Synthesis and Evaluation of Novel 2-Oxo-1,2-dihydro-3-quinolinecarboxamide Derivatives as Potent and Selective Serotonin 5-HT4 Receptor Agonists.

Suzuki, Muneyasu; Ohuchi, Yutaka; Asanuma, Hajime; Kaneko, Toshie; Yokomori, Sadakazu; Ito, Chika; Isobe, Yoshihiko; Muramatsu, Makoto

doi:10.1248/cpb.49.29

Cited by 10 publications

(10 citation statements)

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“…Due to low boiling point of the volatile i PrNH 2 , a 3,4-dihydroquinazolinium salt with an isopropyl substituent on the N1 atom was prepared from the 2-isopropylaminobenzaldehyde, obtained from 2-aminobenzyl alcohol by a literature method. 7 The condensation of 2-(isopropylamino)benzaldehyde with NH 2 R (R = 3,5-Me 2 -phenyl, Bn, or Cy) and subsequent reduction afforded the corresponding diamines 10a−c in 66−78% yields, which underwent cyclization to give 3,4-dihydroquinazolinium salts 11a−c [11a (R = 3,5-Me 2 -phenyl), 11b (R = Bn), and 11c (R = Cy)] in 54−81% yield, respectively (Scheme 5). Chiral 3,4-dihydroquinazolinium salt 13 with an isopropyl substituent was also prepared in 76% yield by the cyclization of diamine 12, which was obtained in 61% yield starting from the condensation of 2-(isopropylamino)benzaldehyde with (S)phenylethylamine (Scheme 6).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…The isopropyl group is often chosen as a sterically demanding N-substituent in the design of NHCs. Due to low boiling point of the volatile i PrNH 2 , a 3,4-dihydroquinazolinium salt with an isopropyl substituent on the N1 atom was prepared from the 2-isopropylaminobenzaldehyde, obtained from 2-aminobenzyl alcohol by a literature method . The condensation of 2-(isopropylamino)benzaldehyde with NH 2 R (R = 3,5-Me 2 -phenyl, Bn, or Cy) and subsequent reduction afforded the corresponding diamines 10a – c in 66–78% yields, which underwent cyclization to give 3,4-dihydroquinazolinium salts 11a – c [ 11a (R = 3,5-Me 2 -phenyl), 11b (R = Bn), and 11c (R = Cy)] in 54–81% yield, respectively (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

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Fine-Tunable 3,4-Dihydroquinazol-2-ylidene Carbenes: Synthesis, Rhodium(I) Complexes, and Reactivity

Zhang

Qin

et al. 2012

Organometallics

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The design and synthesis of various new six-membered cyclic formamidinium salts with a 3,4-dihydroquinazoline core have been reported in this paper. Our synthetic strategy allows access to a kind of tailor-made 3,4-dihydroquinazolinium salts bearing different substituent combinations. A series of novel 3,4-dihydroquinazolin-2-ylidene-based rhodium(I) complexes were prepared by the reaction of [Rh(cod)Cl] 2 with the free carbene obtained in situ from the deprotonation of the corresponding 3,4-dihydroquinazolinium salts with KN(SiMe 3 ) 2 . The NHCs prepared in situ can also react with S 8 or CS 2 to afford the corresponding thiones or NHC−CS 2 adducts, respectively. The rhodium(I) complexes were transformed to the corresponding dicarbonyl complexes, and the ν(CO) values of the corresponding dicarbonyl Rh complexes indicate the 3,4-dihydroquinazol-2-ylidenes are stronger electron donors than normal five-membered NHCs. The Rh complexes are highly active in the arylation of carbonyl compounds, and the 3,4-dihydroquinazolin-2-ylidenes prepared in situ upon deprotonation are powerful in palladium-catalyzed Suzuki cross-coupling reactions at room temperature with a ppm scale catalyst loading with TONs of up to 425 000.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Fine-Tunable 3,4-Dihydroquinazol-2-ylidene Carbenes: Synthesis, Rhodium(I) Complexes, and Reactivity

