H₂‐Antihistaminika, 28. Mitt. Synthese und H₂‐antagonistische Wirkung 3‐(3‐piperidinomethyl‐phenoxy)propyl‐substituierter Kohlensäurederivate und Analoge

Abstract

Buschauer, Krämer und Schunack Arch. Pharm. und Kühlen 1.Og (4mmol) 8b in 40ml trockenem Diethylether zutropfen. Nach 1 h Rühren bei Raumtemp. wurden 20 ml Wasser zugegeben und die mit MgSO, getrockneten Etherextrakte i. Vak. eingedampft. Der Riickstand wurde aus Methanomasser (70 %) urnkristallisiert. Farblose Prismen, Schmp. 98", Ausb. 0.8g (78 %). C17H2202 (258.3) Ber. C79.3 H 8.58; Gef. C79.3H 8.77Mol.-Masse 258 (ms). -IR (KBr): 3430, 2960cm-l. -'H-NMR (CDCI,): 6 (ppm) = 1.15 (d, J = 7Hz, 3H), 1.2-1.9 (m, 9H, H/DSH), 2.1 (d, 4H), 2.8 (m, lH), 4.15 (m, lH), 6.7-7.35 (m, 4H). Literntur 114. Mitt. über Untersuchungen an Pyran-Derivaten; 113. Mitt. F. Es wurden 3-(3-piperidinomethyI-phenoxy)propyl-substituierte Kohiensäurederivate wie Harnstoffe, Thioharnstoffe, Guanidine und Cyanoguanidine sowie analoge Nitroethendiamine dargesteut und am isolierten Meerschweinchenvorhof und zum Teil an der histaminstimulierten Säuresekretion der narkotisierten Ratte auf H2-antagonistische Wirkung untersucht. + Herm Prof. Dr. Joachim Knabe mit besten Wünschen zum 65. Geburtstag gewidmet. 0365-6233/mm5-0434 s u 2 . m Q VCH Verlagsgesekhah mbH, D-6940 Weinheim, 1986

[3H]UR‐DE257: Development of a Tritium‐Labeled Squaramide‐Type Selective Histamine H2 Receptor Antagonist

“…[23] For the synthesis of the cyanoguanidines (Scheme 1), the amine 1 was treated with diphenyl cyanocarbonimidate [24] by analogy with published protocols [5,23] formed with an excess of the respective diamine, yielded the cyanoguanidines 3 and 4. By analogy with known procedures, [25] condensation of 1 with 1,1-bis(methylthio)-2-nitroethene gave intermediate 5, and subsequent reaction with an excess of pentane-1,5-diamine yielded the nitroethenediamine 6. For the synthesis of roxatidine-like structures, the wphthalimidoalkanoic acids 7 and 8, [26,27] obtained from the respective w-aminoalkanoic acids and phthalic anhydride as described previously, [18,26,27] were treated with compound 1 using carbonyldiimidazole (CDI) as coupling reagent to yield the amides 9 and 10.…”

Structure-Activity Relationships of Histamine H2 Receptor Ligands+

“…H 2 R antagonistic activity has also been found in conformationally constrained compounds with an aryl ring instead of the chain, e.g. the imidazolylphenylformamidine, mifentidine (48) [109,111], or analogues having different heterocyclic rings instead of imidazole and phenyl, for example pyridyltriazoles [112] and 2-guanidinothiazoles with 4-furyl [113,114], 4-phenyl (see DA 4643 [111]), 4-(4-imidazolyl) (e.g., zaltidine [115,116]) or 4-(2-pyridyl) substituents (e.g., 49 [117]). …”

“…The structural analogues of impromidine described in the literature include, for example, chiral compounds with branched cimetidine-like or homohistamine partial structures [44,45] or substances characterised by other substructures from H 2 R antagonists like thiazoles and furans derived from tiotidine, nizatidine and ranitidine [46,47]. Completely different structures replacing the 5-methylimidazole group are present in the case of hybrid molecules combining the imidazolylpropylguanidine moiety with, for example, arylalkyl [48][49][50][51][52][53][54][55][56], diarylalkyl originating from H 1 R antagonists [57][58][59][60][61], dihydropyridine from calcium channel blockers [62,63] and benzoylimidazolone groups [64] from phosphodiesterase inhibitors (for reviews see [15,65,66]). Examples of H 2 R-selective guanidine-type agonists are depicted in (Fig.…”