Synthesis of Base-Modified "Abbreviated" NAD Analogues

Juricová, Kristina; Smrčková, Svatava; Holý, Antonı́n

doi:10.1135/cccc19950237

Cited by 6 publications

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“…22 The R-hydroxy enantiomers (19 and 21) were prepared from the corresponding R-azido-tosylate (Table 3).…”

Section: Chemistrymentioning

confidence: 99%

“…The combined organic extracts were dried (Na 2SO4) and concentrated to give about 70 g of oil. A mixture of the oil and (2S)-3-azido-2-hydroxypropyl p-toluenesulfonate S-35 22 (91 g, 335 mmol) was stirred at 100 °C in NMP in the presence of triethylamine (70 g, 690 mmol) for 30 h. The cooled mixture was diluted with water and extracted with ether (3 × 500 mL), back-washed once with NaCl (sat.) (100 mL), dried (Na 2SO4), and concentrated.…”

Section: -(4-chlorophenyl)-23-dihydro-n-[2-hydroxy-3-[4-[2-(1-methyle...mentioning

confidence: 99%

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Design, Synthesis, and Structure−Activity Relationships of Phthalimide-Phenylpiperazines: A Novel Series of Potent and Selective α₁_a-Adrenergic Receptor Antagonists

et al. 2000

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Beginning from the screening hit and literature alpha(1)-adrenergic compounds, a hybridized basic skeleton A was proposed as the pharmacophore for potent and selective alpha(1a)-AR antagonists. Introduction of a hydroxy group to increase the flexibility afforded B which served as the screening model and resulted in the identification of the second-generation lead 1. Using the Topliss approach, a number of potent and selective alpha(1a)-AR antagonists were discovered. In all cases, binding affinity and selectivity at the alpha(1a)-AR of S-hydroxy enantiomers were higher than those of the R-hydroxy enantiomers. As compared to the des-hydroxy analogues, the S-hydroxy enantiomers had slightly lower binding affinity at alpha(1a)-AR but gained more than 2-fold selectivity for alpha(1a)-AR over alpha(1b)-AR, and 2- to 6-fold selectivity for alpha(1a)-AR over alpha(1d)-AR. They also had less cross activities against a panel of 25-35 peripheral and CNS receptors. The S-hydroxy enantiomers 23 and 24 (K(i) = 0.29 nM, 0.33 nM; alpha(1b)/alpha(1a) >5690, >6060; alpha(1d)/alpha(1a) = 186, 158, respectively) were slightly less potent but much more selective at alpha(1a)-AR than tamsulosin (K(i) = 0.13 nM, alpha(1b)/alpha(1a) = 14.8, alpha(1d)/alpha(1a) = 1.4). In the functional assay, the S-hydroxy enantiomers 20, 23, and 24 were less potent than tamsulosin in inhibiting contractions of rat prostate tissue but more selective in the inhibition of tissue contractions of rat prostate versus rat aorta. Compound 24 was selected as the development candidate for the treatment of BPH.

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“…22 The R-hydroxy enantiomers (19 and 21) were prepared from the corresponding R-azido-tosylate (Table 3).…”

Section: Chemistrymentioning

confidence: 99%

Section: -(4-chlorophenyl)-23-dihydro-n-[2-hydroxy-3-[4-[2-(1-methyle...mentioning

confidence: 99%

Design, Synthesis, and Structure−Activity Relationships of Phthalimide-Phenylpiperazines: A Novel Series of Potent and Selective α₁_a-Adrenergic Receptor Antagonists

et al. 2000

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“…However, there were some drawbacks associated with this approach that were not ideal for larger scale synthesis. First, the preparation of azido-diol 1 [2] involved the use of the highly toxic and potentially explosive sodium azide reagent. Second, the chromatographic purification of azido-tosylate 2 [2] was not trivial even on multi-gram scale.…”

mentioning

confidence: 99%

“…First, the preparation of azido-diol 1 [2] involved the use of the highly toxic and potentially explosive sodium azide reagent. Second, the chromatographic purification of azido-tosylate 2 [2] was not trivial even on multi-gram scale. Third, in order to obtain greater than 99% ee of RWJ 69442, column chromatography followed by repeated recrystallizations of the intermediates were required.…”

