Antifilarial agents. Diazabicyclooctanes and diazabicycloheptanes as bridged analogs of diethylcarbamazine

Thirty-seven (most of them novel) chiral derivatives of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane (2-36, 38, 39) were prepared from (S)-trans-4-hydroxyproline. A selection of these chiral ligands were examined as potential ligands in the preparation of catalysts for the enantioselective addition of diethylzinc to aldehydes and as chiral Lewis acid activators in the asymmetric Diels-Alder reaction. In the former system, diamine 30 induced up to 92 % enantiomeric excess in the formation of (S)-phenyl ethyl carbinol, whereas in the case of the cycloaddition reaction between cyclopentadiene and 3-acryloyloxazolidin-2-one the catalytic complex formed

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“…This oil was dissolved in methanol (25 mL) and bubbled with HCl(g), to afford 16· 2 HCl as a white solid, m.p. 234–236 °C [ref 15b. m.p.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of Novel Derivatives of (1S,4S)‐2,5‐Diazabicyclo[2.2.1]heptane and Their Evaluation as Potential Ligands in Asymmetric Catalysis

et al. 2008

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“…1,4-Diazabicyclo[3.2.1]octane (2). 16 To a slowly stirring suspension of 11.6 g of 13 (0.0523 mol) in 8.7 mL of H20 was added a solution of 8.7 g (0.378 mol) of NaOH in 8.7 mL of H20, which effected almost complete solution.…”

Section: Methodsmentioning

confidence: 99%

“…molecular rigidity imposed on DEC by fusing it with the tetrahydropyrimidone ring in 9 was discussed earlier 2. …”

mentioning

confidence: 97%

“…Compounds 2-8 were evaluated against Litomosoides carinii in the gerbil by methods described in our previous publication. 2 The assay data are compared with those of DEC (1) in Table I. The parent l,4-diazabicyclo[3.2.1]octane (2) gave no reduction of microfilaria count within the experimental error of the assay.…”

mentioning

confidence: 99%

“…In both cases, the piperazine ring also may assume the boat form, a conformation earlier found compatible with high activity in other bicyclic systems. 2 The IV-methyl group of DEC is shown in the axial position to illustrate its equivalence to the 7-position methylene in structure 4a. This methylene is part of a rigid carbon network that does not allow it to become equatorial relative to the piperazine ring portion of the molecule.…”

mentioning

confidence: 99%

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Antifilarial agents. 3-Aminopyrrolidine and 1,4-diazabicyclo[3.2.1]octane derivatives as analogs of diethylcarbamazine

Sturm¹,

Cory²,

Henry³

et al. 1977

J. Med. Chem.

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3-Aminopyrrolidines bearing acyl substituents on either nitrogen and N-acylated 1,4-diazabicyclo[3.2.1]octanes are potent microfilaricides in the Litomosoides carinii gerbil test system but have no effect on adult worms. The high activity of the pyrrolidine derivatives establishes that diethylcarbamazine (DEC) like antifilarial activity does not require that both pharmacophores be incorporated into one ring. Results with the 1,4-diazabicyclo[3.2.1]octanes establish that an axial conformation of the alkyl substituent corresponding to the equatorial N-methyl group of diethylcarbamazine is fully consistent with high activity. Other conformational consideration pertinent to DEC analogues are discussed.

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Synthesis and Structure‐Activity Relationship of Di‐(3, 8‐diazabicyclo[3.2.1]octane) Diquaternary Ammonium Salts as Unique Analgesics

Liu

Cheng

Zhang

et al. 2003

Archiv der Pharmazie

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Based on the structure characteristics of the lead compounds, 1, 1' octanedioyl-4, 4'-dimethyl-4, 4'-dibenzyl dipiperazinium dibromide (2) and 3, 8-disubstituted-3, 8-diazabicyclo [3.2.1]octanes (DBO), di-(3, 8-diazabicyclo [3.2.1]octane) diquaternary ammonium salts 3 a-c were designed and synthesized through a highly practical procedure. Target compounds 3 a-c and the hydrochloride salts of their precursors 10 a-c were evaluated for their in vivo analgesic and sedative activities. Interestingly, the introduction of an endoethylenic bridge in the piperazine of lead compound 2 causes loss of the analgesic activity and increases the toxicity dramatically. This result shows that the flexible conformation of piperazine in compound 2 is favorable for interaction with the receptor, and the quaternization of compounds 10 a-c is the main reason for the toxicity increase.

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Antifilarial agents. Diazabicyclooctanes and diazabicycloheptanes as bridged analogs of diethylcarbamazine

Cited by 43 publications

References 11 publications

Synthesis of Novel Derivatives of (1S,4S)‐2,5‐Diazabicyclo[2.2.1]heptane and Their Evaluation as Potential Ligands in Asymmetric Catalysis

Synthesis of Novel Derivatives of (1S,4S)‐2,5‐Diazabicyclo[2.2.1]heptane and Their Evaluation as Potential Ligands in Asymmetric Catalysis

Antifilarial agents. 3-Aminopyrrolidine and 1,4-diazabicyclo[3.2.1]octane derivatives as analogs of diethylcarbamazine

Synthesis and Structure‐Activity Relationship of Di‐(3, 8‐diazabicyclo[3.2.1]octane) Diquaternary Ammonium Salts as Unique Analgesics

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