Patent CA-1077937-A (CA)
Inventor: SZILAGYI GEZA
IPC: C07D237/24
Filed: 1978-06-12
Granted: 1980-05-20
Abstract: A B S T R A C T This invention relates to a process for the preparation of a pyridazinylhydrazone of the general formula I:                                             (I) or a pharmaceutically acceptable acid addition salt thereof, wherein R1 stands for hydrogen, chlorine, alkyl having from 1 to 4 carbon atoms, methoxy, hydroxyl, carbamoyl or cyano; R2 stands for hydrogen, chlorine or the group NR7Ra, wherein R7 and R8 independently represent hydrogen, alkyl having from 1 to 5 carbon atoms or hydroxyalkyl having from 2 to 4 carbon atoms, or R7 and R8 together with the nitrogen atom to which they are attached can form a morpholine, piperidine, piperazine or N-methylpiperazine ring; K represents either a group having the general formula II or a group having the general formula III                                    (II)                             (III) wherein R3 stands for hydrogen, alkyl having from 1 to 10 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, trifluoromethyl, phenyl, phenyl substituted with chlorine atom, nitro or one or more methoxy groups, pyridyl or alkoxycarbonyl having from 1 to 4 carbon atoms in the alkoxy moiety; R4 and R5 independently represent hydrogen, alkyl having from 1 to 4 carbon atoms, or alkoxycarbonyl having from 1 to 4 carbon atoms in the alkoxy moiety R6 stands for hydrogen, carboxyl or the group -CO2R9 wherein R9 stands for an alkyl having from 1 to 9 carbon atoms. hydroxyalkyl having from 2 to 4 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, -CONHMH2 or -CONH2 group; n is 0, 1, 2, 3, 4 or 5; Q represents a mono- or bicyclic alkyl having from 3 to 10 carbon atoms; and R10 stands for hydrogen or an alkyl having from 1 to 6 carbon atoms, with the proviso that when R3 stands for an alkyl having from 1 to 6 carbon atoms, R4 and R6 both stand for hydrogen, and n is O then R5 cannot stand for an alkyl having fro  1 to 4 carbon atoms, a)  reacting a compound of the general formula IV                                       (IV) wherein R1 and R2 are as defined above, with a ketone having the general formula V or VI,                     (V)                    (VI) wherein R3, R4, R5, R6, R10, Q and n are as defined above, to prepare a com-pound of the general formula I, in which K stands for a group having the general formula II or III,                 (II)                            (III) wherein R3, R4, R5, R6, R10, Q and n are as defined above; or b)  reacting an acid of the general formula IX or X:                                           (IX)                 (X) wherein R1, R2, R3, R4, R5, R10, Q and n are as defined above, or a reactive derivative thereof with isobutylene or an alcohol having the general formula R9OH or an alkylating functional derivative thereof, wherein R9 is as defined above, or c)  reacting a compound of the general formula IV, wherein R1 and R2 are as defined above, with an ester having the general formula XI                         R3 - C = C - CO2R9           (XI) wherein R3 and R9 are as defined above, to prepare a compound of the general formula I, wherein K stands for a group having the general formula II, wherein R3 is as defined above, R4 and R5 each stand for hydrogen, n is O and R6 is a group having the general formula -CO2R9, wherein R9 is as defined above; d) where a compound of formula (I) is required in which R6 stands for a -CONH2 or -CONH.NH2 group reacting a corresponding compound of formula (I) obtained in which R6 stands for a -CO2R? group, wherein R? is an alkyl hydroxyalkyl or cycloalkyl group with ammonia or hydrazine; and where any of process steps (a) to (d) can be followed by the additional step of converting a base of formula (I) obtained into a corresponding pharmaceutically acceptable acid addition salt.  It also relates to the products obtained by the process, which are useful because they unexpectedly show a considerable tyrosine-hydroxylase and dopamine-.beta.-hydroxylase inhibiting effect, thereby inhibiting the biosynthesis of noradrenaline and exerting a significant and long-lasting blood pressure lowering activity.