Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-10-06
2000-06-27
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514399, 514400, 514311, 514397, 546 14, 546153, 548110, 5483111, 5483121, C07D23364, C07D40112, A61K 314164
Patent
active
060808713
DESCRIPTION:
BRIEF SUMMARY
This invention relates to compounds which bind to histamine H.sub.3 receptors, and to methods of making such compounds.
Histamine is well known as a mediator in certain hypersensitive reactions of the body, such as allergic rashes, hayfever and asthma. These conditions are now commonly treated with potent antagonists of histamine, so-called "antihistamines".
In the 1940s, it was noted that some physiological effects of histamine, such as increased gastric acid secretion and cardiac stimulation, were not blocked by the antihistamines which were then available. This led to the proposal that histamine receptors exist in at least two distinct types, referred to as H, and H2 receptors. Subsequently, H.sub.2 antagonists (such as cimetidine, ranitidine and famotidine) were identified, and they have become important in the treatment of gastric ulcers.
In the early 1980s, it was established that histamine also has a role as a neurotransmitter in the central nervous system. Arrang et al., Nature 302, 832 to 837 (1983), proposed the existence of a third histamine receptor subtype (H3) located presynaptically on histaminergic nerve endings. Arrang et al. postulated that the H.sub.3 receptor is involved in inhibiting the synthesis and release of histamine in a negative feedback mechanism. The existence of the H.sub.3 receptor was subsequently confirmed by the development of selective H.sub.3 agonists and antagonists (Arrang et al., Nature 327, 117 to 123 (1987)). The H.sub.3 receptor has subsequently been shown to regulate the release of other neurotransmitters both in the central nervous system and in peripheral organs, in particular in the lungs and GI tract. In addition, H.sub.3 receptors are reported to regulate the release of histamine from mast cells and enterochromaffin-like cells.
A need exists for potent and selective H.sub.3 ligands (both agonists and antagonists) as tools in the study of the role of histamine as a neurotransmitter, and in its roles as a neuro, endo- and paracrine hormone. It has also been anticipated that H.sub.3 ligands will have therapeutic utility for a number of indications including use as sedatives, sleep regulators, anticonvulsants, regulators of hypothalamo-hypophyseal secretion, antidepressants and modulators of cerebral circulation, and in the treatment of asthma and irritable bowel syndrome.
A number of imidazole derivatives have been proposed in the patent literature as H.sub.3 ligands. Representative are the disclosures of EP-A-0197840, EP-A-0214058, EP-A-0458661, EP-A-0494010, EP-A-0531219, WO91/17146, WO92/15567, WO93/01812, WO93/12093, WO93/12107, WO93/12108, WO93/14070, WO93/20061, WO94/17058, WO95/06037, WO95/11894, WO95/14007, U.S. Pat. No. 4,988,689 and U.S. Pat. No. 5,217,986.
The present invention provides a new class of H.sub.3 receptor ligands, having a sulfonamide or sulfamide group spaced from an imidazole ring.
According to the present invention, there is provided a compound of the formula ##STR2## or ##STR3## wherein R represents from zero to two substituents selected from C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylthio, carboxy, C.sub.1 to C.sub.6 carboalkoxy, nitro, trihalomethyl, hydroxy, amino, C.sub.1 to C.sub.6 alkylamino, di(C.sub.1 to C.sub.6 alkyl)amino, aryl, C.sub.1 to C.sub.6 alkylaryl, halo, sulphamoyl and cyano, atoms may be replaced by halogen, and up to four carbon atoms [and especially from 0 to 3 carbon atoms] may be replaced by oxygen, nitrogen or sulphur atoms, provided that R.sup.1 does not contain an --O--O-- group), hydrogen atoms may be replaced by halogen, and up to three carbon atoms may be replaced by oxygen, nitrogen or sulphur atoms, provided that R.sup.2 does not contain an --O--O-- group), ##STR4## or one X group is --N(R.sup.4)--, --O-- or --S-- (provided that this X group is not adjacent the --NR.sup.2 -- group) and the remaining X groups are independently ##STR5## wherein R.sup.3 is H, C.sub.1 to C.sub.6 alkyl, C.sub.2 to C.sub.6 alkenyl, --CO.sub.2 R.sup.5, --CONR.sup.5.sub.2, --CR.sup.5.sub.2 OR
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Cooke Tracey
Harper Elaine Anne
Kalindjian Sarkis Barret
Low Caroline Minli Rachel
McDonald Iain Mair
Higel Floyd D.
James Black Foundation Limited
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