3-Hydroxyquinuclidine ester

Interesting pharmacological properties were discovered in 3-hydroxyquinuclidine esters (156), which can be considered as bicyclic analogs of the 2-dialkylaminoethyl esters (157). The neurotropic activity of these esters with various carboxylic acids is well known. Investigations of Sternbach, Kaiser, and co-workers 103,140 148,184... 

Very strong cholinomimetic activity was found for 3-hydroxyquinuclidine esters with arylaliphatic acids. For example, 3-(a,a-diphenylpropionyloxy)quinuclidine (162) (which is known in the USSR as Aprolidine219-218 significantly exceeds the similar 2-diethylaminoethyl ester (163) (in the USSRAprophen) in its influence on the central and peripheral cholinergic systems.219... 

Structurally quinuclidine is related to norlupinane (II), pyrrolizidine (III) and other bicyclic nitrogen containing compounds which form an important part of many pharmacologically active alkaloids and synthetic drugs. Some derivatives of quinuclidine also bear a structural resemblance to synthetic compounds derived from alkylamino-alkanes. For example, the 3-hydroxyquinuclidine esters... 

Hydrogenation of quinuclidon-3, or of its derivatives, to the corresponding alcohols followed by esterification gave 3-hydroxyquinuclidine esters with ahphatic, arylaliphatic and aromatic acids of great pharmacological interest [74, 79, 80, 106, 107]. 

The 3-hydroxyquinuclidine esters also exerted a greater and more prolonged action upon the central nervous system than the esters of 2-diethylamino-etha-nol. In the course of investigating a group of iV-aIkyl-3-hydroxy-piperidine ben-zilates, Abood et al. [170], Lipman, Shurrager and Abood [179] noted that the compounds produced a marked and characteristic h5q>eractivity in rats which ac-... 

Methyl 3-hydroxy-4-methyl-2-methylenepentanoate3 was obtained by the means of a Baylis-Hillman reaction4 5 as follows. To a 500-mL, one-necked, round-bottomed flask equipped with a magnetic stir bar were added 82.3 g (1.14 mol) of isobutyraldehyde, 109.2 g (1.27 mol) of methyl acrylate, 7.28 g (0.057 mol) of 3-hydroxyquinuclidine, and 20 mL of chloroform (to predissolve the catalyst). The mixture was stirred at room temperature for 48 hr and concentrated to give the hydroxy ester (50.0 g, 28%) as a pale yellow oil. The product can be distilled (bp 83-87°C at 3 torr) or used in Part A without further purification. In the latter event, yields are 10-20% lower. 

Grignard reactions on quinuclidine-2-carboxylic esters (73) and 3-hydroxyquinuclidine-3-carboxylic esters (87 and 88) gave the corresponding carbinols (89)24 and pinacols (90).144... 

P-Hydroxy-2P-tropanecarboxylic Acid Methyl Ester, Benzoate 3-Hydroxypropene 3-Hydroxyquinuclidine 3-Hydroxyquinuclidine Benzilate 3-(Mercaptomethyl)-l,2,3-benzotriazin-4(3H)-one 0,0-Dimethyl Phosphorodithioate 3-(Mercaptomethyl)-l,2,3-benzotriazin-4(3H)-one 0,0-Dimethyl Phosphorodithioate S-Ester 3-Methyl-4-(dimethylamino)phenyl Methylcarbamate... 

Esters of 3-Hydroxyquinuclidine and Its Homologues with Aliphatic Acids. . 306... 

To find the structure-activity relationships in this series esters of both non-substituted 3-hydroxyquinuclidine and 3-hydroxyquinuclidines having various substituents in the 3-, 6- and other positions have been synthesized. Esters of homologous aminoalcohols 3-hydroxymethyl- and 3-(j8-hydroxyethyl)-qui-nuchdines, esters of isomeric and homologous 1-azabicycloalkanols - 1-aza-bicyclo(3,2,l)-octanol-6 and l-azabicyclo(3,3,2)-nonanole-4 and also esters containing the opened 3-hydroxy-quinuclidine structure, e.g. AT-alkyl-3-hy-... 

Esters of 3-Hydroxyquinuclidine, 3-Hydroxymethyl- and 3-(j8-Hydroxy-ethyl)-Quinuchdine with Aromatic and Heterocyclic Acids... 

In this group the following compounds have been studied four 3-hydroxy-quinuclidine esters with phenylaliphatic acids, i.e. the phenylacetic (IVi), phenylpropionic (IV k), phenoxyacetic (IV1) and cinnamic (IVm) esters, and two esters of 3-hydroxyquinuclidine with diphenylaliphatic acids, i.e. the diphenylpropionic (IVo) and benzilic esters (IVp). 

