3-Heteroaryl-Substituted Quinuclidin-3-ol and Quinuclidin-2-ene Derivatives as Muscarinic Antagonists. Synthesis and Structure-Activity Relationships

Nilsson, Björn M.; Sundquist, Staffan; Johansson, Gary; Nordvall, Gunnar; Glas, G.; Nilvebrant, Lisbeth; Hacksell, Uli

doi:10.1021/jm00003a011

Cited by 24 publications

(32 citation statements)

References 43 publications

(30 reference statements)

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“…The pK i (m 3 ) were correlated in decreasing order with ovality (O e , r = 0.65), dipole moment ( D, r = 0.53), and calculated lipophilicity (QLogP, r = 0.39). Lipophilicity has been long recognized as an important factor determining antimuscarinic activity (54)(55)(56). Because O e and D are essentially perpendicular (show very little intercorrelation: r = -0.038, Table 9) and both of them are well correlated with pK i (m 3 ), the combination gives a reasonably good description: pK i (m 3 Table 8) provides some improvement in the correlation (r = 0.88, SE = 0.39) and is statistically justified (at a p < 0.06 level), but because on the included data O e and QLogP are intercorrelated, the improvement is less significant.…”

Section: Quantitative Structure-activity Relationships (Qsars)mentioning

confidence: 99%

Receptor binding studies of soft anticholinergic agents

et al. 2001

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Section: Quantitative Structure-activity Relationships (Qsars)mentioning

confidence: 99%

Receptor binding studies of soft anticholinergic agents

et al. 2001

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Section: )mentioning

confidence: 99%

“…[21][22][23] To the best of our knowledge, this selective epoxide rearrangement has never been reported earlier for bicyclo[2,2,2]heterocycles containing epoxides. [24][25][26][27][28][29] While three type of products could be obtained, allyl alcohols, aldehyde and saturated alcohols, arising most likely by carbenoid insertion processes, 24-26) the transformation was highly selective and afforded the desired crucial allyl alcohol 6 exclusively, in 96% of isolated yield (see Experimental).Alternatively, we have also discovered that 6 could be efficiently generated via the Shapiro reaction, [30][31][32] by the known trisylhydrazone 7 with excess n-BuLi followed by quenching the nucleophilic vinyllithium reagent with paraformaldehyde.33) After acetylation of the alcohol 6 under standard conditions affording the allylic acetate 8, 34) the critical allylic alkylation step was studied and optimized. Palladium-catalyzed allylic amination is a well-established method for the synthesis of allyl amines.…”

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“…Alternatively, we have also discovered that 6 could be efficiently generated via the Shapiro reaction, [30][31][32] by the known trisylhydrazone 7 with excess n-BuLi followed by quenching the nucleophilic vinyllithium reagent with paraformaldehyde. 33) After acetylation of the alcohol 6 under standard conditions affording the allylic acetate 8, 34) the critical allylic alkylation step was studied and optimized.…”

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confidence: 99%

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Expedient Synthesis of Mequitazine an Antihistaminic Drug by Palladium Catalyzed Allylic Alkylation of Sodium Phenothiazinate

Gonnot

Nicolas

Mioskowski

et al. 2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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The synthesis of therapeutically important drugs remains a major focus of attention among organic chemists in the academic world as well as in pharmaceutical companies. Particularly appealing is the notion of using green, short and scalable mild processes that rely on atom economy transformations.2-4) Importantly, a large number of synthetic bioactive molecules possess the 3-substituted quinuclidine moiety that exhibits a broad pharmacological profile (Fig. 1). [5][6][7][8][9][10] Mequitazine 1, is a potent H 1 -receptors selective antihistaminic drug widely studied and used for allergic disorders such as hay fever and urticaria. This molecule is also one of the earliest second-generation antihistamines on the market, sold as the trade name Primalan ® , which is beneficial in the symptomatic treatment of allergic rhinitis.11) Recent studies have demonstrated its potential use for the treatment of allergic conjunctivitis, and for its possible sedative properties. 12)As a consequence the development of efficient synthesis of 1 is of prime importance for clinical evaluations, and more importantly for the elucidation of the mechanism of action with different biological targets and receptors. The existing strategies for the preparation of mequitazine 1, most of which have been patented, rely mainly on the construction of the C9-N bond, either by alkylation or acylation of phenothiazine using appropriate 3-substituted quinuclidine electrophiles. [13][14][15][16][17][18] However, these approaches are plagued by severe drawbacks such as, the rapid formation of large amount of the elimination product arising from 3-halomethyl-quinuclidine electrophiles, or the degradation of the sensitive 3-acyl-quinuclidine halide derivative. As part of our ongoing program on medicinal chemistry, 16) we wish to describe a new strategic approach that circumvents these limitations in developing a reliable synthetic route for an expedient synthesis of racmequitazine. The key step of our approach is based on the palladium catalyzed allylic alkylation of sodium phenothiazinate. As shown in Chart 1, we first started with the preparation of the key allyl acetate 8. The treatment of the known epoxide 19,20) 5 with lithium diethylamide in ether under reflux conditions, resulted in a remarkably clean conversion to the corresponding allyl alcohol 6. [21][22][23] To the best of our knowledge, this selective epoxide rearrangement has never been reported earlier for bicyclo[2,2,2]heterocycles containing epoxides. [24][25][26][27][28][29] While three type of products could be obtained, allyl alcohols, aldehyde and saturated alcohols, arising most likely by carbenoid insertion processes, 24-26) the transformation was highly selective and afforded the desired crucial allyl alcohol 6 exclusively, in 96% of isolated yield (see Experimental).Alternatively, we have also discovered that 6 could be efficiently generated via the Shapiro reaction, [30][31][32] by the known trisylhydrazone 7 with excess n-BuLi followed by quenching the nucleophilic vinyllithium ...

