A synthesis of 1-pyridylnaphthalene lignan analogs

Sugahara, Masakatsu; Moritani, Yasunori; Terakawa, Yoshihiro; Ogiku, Tsuyoshi; Ukita, Tyunosin; Iwasaki, Tameo

doi:10.1016/s0040-4039(97)10849-8

Cited by 14 publications

(7 citation statements)

References 23 publications

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“…As shown in Scheme , hydroxy acetals 10 were prepared by the usual method from the bromo acetals 9 . 1-(Halogenopyridyl)naphthalenes 11a − e , h − m were synthesized by the Diels−Alder reaction of isobenzofurans generated from 10 with dimethyl fumarate or methyl acrylate, followed by aromatization with BF 3 ·Et 2 O …”

Section: Chemistrymentioning

confidence: 99%

Novel, Potent, and Selective Phosphodiesterase-4 Inhibitors as Antiasthmatic Agents: Synthesis and Biological Activities of a Series of 1-Pyridylnaphthalene Derivatives

Ukita¹,

Sugahara²,

Terakawa³

et al. 1999

J. Med. Chem.

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The structural requirements for potent and selective PDE4 inhibition were revealed in a 1-pyridylnaphthalene series, and the best compound (3kg, T-2585.HCl) was chosen for further biological evaluation (PDE4 inhibition IC50 = 0.13 nM, selectivity PDE3/4 ratio = 14 000). Compound 3kg showed potent antispasmogenic activities (ED50 = 0.063 mg/kg for reduction of antigen-induced bronchoconstriction, intravenously; ED50 = 0.033 mg/kg for reduction of histamine-induced bronchoconstriction, intraduodenally) in guinea pigs with little cardiovascular effects. Furthermore, 3kg induced significantly weaker emetic effects than RP73401 after oral administration in ferrets and intravenous administration in dogs (3kg, none of 4 ferrets vomited at a dose of 10 mg/kg, po and none of 8 dogs vomited at a dose of 0.3 mg/kg, iv; RP73401, 4 of 8 ferrets vomited at a dose of 3 mg/kg, po and 6 of 8 dogs vomited at a dose of 0.3 mg/kg, iv); that is compatible with the lower affinity for the high-affinity rolipram binding site (3kg, 2.6 nM; RP73401, 0. 85 nM). This may imply that 3kg has an improved therapeutic ratio because of a broad margin between the Ki value of binding affinity and the IC50 value of PDE4 inhibition (ratio = 0.050).

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Section: Chemistrymentioning

confidence: 99%

Novel, Potent, and Selective Phosphodiesterase-4 Inhibitors as Antiasthmatic Agents: Synthesis and Biological Activities of a Series of 1-Pyridylnaphthalene Derivatives

Ukita¹,

Sugahara²,

Terakawa³

et al. 1999

J. Med. Chem.

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“…In particular, BF 3 ؒEt 2 O furnished 6 in the highest chemical yield as we reported in our previous paper. 6 The use of one or two mol of BF 3 ؒEt 2 O resulted in the formation of 6 in lower yields with the recovery of starting materials (runs 6 and 7).…”

Section: Resultsmentioning

confidence: 97%

“…2, 5 We recently reported a practical synthesis of 1-pyridylnaphthalene derivatives, heterocyclic analogues of 1-arylnaphthalene lignans. 6 In that paper, we reported that the Diels-Alder reaction of 1 with dienophiles followed by aromatisation by BF 3 ؒEt 2 O furnished 1-pyridylnaphthalene derivatives in moderate to good yields. Although intensive investigations have been done on the Diels-Alder reaction (reactivity, regio-and stereoselectivity) of C(1)substituted isobenzofurans with dienophiles, 7 there are few reports that illustrate the ring opening of a 1,4-epoxide, followed by dehydration.…”

Section: Introductionmentioning

confidence: 98%

Synthetic and mechanistic study of the acid-promoted aromatisation of the Diels–Alder adduct: 6,7-dimethoxy-1-(4-pyridyl)-1,4-epoxytetrahydronaphthalene-2,3-dicarboxylate

Sugahara

Moritani

Kuroda

et al. 2002

J. Chem. Soc., Perkin Trans. 1

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“…1-(2-Bromo-4-pyridyl)-6,7-dimethoxy-2,3-bis( methoxycarbonyl)naphthalene (9j) : yield 60%; mp 192−194 °C; 1 H NMR (CDCl 3 ) δ 3.68 (s, 3H), 3.80 (s, 3H), 3.95 (s, 3H), 4.04 (s, 3H), 6.65 (s, 1H), 7.3−7.37 (m, 2H), 7.55 (d, 1H, J = 0.7 Hz), 8.48−8.58 (m, 2H); EIMS m / z 459/461 (M + , base), 428/430.…”

Section: Methodsmentioning

confidence: 99%

1-Arylnaphthalene Lignan: A Novel Scaffold for Type 5 Phosphodiesterase Inhibitor

Ukita¹,

Nakamura²,

Kubo³

et al. 1999

J. Med. Chem.

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113

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1-Arylnaphthalene lignan, which had been reported as a PDE4 inhibitor by Iwasaki, was disclosed as a new structural class of PDE5 inhibitors. The structural requirements for potent and specific PDE5 inhibition were revealed in a 1-arylnaphthalene lignan series, in which 1-(3-bromo-4, 5-dimethoxyphenyl)-5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinylcarbon yl]-2-(methoxycarbonyl)naphthalene hydrochloride (27q) showed the most potent and specific inhibition (PDE5 inhibition IC50 = 6.2 nM, selectivity for PDE5 against PDE1, -2, -3, and -4 >16 000). It is noteworthy that 27q has the best selectivities against PDE isoforms among PDE5 inhibitors so far reported. Compound 27q exhibited almost the same relaxant effects on rat aortic rings as sodium 1-[6-chloro-4-[(3, 4-methylenedioxybenzyl)amino]quinazolin-2-yl]piperidine-4-ca rboxylate (35) (27q, EC50 = 0.10 microM; 35, EC50 = 0.20 microM) and was selected for further biological evaluation.

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A synthesis of 1-pyridylnaphthalene lignan analogs

Cited by 14 publications

References 23 publications

Novel, Potent, and Selective Phosphodiesterase-4 Inhibitors as Antiasthmatic Agents: Synthesis and Biological Activities of a Series of 1-Pyridylnaphthalene Derivatives

Novel, Potent, and Selective Phosphodiesterase-4 Inhibitors as Antiasthmatic Agents: Synthesis and Biological Activities of a Series of 1-Pyridylnaphthalene Derivatives

Synthetic and mechanistic study of the acid-promoted aromatisation of the Diels–Alder adduct: 6,7-dimethoxy-1-(4-pyridyl)-1,4-epoxytetrahydronaphthalene-2,3-dicarboxylate

1-Arylnaphthalene Lignan: A Novel Scaffold for Type 5 Phosphodiesterase Inhibitor

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