Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-01-14
1999-12-14
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546199, 546200, 546201, 546234, 546229, 546230, 546231, 546232, 546233, 546235, C07D40112, C07D21128, C07D21166, C07D21132
Patent
active
060020091
DESCRIPTION:
BRIEF SUMMARY
The present invention refers to novel pharmacologically active derivatives of di-substituted 1,4-piperidine, the processes for their preparation and the pharmaceutical compositions containing them.
The novel compounds, object of the present invention, have a high affinity and specificity for 5-HT.sub.4 serotoninergic receptors. They are able to inhibit, either at central or peripheral level, those effects mediated by the activation of this receptor subtype. Therefore, the compounds, object of the present invention, may be defined novel antagonists "in vitro" and "in vivo" of 5-HT.sub.4 receptors. 5-HT.sub.4 receptors belong to the numerous family of serotoninergic receptors and they are among those more recently discovered, pharmacologically characterized and cloned. After the first identification in discrete areas of guinea-pig CNS [Dumuis et al.; Mol. Pharmacol. (1988), 34, 880; Bockaert et al.; Trends, Pharmacol. Sci. (1992) 13, 141] the 5-HT.sub.4 serotoninergic receptors have been localized also in other districts, either central or peripheral (ileum, atrium, esophagus, colon, urinary bladder and adrenal glands) of different species, including humans. [Craig et al.; Brit. J. Pharmacol. (1989) 96, 246 P; Craig et al.; J. Pharmacol. Exp. Ther. (1990) 352, 1378; Kauman et al.; Brit. J. Pharmacol. (1989), 98, 664 P; Hoyer et al.; Pharmacological Reviews (1994), 46, 157]. The presence of these receptors in different organs and tissues, make it possible that compounds able to block the effects of their hyperstimulation, may be advantageously used in the treatment and in the prophylaxis of different pathological situations.
Thus for example, since the stimulation of 5-HT.sub.4 atrial cardiac receptors, besides causing inotropic and chronotropic positive effects, is responsible for arrhythmias observed in some experimental conditions [Kauman et al.; Naunyn-Schmiedeberg's Arch Pharmacol, (1994) 349, 331], antagonists to these receptors may be used in the specific treatment of cardiac rhythm disorders, such as atrial fibrillation and other types of arrhythmias. In the gastro-intestinal tract since the 5-HT.sub.4 receptors mediate the prokinetic and secretory action of serotonin [Kilbinger et al; Naunyn-Schmiedeberg's Arch. Pharmacol. (1992) 345, 270; Burleigh; Eur. J. Pharmacol. (1991), 202, 277], it can be suggested the use of 5-HT.sub.4 antagonists in the treatment of disorders connected to an altered intestinal motility or secretion such as I.B.S. (irritable bowel syndrome), more particularly in those forms of I.B.S. combined to diarrhoic states. The presence of 5-HT.sub.4 receptors in central nervous system either in rat or in humans is not ubiquitary but limited to defined areas [Waeber et al.; Neuro Report (1993), 4, 1239; Monferini et al.; Life Sci. (1993), 52, 61] such as hippocampus, frontal cortex, basal ganglia and limbic structures. Compounds able to control an altered stimulation of the 5-HT.sub.4 receptors in central nervous system may therefore be used in the psychiatric and neurological fields such as the therapeutical treatment of anxiety, depression, psychosis, cognitive disorders, motility disorders and migraine. Moreover, since it has been described [Panocka et al.; Pharmacol. Biochem. Behav. (1995) 52, 255] that 5-HT.sub.4 receptors partially mediate the effect of 5-HT in controlling the ethanol intake, 5-HT.sub.4 antagonists might be useful in the treatment of alcohol abuse. 5-HT.sub.4 receptors are also involved in the control of other functions of the genitourinary and adrenal glands system, where they seem to mediate the release of steroidal hormones [Lefebre et al.; Neuroscience, (1992), 47, 999]. Consequently, pathologies characterized by an altered secretion of hormones or urinary incontinence might be also treated with compounds able to block the S-HT.sub.4 receptors.
WO 94/08965 describes N-alkylpiperidinyl-4-methyl carboxylic esters/amides of condensed ring systems having 5-HT.sub.4 antagonist activity. WO 93/18027 describes 5-HT.sub.4 receptor antagonists derived from a heterocyc
Bignotti Maura
Cereda Enzo
Martino Vincenzo
Sagrada Angelo
Schiavi Giovanni Battista
Boehringer Ingelheim Italia S.p.A.
Desai Rita
Devlin M-E. M.
Raymond R. P.
Rotman Alan L.
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