Some esters of 3-hydroxyquinuclidine with diphenylaliphatic acids, i.e. diphenylacetic [compound (IVn)], benzilic (IVp) and fluorene-9-carboxylic esters (IVq) have been synthesized by Sternbach and Kaiser [155-157] and investigated by Randall, Benson and Stefko [158]. These compounds have been shown to have an antiacetylcholine action on isolated rabbit intestine, the i-, /-forms of (IVn) being equal to atropine in activity, and (IVp) and (IVq) being twice as active as atropine. 

A more detailed investigation of the pharmacological properties of compounds (IVn), (IVo) and (IVp) was of interest as they can be regarded as the bicyclic analogues of adiphenine (LXX), 2-diethylaminoethanol diphenyl-propionate (LXXI) and benactizine (LXXII). There is still closer relationship between these derivatives of 3-hydroxyquinuclidine and the corresponding esters of V-alkylpiperidol-3 [compounds (LXXIII)-(LXXV)]. 

Table 4 Peripheral anticholinergic activity of 3-hydroxyquinuclidine and 2-diethylamino-ethanol esters [177]...

The data in Table 4 also show that of the quinuclidine and diethylaminoethanol derivatives the benzilic acid esters (LXXII) and (IVp) are more potent than the corresponding diphenylpropionates (LXXI) and (IVo). Enhancement of anticholinergic activity is not accompanied by a parallel increase in toxicity (Table 5). The benzilic acid esters were somewhat more toxic than the diphenylpropionates. However, esters of 3-hydroxyquinuclidine did not differ substantially from the corresponding esters of 2-diethylaminoethanol in toxicity [only (IVo) being somewhat more toxic than (LXXI) on intravenous administration]. 

Intensity (ordinate) and duration (dbscisse) of hyperactivity induced by Aprophen-1 (Compound LXXI), Benactizine -II (Compound LXXII), Aprolidine - III (Compound I Vo) and Benzilic acid ester of 3-hydroxyquinuclidine -IV (Compound IVp). All drugs injected intra-... 

According to Morpurgo [181] the central anticholinergic compounds reduce catalepsia induced in rats by phenothiazine derivatives. In our experiments [182] catalepsia was induced in rats by compazine [5 mg/kg intraperitoneally]. In these conditions also the esters of 3-hydroxyquinuclidine were shown to be more active than the corresponding esters of 2-diethylaminoethanol, and the benzilic acid esters were shown to be more active than the diphenylpropionic acid esters (Fig. 2). The benzilic acid ester of 3-hydroxyquinuclidine (IVp) appeared to be the most potent. When the compound was administered intraperitoneally at a dose of... 

Esters of 3-hydroxyquinuclidine with arylaliphatic acids, have proved by their central and peripheral cholinolytic activity to be more potent than related esters (diphenylpropionates, benzilates) of 2-diethylaminoethanol (Table 4) and 3-hydroxy-iV-methylpiperidine. 

As is known [219, 220] dialkylaminoalkanols acylated with certain acids show an increased cholinolytic activity on transition from tertiary to quaternary compounds. With the analogous esters of 3-hydroxyquinuclidine the methiodides showed significantly less antiacetylcholine activity than the corresponding tertiary amines. 

The conformational peculiarities of quinuchdine derivatives explain the absence of intramolecular interactions in esters of 3-hydroxyquinuclidine wherein the acyl part of the molecule and the free lone pair electrons attached to the nitrogen are pointed in different directions. A selective action of, for example, aceclidine on the muscarine rather than the nicotine receptors appears to be connected with the conformational peculiarities of quinuclidine derivatives. 

The Bayliss-Hillman reaction is commonly used for the coupling of Michael acceptors with aldehydes to give /3-hydroxy-a-methylene esters/ketones/nitriles. The use of imines in place of aldehydes provides entry to the corresponding /3-amino products. Examples of the asymmetric Bayliss-Hillman reaction with imines are very rare. Aggarwal and co-workers have shown that indium(III) triflate in combination with 3-hydroxyquinuclidine (3-HQD) catalyzes the reaction of enantiomerically pure N-p-toluenesulfinimine with methyl acrylate in an asymmetric Bayliss-Hillman reaction (eq 15). Higher diastereoselectivity was observed in the reaction of A-tert-butanesulfinimines, however, the yields were much poorer. ... 

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