Patent GB-743495-A (GB)
Title: Therapeutically active benzhydryl derivatives and processes of manufacturing the same
IPC: C07C209/08
Filed: 1953-04-02
Abstract: <FORM:0743495/IV(a)/1> <FORM:0743495/IV(a)/2> <FORM:0743495/IV(a)/3> <FORM:0743495/IV(a)/4> The invention comprises compounds of the formula I where Ar1 and Ar2 are phenyl groups (one or both substituted in one or both ortho positions by alkyl or halogen, but otherwise unsubstituted), Z is O, S or NH, Y is a straight or branched hydrocarbon chain of not more than 6 carbon atoms and R is alkyl of not more than 6 carbon atoms; also their salts and quaternary derivatives.  The compounds are made (1) by reacting together substances of the formul  II and III, where one of A and B is halogen and the other is -O- metal, -S-metal or -NH2; (2) by reacting together compounds II (A=halogen) and III (B=OH) in the presence of an acid-binding agent (which may be an excess of III); a solvent may also be present; (3) as in (1) or (2) using a compound III with halogen in place of NR2 and then replacing the halogen by NR2; (4) in the case where Z=O by heating a compound IV (as in Specification 722,009).  Examples show the production of the following:  2-methylbenzhydryl b -dimethylaminoethyl ether (by all four methods) and its hydrochloride, oxalate, citrate, maleate, 8-chlorotheophyllinate, 8-8-bromotheophyllinate, 8-chloroxanthinate and methiodide; 2 : 21-dimethyl-benzhydryl b -di-methylaminoethy ether and its hydrochloride and 8-chlorotheophyllinate; 2-ethyl-benzhydryl b -dimethylaminoethyl ether and hydrochloride; 2 : 6 - dimethylbenzhydryl b  - dimethylaminoethyl ether and hydrochloride and 8-chlorotheophyllinate; 2 : 6 : 21 : 61 - tetramethylbenzhydryl b -dimethylaminoethyl ether and hydrochloride and 8-chlorotheophyllinate; 2-methylbenzhydryl b  - diethylaminoethyl ether and hydrochloride and 8-chlorotheophyllinate; 2-methylbenzhydryl b  - dimethylaminopropyl ether and hydrochloride; 2-bromobenzhydryl b -dimethylaminoethyl ether and hydrochloride; 2 - methylbenzhydryl - g  - dimethylaminopropyl-amine (as hydrochloride), and 2-methylbenzhydryl b  - dimethylaminoethyl thioether (as hydrochloride).  U.S.A.  Specifications 2,454,092, 2,483,434 and 2,483,436 also are referred to.ALSO:<FORM:0743495/VI/1> Therapeutic compositions effective against travel sickness contain as essential ingredient a benzhydryl derivative of formula I where Ar1 and Ar2 are phenyl groups (one or both substituted in one or both ortho positions by alkyl or halogen, but otherwise unsubstituted), Z is O,S or NH, Y is a straight or branched hydrocarbon chain of not more than 6 carbon atoms and R is alkyl of not more than 6 carbon atoms; also their salts and quaternary derivatives.  The compounds, finely divided or in the form of tablets, are preferably provided with a soluble coating which does not dissolve until it has passed the mouth and pharynx. In examples 2-methylbenzhydryl b-dimethylaminoethyl ether is mixed with lactose, oxidised starch, tallow and either a triglyceride (e.g. cocoa butter) or methylcellulose, carboxymethyl-cellulose, pectin or an alginate.  Other constituents of such tablets may be magnesium stearate, collagen, gelatin, plant slime and agar-agar. Alternatively the compounds may be prepared in the form of capsules or sugar-coated tablets.  It is also stated that the compounds in aqueous solution can be used as local anaesthetics. Many other suitable benzhydryl derivatives are listed; their salts with hydrochloric, oxalic, citric and maleic acids and with 8-chlorotheophylline, 8-bromotheophylline and 8-chloroxanthine are mentioned.  U.S.A. Specifications 2,454,092, 2,483,434 and 2,483,436 are referred to.