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“…In addition to CÐHÁ Á Á% interactions, molecules are held together in the solid state by van der Waals interactions. Comment 1-Azabicyclo[2.2.2]octane ring systems linked to ®ve-or sixmembered heteroaromatics are known to be muscarinic agonists (Nilsson et al, 1995). Also, the 5-HT-3 receptor antagonist zacopride contains a 1-azabicyclo[2.2.2]octane moiety (Paulis et al, 1997).…”

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(Z)-2-(4-Methoxybenzylidene)-1-azabicyclo[2.2.2]octan-3-one

2006

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The crystal structure of the title compound, C 15 H 17 NO 2 , contains two nearly identical but crystallographically independent molecules, each with a double bond connecting an azabicyclic ring system to a 3-methoxybenzylidene moiety. The space group is triclinic P1. The benzene ring is twisted by 18.44 (5) and 22.35 (4) with respect to the plane of the double bond connected to the azabicyclic ring system for the two molecules. In addition to CÐHÁ Á Á% interactions, molecules are held together in the solid state by van der Waals interactions. Comment 1-Azabicyclo[2.2.2]octane ring systems linked to ®ve-or sixmembered heteroaromatics are known to be muscarinic agonists (Nilsson et al., 1995). Also, the 5-HT-3 receptor antagonist zacopride contains a 1-azabicyclo[2.2.2]octane moiety (Paulis et al., 1997). In continuation of our work with 1-azabicyclo[2.2.2]octan-3-ones as precursors of medicinal agents, we synthesized a series of 2-(substituted benzylidene/ hetero-3-arylmethylene)-1-azabicyclo[2.2.2]octan-3-ones (Sonar et al., 2004), and their crystal structures were determined in order to con®rm the geometry and to establish the conformations of the molecules. The title compound, (I), was prepared by condensation of 3-methoxybenzaldeyde with 1-azabicyclo[2.2.2]octan-3-one under base catalysis, to afford a single geometrical isomer, viz. (Z)-2-(3-methoxybenzylidene)-1-azabicyclo[2.2.2]octan-3-one. In order to con®rm the geometry of this compound, and to obtain more detailed information on the structural conformation of the molecule, its X-ray structure determination has been carried out and the results are presented here.The asymmetric unit of (I) contains two independent molecules, A and B (Fig. 1), with very similar geometries ( Table 1). The molecule contains a double bond between atoms C7 and C8 that connects a 1-azabicyclo[2.2.2]octan-3-one ring system to a 3-methoxybenzylidene group, and has a Z geometry in which the C1ÐC7 bond is in the trans position with respect to the C8ÐC9 bond. The C7 C8 bond is essentially planar, since the r.m.s. deviations from the mean planes passing through atoms N1, C8, C9, C7 and C1 are 0.0270 (5) and 0.0060 (5) for molecules A and B, respectively.Deviations from ideal geometry are observed in the bond angles around atoms C1, C7, C8 and C9. While the C7 C8Ð C9 angle [121.27 (7) in A and 121.07 (7) in B] is close to the ideal angle of 120 , the C2 C1ÐC7, C1ÐC7 C8, N1Ð C8 C7, C8ÐC9ÐC10 and N1ÐC8ÐC9 angles [124.25 (7), 130.35 (8), 125.30 (8), 110.88 (7) and 113.24 (7) in molecule A, and 123.93 (7), 130.65 (8), 125.36 (8), 110.59 (7) and 113.54 (7) in molecule B, respectively] are more distorted, a consequence of the strain induced by the double-bond linkage at atoms C8 and C9. These deviations in the angles contribute to the release of the intramolecular non-bonded interactions within the 1-azabicyclo[2.2.2]octane ring. In both cases, Csp 2 atoms replace Csp 3 atoms and, as a result, atoms N1, C8, C9 and C10 assume a planar con®guration [the N1ÐC8ÐC9Ð C10 torsion angle is À4.81 ...

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3-Heteroaryl-Substituted Quinuclidin-3-ol and Quinuclidin-2-ene Derivatives as Muscarinic Antagonists. Synthesis and Structure-Activity Relationships

Cited by 24 publications

References 43 publications

Receptor binding studies of soft anticholinergic agents

Receptor binding studies of soft anticholinergic agents

Expedient Synthesis of Mequitazine an Antihistaminic Drug by Palladium Catalyzed Allylic Alkylation of Sodium Phenothiazinate

(Z)-2-(4-Methoxybenzylidene)-1-azabicyclo[2.2.2]octan-3-one

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