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confidence: 99%

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An improved synthesis of enantiomerically pure RWJ 69442, a development candidate for the treatment of benign prostatic hyperplasia

Kuo¹,

Prouty²,

Murray³

et al. 2001

Journal of Heterocyclic Chem

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This report describes an improved synthesis of enantiomerically pure (S)-2-[4-(Dimethylamino)phenyl]-2,3-dihydro-N- [2-hydroxy-3-[4-[2-(1-methylethoxy)-phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-isoindole-5-carboxamide (RWJ 69442), a potent and selective α 1a -adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia. The synthesis highlights less hazardous reagents, easier purification and higher enantiomeric purity. The N-benzyl-N-t-butoxycarbonyl amine 6 could serve as an enantiomerically pure chiral building block for asymmetric synthesis. In a program to develop a potent and selective α 1a -adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia (BPH),was identified as a development candidate [1]. A sample of 25 g of RWJ 69442 was prepared based upon the approach shown in Scheme I [1]. However, there were some drawbacks associated with this approach that were not ideal for larger scale synthesis. First, the preparation of azido-diol 1 [2] involved the use of the highly toxic and potentially explosive sodium azide reagent. Second, the chromatographic purification of azido-tosylate 2 [2] was not trivial even on multi-gram scale. Third, in order to obtain greater than 99% ee of RWJ 69442, column chromatography followed by repeated recrystallizations of the intermediates were required.In our efforts to improve the synthesis without involving azide functionality, we examined a variety of amine equivalents including methoxyamine, phthalimide, aminodiphenylmethane, benzylamine, tritylamine, benzophenone imine, di-t-butyl iminodicarboxylate and ammonia. We found that the use of benzylamine followed by t-butyloxycarbonyl (Boc) protection best fulfilled our overall requirements (Scheme II).

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Synthesis and chiroptical properties of some abbreviated NAD+ analogues

Hocková

Votavová

Holý

1995

Tetrahedron: Asymmetry

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Synthesis of Base-Modified "Abbreviated" NAD Analogues

Cited by 6 publications

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Design, Synthesis, and Structure−Activity Relationships of Phthalimide-Phenylpiperazines: A Novel Series of Potent and Selective α₁_a-Adrenergic Receptor Antagonists

Design, Synthesis, and Structure−Activity Relationships of Phthalimide-Phenylpiperazines: A Novel Series of Potent and Selective α₁_a-Adrenergic Receptor Antagonists

An improved synthesis of enantiomerically pure RWJ 69442, a development candidate for the treatment of benign prostatic hyperplasia

Synthesis and chiroptical properties of some abbreviated NAD+ analogues

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Synthesis of Base-Modified "Abbreviated" NAD Analogues

Cited by 6 publications

References 0 publications

Design, Synthesis, and Structure−Activity Relationships of Phthalimide-Phenylpiperazines: A Novel Series of Potent and Selective α1a-Adrenergic Receptor Antagonists

Design, Synthesis, and Structure−Activity Relationships of Phthalimide-Phenylpiperazines: A Novel Series of Potent and Selective α1a-Adrenergic Receptor Antagonists

An improved synthesis of enantiomerically pure RWJ 69442, a development candidate for the treatment of benign prostatic hyperplasia

Synthesis and chiroptical properties of some abbreviated NAD+ analogues

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Design, Synthesis, and Structure−Activity Relationships of Phthalimide-Phenylpiperazines: A Novel Series of Potent and Selective α₁_a-Adrenergic Receptor Antagonists

Design, Synthesis, and Structure−Activity Relationships of Phthalimide-Phenylpiperazines: A Novel Series of Potent and Selective α₁_a-Adrenergic Receptor Antagonists