Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-11-22
1999-10-05
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548229, A61K 3142, C07D41304, C07P41306
Patent
active
059624868
DESCRIPTION:
BRIEF SUMMARY
The present invention is concerned with new chemical compounds, their preparation, pharmaceutical formulations containing them and their use in medicine, particularly the prophylaxis and treatment of migraine.
Receptors which mediate the actions of 5-hydroxytryptamine (5-HT) have been identified in mammals in both the periphery and the brain. Currently, as many as seven 5-HT receptor classes are proposed (Humphrey et al., Trends Pharmac Sci., 14, 233-236, 1993), although only the classes nominated 5-HT.sub.1, 5-HT.sub.2, 5-HT.sub.3, and 5-HT.sub.4 have established physiological roles. European Patent Specification 0313397 describes a class of 5-HT agonists which act selectively at a particular subtype of 5-HT.sub.1 receptor and are effective therapeutic agents for the treatment of clinical conditions in which a selective agonist for this type of receptor is indicated. For example, the receptor in question mediates selective cranial arterial vasoconstriction and inhibition of plasma protein extravasation into the dura mater evoked by activation of the Vth (trigeminal) nerve. The compounds described in the European specification are therefore beneficial in the treatment or prophylaxis of conditions wherein these actions are indicated, for example migraine, a condition associated with and/or neurogenically-evoked inflammation dilation of the cranial vasculature. However, it is within the scope of the earlier application that the target tissue may be any tissue wherein action is mediated by 5-HT.sub.1 receptors of the type referred to above.
EP-A-0486666 discloses a class of compounds having exceptional activity at the 5-HT.sub.1 receptor mentioned above and excellent absorption following oral dosing. These properties render the compounds particularly useful for certain medical applications, notably the prophylaxis and treatment of migraine, cluster headache and headache associated with vascular disorders, hereinafter referred to collectively as "migraines".
There has now been discovered a class of compounds which, although having relatively little activity themselves at the 5-HT.sub.1 receptor, act as prodrugs releasing active compound after administration. Such compounds thereby provide active compound with improved metabolic stability and bioavailability.
Thus, according to a first aspect of the present invention there is provided a compound of formula (I): ##STR2## wherein A is C.sub.1-6 alkyl, --O--C.sub.1-6 alkyl, or --O--phenyl, or phenyl, optionally substituted by C.sub.1-3 alkyl or halogen; ##STR3## wherein R is hydrogen or C.sub.1-4 alkyl, X is --O--, --S--, --NH--, or --CH.sub.2 --, Y is oxygen or sulphur and the chiral centre * in formula (i) or )ii) is in its (S) or (R) form or is a mixture thereof in any proportions; and ##STR4## wherein R.sup.1 and R.sup.2 are independently selected from hydrogen and C.sub.1-4 alkyl and R.sup.3 is hydrogen or C.sub.1-4 alkyl; and salts, solvates and physiologically functional derivatives thereof.
Preferably W is a group of formula (i) and Z is a group of formula (iv)
In another aspect the present invention provides a compound of the formula (Ia) ##STR5## wherein A is C.sub.1-6 alkyl, --O----C.sub.1-6 alkyl, --O--phenyl or phenyl, optionally substituted by C.sub.1-3 alkyl or halogen; alkyl and salts, solvates and physiologically functional derivatives thereof.
Preferred compounds of formula (Ia) are those wherein n is 1, X is --O-- and Y is oxygen. Compounds wherein R.sup.1 and R.sup.2 are independently selected from hydrogen and methyl are preferred, with compounds wherein R.sup.1 and R.sup.2 are both methyl being particularly preferred.
Compounds of formula (I) and (Ia) are capable of existing as optical isomers. All such isomers, individually and as mixtures, are included within the scope of the present invention.
Examples of preferred compounds of the invention include: acetate; oxazolidin-2-one acetate; oxazolidin-2-one acetate; in-2-one; oxazolidin-2-one acetate; and acetate.
Physiologically acceptable salts are particularly suitable for medical application
REFERENCES:
patent: 5348968 (1994-09-01), Lavielle et al.
patent: 5399574 (1995-03-01), Robertson et al.
patent: 5466699 (1995-11-01), Robertson et al.
Blade Robert John
Pang Yih Sang
Selwood David Lawrence
Mitchell Kenneth F.
Morris Patricia L.
Zeneca Limited
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