Synthese und absolute Konfiguration von Clemastin und seiner Isomeren

Abstract

Synthesis and Absolute Configuration of Clemastine and its Isomers. -Sztmmary. Condensation of 4-chloro-cc-mothylbenzhydrylalkohol (1) with 2-(2-chlorocthyl)-l-methylpyrrolidinc (2) gavc an isomeric mixture of 2-[2-(p-chloro-cr-methyl-cc-phenylbenz)-loxy)ethyl]-l-methylpyrrolidine (3) and 4-(p-chloro-cr-phenylbenzyloxy)-l-methyl-hexahydroazepi1~ (4). The separation of the four possible optically active isomers of 3 is described and their absolute configuration established by degradation to (R)-and (S)-l-methyl-2-pyrrolidincethanol ( 6 ) , respectively, and by an X-ray cristallographic analysis of the quarternary mcthiodide of t h e isomer 3-A. ClemastineClemastin (3-A) ist der wirksame Bestandteil des seit 1967 im Handel befindlichen Antihistaminicums Tavegyl. Es besitzt zwei chirale C-*4tome. Antipoden von Benzhydrylithern vom Typ des Diphenhydraininsl) init einem chiralen C-Atom sind sclion vereinzelt hergestellt worden 1-11. Es zeigte sich, dass bei stark wirksanien Antihistaminica \vie z. B.

Differential Effects of Histamine Receptor Antagonists on Human Natural Killer Cell Activity

“…A recent report indicates that long term incubation of lymphocytes with cimetidine at 10~3 M or higher concentrations induces significant lymphocyte toxicity [30]. As regards the histamine H|-receptor antagonist clemastin, our data clearly suggest that the earlier re ported NKCC suppression induced by this com pound [15] is not explained by its antagonism of H|-receptors since a clemastin isomer with very low affinity for the pharmacological receptor [23] was equally effective in NKCC suppression. An alterna tive explanation for the suppressive effects of clemas tin would be its membrane-stabilizing properties, since this effect of clemastin is unrelated to receptor specificity [21].…”

“…This suppression was seen to a similar extent when an isomer of clemastin (3-C) with very low H|-receptor affinity [23] was tested ( fig. 5).…”

Overview on the Recent Strategies for the Enantioselective Synthesis of 1, 1‐Diarylalkanes, Triarylmethanes and Related Molecules Containing the Diarylmethine Stereocenter

“…Later,t he Glorius group furtherd eveloped ad irected intramolecular sp 3 CÀHa rylation of 8-benzylquinoline for the enantioselective synthesis of triarylmethanes (Scheme 30). Using the rhodiumc atalyst allowed high yield of the products.…”

“…[1] This class of molecules has also found ap rofoundr ole in the development of variouspharmaceutical agentswith interesting physiologically important properties which include antidepressive, antilaxative, antiarrhymthmic, diuretic,l ocal-anesthetic and anticholinergic activities. [2] For example, Clemastinew as developed as af irst generation Histamine H 1 antagonist for the treatment of allergicd iseases, [3] and wasl ater modified and developed into Cetrizineh ydrochloride, which acts as a second generation antagonist with more selectivityt owards H 1 receptors. [4] Interestingly,t he (S)i somer of Cetrizine hydrochloride is more potent than the corresponding (R)-isomer.…”

Structures of histamine H1-receptor antagonists derived from the cimetidine group of histamine H2-receptor antagonists

“…This extended study included the compounds of which the crystal structures are reported here: seven of the older types of H~ antagonist: methapyrilene (13) (Clark & Palenik, 1972), Z isomer of triprolidine (Pepinsky, Rathlev & Turley, 1959) and triprolidine (14) (James & Williams, 1974a) and (15), (R)-and (S)-chloropheniramine (16) and (17) (James & Williams, 1974b), diphenylpyraline (18) (Precigoux, Barrans, Busetta & Marsau, 1975), clemastine (19) (Ebnother & Weber, 1976), and cyproheptadine (20) (Birknes, 1977); five thiadiazole-l-oxide derivatives compounds, (21)-(25), that had been synthesized and screened for H~ antagonist activity; the isocytosines (26), (27) and (28). This extended study included the compounds of which the crystal structures are reported here: seven of the older types of H~ antagonist: methapyrilene (13) (Clark & Palenik, 1972), Z isomer of triprolidine (Pepinsky, Rathlev & Turley, 1959) and triprolidine (14) (James & Williams, 1974a) and (15), (R)-and (S)-chloropheniramine (16) and (17) (James & Williams, 1974b), diphenylpyraline (18) (Precigoux, Barrans, Busetta & Marsau, 1975), clemastine (19) (Ebnother & Weber, 1976), and cyproheptadine (20) (Birknes, 1977); five thiadiazole-l-oxide derivatives compounds, (21)-(25), that had been synthesized and screened for H~ antagonist activity; the isocytosines (26), (27) and (28).…”