Patent GB-1221061-A (GB)
Title: Quaternary ammonium derivatives, their use as anthelmintics and methods for their preparation
Inventor: BERG SAMUEL SIDNEY
IPC: C07D521/00
Filed: 1967-01-18
Abstract: 1,221,061. Quaternary ammonium derivatives. MAY & BAKER Ltd. 18 Jan., 1968 [18 Jan., 1967; 18 July, 1967], Nos. 2765/67 and 32943/67. Heading C2C. [Also in Division A5] The invention comprises compounds of the Formula I: wherein (a) R represents a phenyl group or R<SP>1</SP> where R<SP>1</SP> is a 5- or 6-membered monocyclic heterocyclic group containing one or two hetero atoms selected from oxygen, nitrogen and sulphur, linked to the group A through a carbon atom of the heterocycle, the phenyl and heterocyclic groups being optionally substituted by one or two atoms or groups selected from halogen, alkyl, alkoxy, hydroxy, nitro, dialkylamino and acylamino, A represents the group -CH= CH-, and Z, together with the nitrogen atom to which it is joined, represents a 5- or 6- membered tertiary monocyclic or bicyclic heterocyclic group, which may contain one or two further hetero atoms selected from alkyl, phenyl, 4-thiazolyl, 2-furyl, 2-thienyl, formyl, hydroxyiminomethyl, acyl, amino and acetamide groups or (6) R represents R<SP>1</SP> where R<SP>1</SP> is as defined above, A represents the group -CH 2 .CH 2 -, and Z together with the nitrogen atom to which it is joined is as defined in (a); or (c) R is as defined in (a), A represents the group -CH 2 .CO-, and Z together with the nitrogen atom to which it is joined, represents a pyridinium, 3- or 4-aminopyridinium, 3- or 4- acetamido pyridinium, 2-, 3- or 4-hydroxyimino methyl pyridinium, 1-alkyl-1,2-dihydropyridinium, pyridazinium, 1 - methyl - 1,4,5,6- tetrahydropyrimidinium, 1 - alkyltetrahydropyridinium, 1 - alkylpyrazolium, 2 - alkylpyrazolium, 1 - alkyl - 2 - phenyl -, 1 - alkyl - 2 - (4 - thiazolyl) -, 1 - alkyl - 2 - (2 - furyl) - or 1- alkyl - 2 - (2 - thienyl) - benzimidazolium group; or (d) R is as defined in (b), A represents the group -CH 2 CO-, and Z, together with the nitrogen atom to which it is joined, represents a pyrazinium or 2-alkylpyrazinium group and X- represents a pharmaceutically acceptable anion, with the proviso that (i) when A represents -CH= CH-, and Z, together with the nitrogen to which it is joined, represents the pyridinium group, X- is other than the bromide, picrate, oxalate, perchlorate or perbromide ion when R is phenyl; other than the bromide, chlorate or picrate ion when R is 2-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl or 4-nitrophenyl; other than the bromide ion when R is 2,5- dichlorophenyl or 2- or 4-methylphenyl; other than bromide or picrate when R is 3-nitrophenyl; other than the bromide or chlorate ion when R is 3-hydroxyphenyl, 4-methoxyphenyl or 2-thienyl; other than the iodide or chlorate ion when R is 3,4-dimethoxyphenyl; other than the bromide or perchlorate ion when R is 2-furyl, (ii) when A represents -CH=CH- and R is phenyl, X- is other than the bromide or chlorate ion when Z (which in this context is taken to include the nitrogen atom to which Z is joined) is 3-methylpyridinium or 4-n-amylpyridinium; other than the bromide ion when Z is 3,5-dimethylpyridinium; other than the chlorate ion when Z is 3,5-diphenylpyridinium; other than the bromide, chlorate, iodide or nitrite ion when Z is isoquinolinium; other than the bromide ion when Z is quinolinium, (iii) when A is the group -CH 2 CO-, R is phenyl, and Z, together with the nitrogen atom to which it is joined is 2- or 4-hydroxyiminomethylpyridinium, X- is other than the bromide or chloride ion, respectively, (iv) when A is -CH 2 CO-, and Z, together with the nitrogen atom to which it is joined is pyridinium X- is other than the bromide, chloride, iodide, periodide, sulphate, chlorate, phosphate or tosylate ion when R is phenyl; other than chloride, bromide, iodide or chlorate when R is 2-furyl; other than the bromide, iodide or chlorate ion when R is 2-thienyl; other than the chloride ion when R is 4,5-dichloro-2-thienyl or X- is other than the iodide or perchlorate ion when R is 2-pyridyl. In the above the -CH 2 CO- group is attached to the heterocyclic ring via the -CH 2 -moiety. They are prepared by reacting a compound of the Formula (II) RCH 2 CH 2 X 1  with a tertiary heterocyclic compound of the general Formula (III) or by eliminating the molecule HY from a quaternary salt of the Formula (IV): or by reacting a compound of the formula with (III), or by reacting a ketone of the formula R.CO.CH 3  with an equimolar amount of iodine and two molar equivalents of (III) or by reacting diazoacetophenone with the HX salt of (III), or by quaternizing a tertiary heterocyclic amine of the formula or by converting the anion X- into a different pharmaceutically acceptable anion, wherein X 1  represents a halogen atom or a methyl sulphate, ethyl sulphate, methanesulphonate, ethanesulphonate, benzenesulphonate, toluene p-sulphonate or p-chlorobenzenesulphonate, Y represents a hydroxy group or acyloxy group derived from a carboxylic group or a halogen atom and R, A, Z and X- are as defined above. Compounds of Formula I have anti-helminthic properties. The starting materials of Formula IV in which Y represents hydroxy may be prepared by the reaction of an aldehyde RCHO with a quaternary salt of Formula (I) in which A represents -CH 2 CO-, or with a quaternary derivative of the general formula When X- represents chloride, bromide or iodide a compound of Formula (III) may be reacted with a compound RCH(OH)CH 2 X 2 , where X 2  is Cl, Br or I, to produce a compound of Formula (IV). The compounds of Formula (IV) in which Y represents an acyloxy group are prepared by acylating the corresponding compound in which Y is hydroxy by means of the appropriate carboxylic acid halide or anhydride, the compounds of Formula (IV) in which Y represents a halogen atom are prepared from the corresponding compound in which Y is OH by reaction with an inorganic halide such as thionyl chloride or bromide or phosphorus oxychloride. 1 - (2 - Hydroxy - 2 - o - fluorophenethyl) pyridinium bromide is prepared from o-fluorobenzaldehyde and phenacyl pyridinium bromide. 4 - Acetamide - 1 - (2 - hydroxy - 2 - phenethyl)- pyridinium bromide is prepared from 4-acetamide pyridine and styrene bromohydrin. 2 - (2 - Chloro - 2 - phenethyl) - 1 - methylpyrazolium bromide is prepared from 2-(2- hydroxy - 2 - phenethyl) - 1 - methylpyrazolium bromide and thionyl chloride. 2-Furoyl methyl tosylate is prepared from 2- furoylmethyl bromide and silver tosylate. 4-Bromoacetylthiazole hydrobromide is prepared from 4-acetylthiazole and dioxane dibromide. Reference has been directed by the Comptroller to Specifications 1,163,904 and 1,192,393.