Therapeutic heterocyclic compounds

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

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514369, 514376, 514392, 514414, 514415, 514422, 514424, 540362, 548182, 548213, 548214, 548229, 5483121, 5483147, 5483251, 548524, 548543, 548469, 548491, 548504, A61K 31415, A61K 3142, C07C32500, C07D40306

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057444668

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BRIEF SUMMARY
This application is a 3H of PCT/GB95/00142 filed Jan. 25, 1995. 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 (Hoyer et al., Pharmacol. Rev., 46, 157-203, 1994), 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 "migraine".
There has now been discovered a class of compounds which not only demonstrate improved metabolic stability and the necessary 5HT.sub.1 receptor agonism, but also display a potentially selective inhibition of neurogenic inflammation and the nerve pathways responsible for the transmission of head pain. The compounds also display partial agonism at the 5HT.sub.1 receptor and thus may have reduced side effects compared to previously known 5HT.sub.1 receptor agonists.
Thus, according to a first aspect of the present invention there is provided a compound of formula (I): ##STR2## wherein
R and R.sup.1 are each independently hydrogen or C.sub.1-4 alkyl or R and R.sup.1 are linked to form an azetidine ring;
A is C.sub.3-6 cycloalkyl or C.sub.1-3 alkyl-C.sub.3-6 cycloalkyl;
n is an integer of from 0 to 3;
W is a five or six membered ring containing from 1 to 3 hetero atoms independently selected from nitrogen, oxygen, and sulphur, said ring being optionally substituted by one or more substituents independently selected from C.sub.1-4 alkyl, C.sub.3-8 cycloalkyl, carbonyl or sulphonyl and optionally said ring is fused to a phenyl ring; or W is an aryl, heteroaryl, aryloxy or thiophenoxy group containing from 1 to 8 carbon atoms said group being optionally substituted by one or more substituents independently selected from C.sub.1-4 alkyl, phenyl, amino or mono- or di- C.sub.1-4 alkylamino, and said heteroaryl group containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulphur; or W is a group --SO.sub.2 NR.sup.6 R.sup.7 --NHC(O)R.sup.6 R.sup.7 or --C(O)NHR.sup.6 R.sup.7 wherein R.sup.6 and R.sup.7 are independently selected from hydrogen, C.sub.1-4 alkyl optionally substituted by an aryl group or C.sub.1-4 alkoxy;
and salts, solvates and physiologically functional derivatives thereof;
with the proviso that said compound is not -indole or -H-indole
Compounds of formula (I) wherein A is C.sub.3-6 cycloalkyl are particularly suitable.
Preferably, R and R.sup.1 are each independently h

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