Partition coefficients of some N-alkyl- and N,N-dialkyl-derivatives of some cinnamamides and benzalcyanoacetamides in the system cyclohexane–water

Delaney, A. D.; Currie, D. J.; Holmes, H. L.

doi:10.1139/v69-543

Cited by 15 publications

(6 citation statements)

References 5 publications

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“…This was also found to be in good agreement with previously reported values. 24 Effect of Bile Salts and Lecithin on Solubility and DissolutionsSIBLM increased the solubility of phenytoin and its prodrugs moderately for some (1)(2)(3)(4)(5) and dramatically for others (6-10) ( Table 3). To study the effect of the lecithin, a component of SIBLM, phenytoin solubility was measured in a simulated intestinal bile salts mixture (SIBM) and compared to that in SIBLM.…”

Section: Resultsmentioning

confidence: 99%

Some Relationships Between the Physical Properties of Various 3-Acyloxymethyl Prodrugs of Phenytoin to Structure: Potential in Vivo Performance Implications

Stella

Martodihardjo²,

Terada³

et al. 1998

Journal of Pharmaceutical Sciences

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Physicochemical properties of neutral N-acyloxyalkyl derivatives of phenytoin in aqueous, organic solvents and simulated intestinal fluid were evaluated. Based on the hypothesis that these low melting prodrugs may have improved physical properties such as solubility and dissolution rate in gastrointestinal fluid, an enhanced bioavailability of these prodrugs may be observed relative to phenytoin. Melting points, aqueous solubilities, and octanol-water (Poct) and cylcohexane-water (Pcyc) partition coefficients of phenytoin and its prodrugs were determined. A simulated intestinal bile salts-lecithin mixture (SIBLM) was also prepared to possibly mimic the intestinal fluid content. Solubility and dissolution rates of phenytoin and its prodrugs were conducted in aqueous buffer and SIBLM. Apparent micelle-water partition coefficients (Kapp) were calculated by using the aqueous and SIBLM equilibrium solubility data. These properties were qualitatively or quantitatively correlated to the alkyl chain length of the prodrugs. The melting points and aqueous solubilities of all the prodrugs were lower than that of the parent compound, phenytoin. The apparent micelle-water partition coefficient increased with an increase in chain length but unlike the octanol-water and cyclohexane-water partition coefficients the relationship was complex. There was a disproportionate increase in the interaction between the micelle and the prodrug with the prodrugs with alkyl groups larger than four carbons. In SIBLM, the solubilities and dissolution rates were increased to a greater extent for the prodrugs than that for phenytoin. The implications are that the bioavailability of phenytoin from these prodrugs may be comparable to or higher than that of phenytoin despite having lower aqueous solubilities, especially after a meal inducing bile flow.

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Section: Resultsmentioning

confidence: 99%

Some Relationships Between the Physical Properties of Various 3-Acyloxymethyl Prodrugs of Phenytoin to Structure: Potential in Vivo Performance Implications

Stella

Martodihardjo²,

Terada³

et al. 1998

Journal of Pharmaceutical Sciences

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“…and KOH (4 mol equiv.) the azalactam 20 gave homaline 1 as a mixture of diastereoisomers, ( k ) and meso, in 63% yield, along with a little unchanged starting material and 6% of the butenyl by-product 28 (R = Me). Under similar conditions the use of 1,4-diiodobutane was less satisfactory.…”

mentioning

confidence: 99%

Synthesis of the alkaloid homaline in (±) and natural (S,S)-(–) forms, using amination and transamidative ring expansion in liquid ammonia

Crombie¹,

Haigh²,

Jones³

et al. 1993

J. Chem. Soc., Perkin Trans. 1

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Synthesis of the alkaloid homaline in ( k ) and natural (S,S)-(-) forms is reported. Linking of 2azacyclooctanone units either directly or successively using 1,4-dihalogenobutanes or 1,4dihalogenobut-2-ynes is examined. ( k ) -5-Methyl-4-phenyl-I ,5-diazacyclooctan-2-one is first made by a 2,2'-dithiodipyridine/triphenylphosphine-mediated cyclisation, and then by amination and transamidative ring expansion from N-(3-chloropropyl) -4-phenylazetidin-2-one in liquid ammonia, followed by N-methylation. Coupling through a 1.4-dihalogenobutane of either the N-methylated azalactam, or the unmethylated azalactam followed by methylation, gave homaline in ( k ) and meso forms.( R ) -(-)-Phenylglycine was converted via (S)-p-phenyl-p-alanine into an (S)-p-lactam which was then alkylated with 1 -bromo-3-chloropropane. and aminated and ring expanded in liquid ammonia. Coupling of the homochiral azalactam (2 mol) so formed with 1,4-dibromobutane, followed by N-methylation, gave (S,S) -(-)homaline identical with the natural material.The Homalium (homaline) alkaloids constitute a group of alkaloids isolated from the leaves of an African Homalium species and HomaZium pronyense Guillaum (Flacourtiacae) found in the forests of New Caledonia. They were investigated by Pays and colleagues and found to contain a spermine structural backbone. The best defined of these alkaloids is homaline 1,1-3 for which an X-ray single-crystal structure is a ~a i l a b l e . ~ Also occurring with the latter are the unsymmetrical alkaloids hopromine 2, hoprominol3 and hopromalinol 4.5

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“…mopo 88'-89'C, C13H28C1NOTe, Calcd. C,41.37,H,7.48,N,3.71; Found c, 41.63, H , 7 ..26, N, 3.9 c, 53.91,H,5*27,N,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]54.13,H,5.06,N,5.52. …”

Section: Synthesis Of Dibutyl(isoprorylcarbamoylmethy1)telluro-mentioning

confidence: 99%

Stereoselective Synthesis of (2E)-,(2E,4E)-Unsaturated Carboxamides via Tellurium Ylides

Huang¹,

Wen²,

Huang³

1990

Synthetic Communications

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Partition coefficients of some N-alkyl- and N,N-dialkyl-derivatives of some cinnamamides and benzalcyanoacetamides in the system cyclohexane–water

Abstract: Substituent constants, π, and substituent interaction constants, π interaction, for the groups —CONHR and —CONRR have been derived which allow the calculation of the partition coefficients of the title compounds.

Cited by 15 publications

References 5 publications

Some Relationships Between the Physical Properties of Various 3-Acyloxymethyl Prodrugs of Phenytoin to Structure: Potential in Vivo Performance Implications

Some Relationships Between the Physical Properties of Various 3-Acyloxymethyl Prodrugs of Phenytoin to Structure: Potential in Vivo Performance Implications

Synthesis of the alkaloid homaline in (±) and natural (S,S)-(–) forms, using amination and transamidative ring expansion in liquid ammonia

Stereoselective Synthesis of (2E)-,(2E,4E)-Unsaturated Carboxamides via Tellurium Ylides

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