Azetidine, pyrrolidine and piperidine derivatives as 5HT1 recept

Details Azetidine, pyrrolidine and piperidine derivatives as 5HT1 recept Azetidine, pyrrolidine and piperidine derivatives as 5HT1 recept

1997-05-28

2000-02-15

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514331, 514376, 514415, 514414, 546208, 548221, 548468, 548491, A61K 31445, C07D20902, C07D40100, C07D26358

Patent

active

060253746

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a class of substituted azetidine, pyrrolidine and piperidine derivatives which act on 5-hydroxytryptamine (5-HT) receptors, being selective agonists of so-called "5-HT.sub.1 -like" receptors. They are therefore useful in the treatment of clinical conditions for which a selective agonist of these receptors is indicated.
It has been known for some time that 5-HT.sub.1 -like receptor agonists which exhibit selective vasoconstrictor activity are of use in the treatment of migraine (see, for example, A. Doenicke et al., The Lancet, 1988, Vol. 1, 1309-11; and W. Feniuk and P. P. A. Humphrey, Drug Development Research, 1992, 26, 235-240).
The human 5-HT.sub.1 -like or 5-HT.sub.1D receptor has recently been shown by molecular cloning techniques to exist in two distinct subtypes. These subtypes have been termed 5-HT.sub.1D.alpha. (or 5-HT.sub.1D-1) and 5-HT.sub.1D.beta. (or 5-HT.sub.1D-2), and their amino acid sequences are disclosed and claimed in WO-A-91/17174.
The 5-HT.sub.1D.alpha. receptor subtype in humans is believed to reside on sensory terminals in the dura mater. Stimulation of the 5-HT.sub.1D.alpha. subtype inhibits the release of inflammatory neuropeptides which are thought to contribute to the headache pain of migraine. The human 5-HT.sub.1D.beta. receptor subtype, meanwhile, is located predominantly on the blood vessels and in the brain, and hence may play a part in mediating constriction of cerebral and coronary arteries, as well as CNS effects.
Administration of the prototypical 5-HT.sub.1D agonist sumatriptan (GR43175) to humans is known to give rise at therapeutic doses to certain adverse cardiovascular events (see, for example, F. Willett et al., Br. Med. J., 1992, 304, 1415; J. P. Ottervanger et al., The Lancet, 1993, 341, 861-2; and D. N. Bateman, The Lancet, 1993, 341, 221-4). Since sumatriptan barely discriminates between the human 5-HT.sub.1D.alpha. and 5-HT.sub.1D.beta. receptor subtypes (cf. WO-A-91/17174, Table 1), and since it is the blood vessels with which the 5-HT.sub.1D.beta. subtype is most closely associated, it is believed that the cardiovascular side-effects observed with sumatriptan can be attributed to stimulation of the 5-HT.sub.1D.beta. receptor subtype. It is accordingly considered (cf. G. W. Rebeck et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 3666-9) that compounds which can interact selectively with the 5-HT.sub.1D.alpha. receptor subtype, whilst having a less pronounced action at the 5-HT.sub.1D.beta. subtype, might be free from, or at any rate less prone to, the undesirable cardiovascular and other side-effects associated with non-subtype-selective 5-HT.sub.1D receptor agonists, whilst at the same time maintaining a beneficial level of anti-migraine activity.
The compounds of the present invention, being selective 5-HT.sub.1 -like receptor agonists, are accordingly of benefit in the treatment of migraine and associated conditions, e.g. cluster headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, tension headache and paediatric migraine. In particular, the compounds according to this invention are potent agonists of the human 5-HT.sub.1D.alpha. receptor subtype. Moreover, the compounds in accordance with this invention have been found to possess at least a 10-fold selective affinity for the 5-HT.sub.1D.alpha. receptor subtype relative to the 5-HT.sub.1D.beta. subtype, and they can therefore be expected to manifest fewer side-effects than those associated with non-subtype-selective 5-HT.sub.1D receptor agonists.
Several distinct classes of heteroaromatic compounds based on inter alia a substituted tryptamine ring system are described in published International patent applications 91/18897, 94/02460 and 94/02477. The compounds described therein are stated to be agonists of 5-HT.sub.1 -like receptors, and accordingly to be of particular use in the treatment of migraine and associated conditions. None of these publications, however, discloses or even suggests the substituted azetidine, pyrrolidine and piperidi

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