Rigidified 2-aminopyrimidines as histamine H4 receptor antagonists: Effects of substitution about the rigidifying ring

Synthesis and antiviral activity of 4-(7,7-dimethyl-4-[4-{N-aroyl/benzyl}1-piperazinyl]-5,6,7,8-tetrahydroquinazolin-2-yl)morpholine derivatives

“…Commercially available 3,3-dimethyl cyclohexanone (6) on treatment with dimethyl carbonate in the presence of sodium hydride in THF gave methyl 4,4-dimethyl-2-oxocyclohexane-1-carboxylate (5). 20,21 The intermediate 5 undergoes cyclization with S-methylisothiourea hemisulfate in water to provide 7,7-dimethyl-2-(methylthio)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (6). 8 7,7-Dimethyl-2-morpholino-5,6,7,8-tetrahydroquinazolin-4(3H)-one (7) was synthesized from 6 by replacing the SMe group with morpholine.…”

Histamine H4 Receptor: A Novel Target for Inflammation Therapy

“…Further SAR studies with different substitutions on the rigidified 2-aminopyrimidine has resulted in compounds with an alphaspiro moiety which is more potent than the corresponding alpha-substituted or alpha-gem-disubstituted analogs. These compounds were shown to reduce H 4 agonist (clobenpropit)-induced itch in mice model [75]. It was found that compound 34 cis-4-(Piperazin-1-yl)-5,6,7a, 8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a H 4 R antagonist showed anti-inflammatory activity in a peritonitis model and reduction of pain in the carrageenan induced thermal hyperalgesia model [76].…”

Histamine H4 Receptor Ligands: Future Applications and State of Art

“…Meta ‐substituted ( 34 , K i 282 n m , pEC 50 6.57, E max ‐79%) or conformationally restricted ( 35 , K i 146 n m , pEC 50 7.36, E max ‐95%) analogs showed inverse agonist activity. The variation in the cycloalkyl and its substituents using as a prototype the A‐943931 was also accessed . These analogs showed slightly lower activity than the prototype, but some compounds showed comparable activity to A‐943931, and the compounds were more potent in the human H 4 R. Nevertheless, compound 36 (p K b 8.57) showed nice antipruritic activity in mice (ED 50 1 mmol/kg) and some selectivity for the human H 4 R (rat H 4 R p K b 6.76 and mouse H 4 R p K b 7.82).…”