Zhang

Qin

et al. 2012

Organometallics

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“…The alkyl chains with different groups such as piperidine, OH, phenoxy, and CN fitted correctly to give rise to agonists more potent than cisapride. TS-951K ( 4 , R = OH, n = 3) was selected as a promising agent to alleviate symptoms of the gastrointestinal dysfunctions …”

Section: Chemistrymentioning

confidence: 99%

5-HT₄Receptor Ligands: Applications and New Prospects

2003

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“…Scheme 4 illustrates the synthesis of cyclic ether diols 38 and 41. Reaction of the Grignard reagent of bromo-THP ether 12 with freshly prepared succinaldehyde 14,15 in THF gave diol 37 (92%). 16 The cyclodehydration 17 and deprotection to tetrahydrofuran derivative 38 were then accomplished by two different methods: first, 37 was condensed by treatment with p-toluenesulfonic acid (pTosOH) in toluene under azeotropic removal 18 of the reaction water.…”

Section: Resultsmentioning

confidence: 99%

Long Hydrocarbon Chain Ether Diols and Ether Diacids That Favorably Alter Lipid Disorders in Vivo

et al. 2004

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Long hydrocarbon chain ethers with bis-terminal hydroxyl or carboxyl groups have been synthesized and evaluated for their potential to favorably alter lipid disorders including metabolic syndrome. Compounds were assessed for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes as well as for their effects on lipid and glycemic variables in female obese Zucker fatty rats following 1 and 2 weeks of daily oral administration. The most active compounds were found to be symmetrical with four to five methylene groups separating the central ether functionality and the gem dimethyl or methyl/aryl substituents. Biological activity was found to be greatest for tetramethyl-substituted ether diols (e.g., 28 and 31), while bis(arylmethyl) derivatives (e.g., 10, 11, and 27), diethers (e.g., 49, 50, and 56), and diphenyl ethers (e.g., 35 and 36) were the least active. For the most biologically active compound 28, we observed as much as a 346% increase in serum HDL-cholesterol and a 71% reduction in serum triglycerides at the highest dose administered (100 mg/kg) after 2 weeks of treatment. For compound 31 we observed a 69% reduction in non-HDL-cholesterol, accompanied by a 131% increase in HDL-cholesterol and an 84% reduction in serum triglycerides under the same treatment conditions.

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Synthesis and Evaluation of Novel 2-Oxo-1,2-dihydro-3-quinolinecarboxamide Derivatives as Potent and Selective Serotonin 5-HT4 Receptor Agonists.

Cited by 10 publications

References 10 publications

Fine-Tunable 3,4-Dihydroquinazol-2-ylidene Carbenes: Synthesis, Rhodium(I) Complexes, and Reactivity

Fine-Tunable 3,4-Dihydroquinazol-2-ylidene Carbenes: Synthesis, Rhodium(I) Complexes, and Reactivity

5-HT₄Receptor Ligands: Applications and New Prospects

Long Hydrocarbon Chain Ether Diols and Ether Diacids That Favorably Alter Lipid Disorders in Vivo

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Synthesis and Evaluation of Novel 2-Oxo-1,2-dihydro-3-quinolinecarboxamide Derivatives as Potent and Selective Serotonin 5-HT4 Receptor Agonists.

Cited by 10 publications

References 10 publications

Fine-Tunable 3,4-Dihydroquinazol-2-ylidene Carbenes: Synthesis, Rhodium(I) Complexes, and Reactivity

Fine-Tunable 3,4-Dihydroquinazol-2-ylidene Carbenes: Synthesis, Rhodium(I) Complexes, and Reactivity

5-HT4Receptor Ligands: Applications and New Prospects

Long Hydrocarbon Chain Ether Diols and Ether Diacids That Favorably Alter Lipid Disorders in Vivo

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Product

Resources

About

5-HT₄Receptor Ligands: Applications and New Prospects