Histamine receptor antagonists preparations

The principal OTC pharmaceutical products include cold remedies, vitamins and mineral preparations, antacids, analgesics, topical antibiotics, antiftingals and antiseptics, and laxatives. Others include suntan products, ophthalmic solutions, hemorrhoidal products, sleep aids, and dermatological products for treatment of acne, dandmff, insect parasites, bums, dry skin, warts, and foot care products (11). More recent prescription-to-OTC switches have included hydrocortisone, antihistamine and decongestant products, antiftingal agents, and, as of 1995, several histamine H2-receptor antagonists. 

From 1981 to 1995 other dmgs switched to OTC were the antifiingal preparations containing micona2ole nitrate [22832-87-7] (7) and clotrima2ole [23593-75-1] (8) the antiinflammatory agent ibuprofen [15687-27-1] (9) and the histamine H2-receptor antagonists famotidine [76824-35-6] (10) and cimetidine [51481-61-9] (11). 

The following amides prepared from 4-(3-nitro-l-pyrazolyl)butanoic acid, CDI, and primary amines represent partial structures of the histamine H2-receptor antagonists roxatidine, cimetidine, ranitidine, and famotidine [37]... 

In the intense search for inhibitors of gastric acid secretion a new class of potent histamine H2-receptor antagonist was discovered. These 1,2,5-thiadiazole-l-oxides (27) were prepared by nucleophilic addition of primary amines to 3,4-dialkoxy-l,2,5-thiadiazole 1-oxide (25). Sequential addition of two different amines to positions C(3) and C(4), respectively, could be achieved via the 3-alkoxy-4-amino adduct (26) (Scheme 5) <82JMC207,82JMC210>. 

Early evidence that prejunctional histamine H3-receptors may modulate the sympathetic nerve activity on the heart was provided by Luo et al., (1991). These authors clearly stated that the selective H3-agonist (R)a-methylhistamine attenuates the inotropic response induced by transmural stimulation of the adrenergic nerve terminals in the isolated right atrium, without affecting basal contractile force of the preparation or the positive inotropic effect elicited by exogenous noradrenaline. The effect of (R)a-methylhistamine, which is not modified by Hi and H2-receptor blockade, was reversed by the specific H3-receptor antagonist thioperamide, at concentrations which do not influence the inhibitory activity mediated by other presynaptic receptors, like a2-adrenoceptors. 

Since the disclosure of thioperamide 1 (K = 4 nM) as a potent and selective histamine H3 receptor antagonist [1], there has been a large number of 4(5)-substituted imidazole derivatives prepared and evaluated for their H3 receptor affinity. Most of the efforts directed towards the design of new H3 antagonists have... 

An example of a drug separated by preparative HPLC is cetirizine dihydrochloride, a racemic drug that is a second generation antihistamine Hi receptor antagonist. Studies on the effect of racemic and R (25) and S-Cetirizine (26) on nasal resistance indicated that both racemic and the R-enantiomer had similar activity. The racemate and R-enantiomer inhibit histamine and induced an increase in nasal resistance, thus indicating the antihistaminic properties of R-Cetirizine (45). TheiS-enantio-... 

H. Stark and co-workers prepared novel histamine Hs-receptor antagonists with carbonyl-substituted 4-[(3-phenoxy)propyl]-1/-/-imidazole structures. The Meyer-Schuster rearrangement was used for the synthesis of one of the compounds. The p-hydroxybenzaldehyde derivative was reacted with ethynylmagnesium bromide to afford a secondary propargylic alcohol. Upon hydrolysis with 2N HCI in a refluxing ethanol/acetone mixture, the corresponding p-hydroxy cinnamaldehyde was obtained. 

Several sulfamoylamidine derivatives have shown7 activity as histamine H2 receptor antagonists and are valuable as gastric secretion inhibitors (see Chapter 11, p. 232), e.g. 3-(4-thiazolemethylthio) propionamidines (149), prepared by Lewis acid catalysed reaction of the propionitrile (150) with sulfamide (136) (Scheme 61). 

Cyclimorph cyclizlne tartrate morphine tartrate, cyclizine [ban, inn) (cyclizIne hydrochloride (usan) cyclizlne tartrate BW 47-83 Valoid ) is one of the piperazine series of histamine H -receptor ANTAGONISTS, and a muscarinic CHOLINOCEPTOR antagonist with SEDATIVE actions. It can be used orally or systemically as an antiemetic in the treatment of nausea, vomiting, vertigo, motion sickness and disorders of the balance function of the inner ear. It is available in preparation together with morphine (e.g. Cyclimorph ). 

Studies of histamine-stimulated adenylate cyclase activity in broken cell preparations of both peripheral and central tissues suggest that the effect of histamine on cyclic-AMP-generating systems is exclusively associated with H2-receptor stimulation [83, 179-183, 188-191]. The data obtained with selective H2-receptor antagonists in slices of guinea-pig hippocampus [ 165]... 

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