Histamine H.sub.3 receptor ligands

Details Histamine H.sub.3 receptor ligands Histamine H.sub.3 receptor ligands

2000-03-13

2000-12-12

Gerstl, Robert

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

548134, C07D41706, A01K 31433

Patent

active

061599948

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.sub.1 and, H.sub.2 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 (H.sub.3) 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 confined 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.
According to the present invention, there is provided a compound of the formula ##STR1## wherein R.sup.1 is 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, carboxy (C.sub.1 to C.sub.6) alkyl, formyl, C.sub.1 to C.sub.6 alkylcarbonyl, C.sub.1 to C.sub.6 alkylcarbonylalkoxy, 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, sulfamoyl and cyano; ##STR2## replaces any available hydrogen atom on a carbon or nitrogen atom in the ring which includes X; atoms may be replaced by halogen atoms, and up to 2 carbon atoms may be replaced by oxygen, nitrogen or sulfur atoms, provided that R.sup.2 does not contain a --O--O-- group; in the ring which includes X, and is hydrogen or C.sub.1 to C.sub.15 hydrocarbyl, in which one or more hydrogen atoms may be replaced by halogen atoms, and up to 3 carbon atoms may be replaced by oxygen, nitrogen or sulfur atoms, provided that R.sup.3 does not contain a --O--O-- group; C.sub.1 to C.sub.6 hydrocarbyl, and aryl (C.sub.1 to C.sub.3 alkyl); wherein R.sup.5 is H, non-aromatic C.sub.1 to C.sub.6 hydrocarbyl, or aryl (C.sub.1 to C.sub.3 alkyl), or one of Y and Z is non-aromatic C.sub.1 to C.sub.6 hydrocarbyl

REFERENCES:
patent: 5580889 (1996-12-01), Shiokawa
Aran et al., "Reactivity of 4-amino-2-benzyl-2,3-dihydro-3-oxo-1,2,5-thiadiazole 1,1-dioxide towards amines: synthesis of potential histamine H.sub. -receptor antagonists, " J. Chem. Soc., 1:955-959 (1987).
Hoffman et al., "Conformational requirements for hisamine H.sub. -2-receptor inhibitors: A structure-activity of phenylene analogues related to cimetidine and tiotidine," J. of Med. Chem.26:140-144 (1983).

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