Patent GB-1061247-A (GB)
Title: 1-aralkyl-4-(thiazolyl-2)-piperazines and preparation thereof
IPC: C07D417/04
Filed: 1966-01-25
Abstract: Novel compounds of the formula <FORM:1061247/C2/1> and their acid addition salts; wherein R1 and R2 are H, a C1- 6 alkyl or C7- 10 aralkyl group, Cl, Br or I, or a phenyl radical which may be substituted by one or more C1-4 alkyl or alkoxy or CF3 groups or F, Cl, Br, or I atoms, or by a methylene dioxy or ethylene dioxy group, or R1 and R2 together form the group -CH=CH-CH=CH-; A is a straight or branched C1-6 alkylene chain and Ar is a 3,4-methylenedioxyphenyl or 3,4-ethylenedioxyphenyl group are prepared by any of the following methods: (a) condensation of Ar-A-X  (II) wherein X is Cl, Br, I, -OH or a C1- 6 alkylsulfonoxy or C6- 10 arylsulfonoxy group, with a compound <FORM:1061247/C2/2> (b) condensation of a compound <FORM:1061247/C2/3> with a compound of formula <FORM:1061247/C2/4> (c) condensation of a compound Ar-A-NH2  (VI) with a compound <FORM:1061247/C2/5> wherein X is as defined above or the two X groups together form an O atom; (d) condensation of a compound <FORM:1061247/C2/6> wherein n is 0-4, with a compound R3-M  (LX) wherein M is MgY or an alkali metal, R3 is an alkyl group and Y is Cl, Br or I, the sum of n and the number of carbon atoms in R3 not, however, being greater than 5; (e) condensation of a compound Ar-(CmH2m)-M  (X) wherein m is 0-5, with a compound <FORM:1061247/C2/7> wherein R4 is H or (when m is less than 5) CH3; (f) treating a compound of Formula (1) which additionally contains one or more chlorine and/or bromine atoms and/or carbonyl groups and/or C-C multiple bonds, with a complex metal hydride and/or hydrogen in the presence of a hydrogenation catalyst, or with a chemical reducing agent. (g) condensation of a compound <FORM:1061247/C2/8> with a compound <FORM:1061247/C2/9> or (h) reaction of a compound Ar-CmH2m-CHO  (XIV) with a piperazine of Formula (III) under catalytic hydrogenation conditions.  The compounds of the invention are useful in pharmaceutical compositions (see Division A5).  Piperazine intermediates of Formula (III) are obtained by reaction of a 2-aminothiazole with diethanolamine, morpholine or bis-(2-chloro-ethyl)-amine or by reacting piperazine with a thiazole derivative of Formula (V) above.  Aralkylpiperazines of Formula (IV) are produced either by the reaction of an aralkylhalide of Formula (II) with 1-benzyl-piperazine and subsequent reductive elimination of the benzyl group or by the reaction of compounds of Formula (VI) with diethanolamine, morpholine or bis(2-chloroethyl)amine.  Aralkylamines of Formula (VI) are obtained by the reaction of a compound of Formula (II) with potassium phthalimide or by reduction of the corresponding nitriles. Aminothiazoles of Formula (VII) are prepared by the reaction of a 2-halogenothiazole of Formula (V) with diethanolamine or of a 2-aminothiazole with ethylene oxide and subsequent conversion of the hydroxy groups into halogen atoms or sulphonoxy groups with for example thionyl chloride or sulphonyl chlorides respectively. Nitriles of Formula (VIII) may be prepared from the corresponding aldehydes of formula Ar-(CnH2n)-CHO by conversion to the bisulphite compound and then by successive reactions with an N-thiazolyl-2-piperazine of Formula (III) and with an alkali metal cyanide. The nitriles of Formula (XI) may be obtained by reaction of compounds of Formula (III) with formaldehyde or acetaldehyde and potassium cyanide.  Thioureas of Formula (XII) may be obtained for example by the reaction of an aralkylpiperazine of Formula (IV) with nitrourea and subsequent reaction of the piperazine carboxamide with phosphorus pentasulphide.  N - (3,4 - methylenedioxyhydrocinnamoyl)-N1 -(4 - methyl - thiazolyl - 2) - piperazine is prepared by reacting 3,4-methylenedioxy-hydrocinnamoyl chloride with N-(4-methyl-thiazolyl-2)-piperazine in the presence of triethylamine.  1 - (3,4 - Methylenedioxyphenyl) - 2 - (N1-carbamoyl -piperazino) - propane is prepared by reacting the carbamoyl unsubstituted piperazine with nitrourea.  Pharmaceutical compositions comprise compounds of Formula (I) in admixture with conventional excipients which are organic or inorganic substances suitable for parenteral or topical application e.g. water, vegetable oils, polyethylene glycols, gelatin, lactose, starch, magnesium stearate, talc, petroleum jelly and cholesterol.