Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-05-13
2000-04-11
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546201, A61K 31445, C07D40114
Patent
active
060488786
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a class of substituted 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.sbsb..alpha. (or 5-HT.sub.1D-1) and 5-HT.sub.1D.sbsb..beta. (or 5-HT.sub.1D-2), and their amino acid sequences are disclosed and claimed in WO-A-91117174.
The 5-HT.sub.1D.sbsb..alpha. receptor subtype in humans is believed to reside on sensory terminals in the dura mater. Stimulation of the 5-HT.sub.1D.sbsb..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.sbsb..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.sbsb..alpha. and 5-HT.sub.1D.sbsb..beta. receptor subtypes (cf. WO-A-91/17174, Table 1), and since it is the blood vessels with which the 5-HT.sub.1D.sbsb..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.sbsb..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.sbsb..beta. receptor subtype, whilst having a less pronounced action at the 5-HT.sub.1D.sbsb..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.sbsb..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.sbsb..alpha. receptor subtype relative to the 5-HT.sub.1D.sbsb..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 substituted five-membered heteroaromatic compounds are described in published European patent applications 0438230, 0494774 and 0497512, and published International patent applications 93/18029, 94/02477 and 94/03446. 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 publ
REFERENCES:
Cram and Hammond, "Organic Chemistry", McGraw-Hill Book Co., NY (1964) 2nd Ed. pp. 565-567.
Castro Pineiro Jose Luis
Collins Ian James
MacLeod Angus Murray
Moyes Christopher Richard
Rowley Michael
McGinnis James L.
Merck Sharp & Dohme Ltd.
Morris Patricia L.
Rose David L.
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