Patent GB-1503058-A (GB)
Title: 2-(piperazinyl)-1-alkyl)-4-oxo-4h-benzo-pyrone derivative
IPC: A61K31/495
Filed: 1976-12-07
Abstract: 1503058 2 - (Piperazinyl - 1 - alkyl) - 4 - oxo- 4H - benzopyran derivatives BOEHRINGER MANNHEIM GmbH 7 Dec 1976 [9 Dec 1975] 50959/76 Heading C2C Novel compounds of the Formula I wherein R 1  is hydrogen, halogen, hydroxy, alkyl, alkoxy, alkylthio or trifluoromethyl; R 2 , R 3 , R 4  and R 5  each independently are hydrogen, halogen, or hydroxy or alkyl or alkoxy optionally substituted one or more times by hydroxy, halogen, mesyloxy or tosyloxy or by an oxirane, dioxan or dioxolane ring, A is C 1-4  alkylene and n is 0, 1 or 2, wherein alkyl groups have up to 6 carbon atoms; and salts thereof with pharmacologically compatible acids, may be prepared by (a) reacting a 2-hydroxyacetophenone II with a compound III where R is C 1-6 -alkyl under Claisen condensation condition to form a compound IV or a tautomer thereof followed by cyclization under acidic conditions or (b) reacting a compound VI wherein X is a group displaceable by an amine, with a compound VII In either of these reactions the hydroxy groups may be temporarily protected. In the products I the groups at R 2  may be interchanged, for example, by etherification of a free hydroxy group, or by de-etherification. The diacetyl derivative of 2-{2-[4-(2-methoxyphenyl) - piperazinyl - 1] - ethyl} - 5 - (2,3- dihydroxypropoxy) - 4 - oxo - 4H - 1 - benzopyran is prepared for identification purposes. Intermediates of the Formula III in which A is ethylene or methylene and R is ethyl are prepared by reacting the appropriate 1-substituted piperazine with ethyl acrylate or ethyl bromoacetate. 1-(2-Methoxybenzyl)-piperazine is prepared by reacting ethyl piperazine-N-carboxylate with 2-methoxybenzaldehyde under catalytic hydrogenation conditions to form ethyl 1-(2- methoxybenzyl) - piperazinyl - 4 - carboxylate which is hydrolysed to the required compound. 2 - Hydroxy - 6 - methoxy - acetophenone and 2 - hydroxy - 4 - methoxy - acetophenone are prepared by etherification of the corresponding dihydroxy-acetophenone. Ethyl 3 - [4 - (4 - tetrahydropyran - 2 - yloxyphenyl) - piperazin - 1 - yl] - propionate is prepared by reacting ethyl 3-[4-(4-hydroxyphenyl) - piperazinyl - 1] propionate with 2,3-dihydropyran. 2 - Hydroxy - 6 - (tetrahydropyran - 2 - yloxy) - acetophenone is prepared by reacting 2,6- dihydroxyaceto phenone with 2,3-dihydropyran to yield 2,6-bis-(tetrahydropyran-2-yloxy)-acetophenone, which with solid carbon dioxide gives the required compound. 2,2 - Dimethyl - 4 - [(2<SP>1</SP> - acetyl - 3<SP>1</SP> - hydroxyphenoxy) - methyl] - dioxalane - 1,3 is prepared by reacting 2,6 - dihydroxyacetophenone with 1-chloro or 1-bromo-propane-2,3-diol to form 2 - hydroxy - 6 - (2,3 - dihydroxypropoxy) - acetophenone which with acetone dimethyl acetal yields the required compound. 2 - Hydroxy - 6 - [2 - tetrahydropyran - 2- yloxy) - propoxy] - acetophenone is prepared by reacting 2,6 - dihydroxyacetophenone with propylene oxide to yield (2-hydroxy-6-(2-hydroxypropoxy) - acetophenone which with 2,3- dihydropyran yields 2-hydroxy-6-[2-tetrahydropyran - 2 - yloxy) - propoxy] - acetophenone. In the initial reaction 2,6-bis-(2-hydroxypropoxy)-acetophenone is also formed and in the second reaction 2-tetrahydropyran-2-yloxy)-6-[2- (tetrahydropyran - 2 - yloxy) - propoxy] - acetophenone is also formed.  Pharmaceutical compositions of the compounds I with the usual excipients show antiallergic activity when administered enterally or parenterally.