - cycloheptadienes having the nucleus of the formula <FORM:0802902/VI/1> which are substituted in the 10-position by a group R-A-, where R is a tertiary amino group disubstituted by alkyl cycloalkyl or alkylene groups or by an alkylene group interrupted by a hetero atom, each of the groups containing not more than 6 carbon atoms, and A is an alkylene residue of not more than 6 carbon atoms, and which may optionally contain substituents in the benzene rings such as halogen atoms or amino, alkyl or alkoxy groups, and salts and quaternary ammonium compounds thereof, in admixture with a p pharmaceutical carrier.  The preparations may contain, for example, water gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly or cholesterol, and may be used in the form of tablets, dragees, salves, creams or solutions.  They may also contain preserving agents, stabilizing agents, wetting or emulsifying agents, salts for varying the osmolic pressure or buffers.  Specified dibenzo-thia-aza-cycloheptadienes are the 10-b -dimethylaminoethyl-, 10 - b  - diethylaminoethyl-, 10 - g  - diethylaminopropyl-, 10 - g - pyrrolidinopropyl- and 10-b -dimethylaminopropyl derivatives and the 8 - chloro - 10 - g  - dimethylaminopropyl-, 8-chloro - 10 - g  - diethylaminopropyl-, 7 - chloro-10 - g  - diemthylaminopropyl-, 7 - chloro - 10-b -diethylaminoethyl- and 6 - chloro - 10 - g  - dimethylaminopropyl derivatives having the nucleus of the above general formula.  Specification 802,901 is referred to.