Angiotensin II receptor antagonists: imidazoles and pyrroles bearing hydroxymethyl and carboxy substituents

Yanagisawa, Hideyoshi; Amemiya, Yoshiya; Kanazaki, Takuro; Fujimoto, Koichi; Shimoji, Yasuo; Fujimoto, Yoshiko; Sada, Toshio; Mizuno, Makoto; Koike, Hiroyuki

doi:10.1016/s0960-894x(01)81143-4

Cited by 8 publications

(7 citation statements)

References 13 publications

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“…Accordingly, it was planned to do the coupling of the imidazole (3) with the bromo biphenyl moiety (4) followed by o-methylation, ester hydrolysis, introduction of the 4,5-dimethyl-2-oxo-1,3-dioxolene moiety and finally deprotection of trityl group to afford the desired compound 2. As decided, 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-ethylcarboxylate 3 [7] was coupled with 4-{(2-trityltetrazol-5-yl)-phenyl}-benzyl bromide 4 [8] using potassium carbonate in acetone, and the product was crystallized to give 5 [9] in 85 % yield. This method has advantages over the reported method [9] where dimethyl acetamide or DMF was used and the product was isolated by column chromatography with low yield.…”

Section: Resultsmentioning

confidence: 99%

“…As decided, 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-ethylcarboxylate 3 [7] was coupled with 4-{(2-trityltetrazol-5-yl)-phenyl}-benzyl bromide 4 [8] using potassium carbonate in acetone, and the product was crystallized to give 5 [9] in 85 % yield. This method has advantages over the reported method [9] where dimethyl acetamide or DMF was used and the product was isolated by column chromatography with low yield. Methylation of 5 with methyl iodide and sodium hydride was successful however the yields were low (39 %).…”

Section: Resultsmentioning

confidence: 99%

“…To the residue 500 mL isopropyl alcohol was added and the resulting solution was stirred at ambient temperature for 12 hours. The solids were filtered, washed with isopropyl alcohol (100 mL) and dried in air at 40-45°C for 12 hours to afford 5 [9] Ethyl-4-(1-methoxy-1-methylethyl)-2-propyl-1-{4-(2-trityltetrazol-5-yl) phenyl}phenylmethylimidazole-5-carbox-ylate (6). To a stirred suspension of sodium hydride (3.0 g, 0.075 mole) in THF (100 mL) was slowly added drop wise a solution of 5 (25 g, 0.034 mole) and methyl iodide (6.5 mL, 0.104 mole) in THF (100 mL) at 0°C.…”

Section: Ethyl-4-(1-hydroxymethylethyl)-2-propyl-1-{ 4-(2-trityltetramentioning

confidence: 99%

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A convenient and practical synthesis of olmesartan medoxomil methyl ether

Pati¹,

Lahiri²,

Sabbam³

et al. 2008

Journal of Heterocyclic Chem

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Ethyl-4-(1-hydroxymethylethyl)-2-propyl-1-{ 4-(2-trityltetramentioning

confidence: 99%

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A convenient and practical synthesis of olmesartan medoxomil methyl ether

Pati¹,

Lahiri²,

Sabbam³

et al. 2008

Journal of Heterocyclic Chem

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“…The hydroxy group of compound 14 8) was oxidized by manganese dioxide to give aldehyde. Alkylation of aldehyde with allyltrimethylsilane gave the corresponding alcohol, 9) which was protected using tert-butyldimethylchlorosilane to yield 15.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Pharmacological Activity of the Metabolites of Pratosartan

Sonegawa

Suzaka

Tomiyama

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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In the previous paper, 1) we reported the design and synthesis of Pratosartan (Chart 1), which is an orally active angiotensin II (AII) antagonist, exhibiting selective and potent antagonistic activity to AT 1 subtype. Furthermore, long duration was shown in various animal models in vivo experiment. Clinical trials of Pratosartan are now in progress as an antihypertensive agent.Clarification of the possible metabolites and their therapeutic or toxic effects during the development process of new drugs is mandatory. For this purpose, we have tried to synthesize possible metabolites in human and rat to identify their structures and activities. In a pharmacokinetic study of Pratosartan, three hydroxylated metabolites were observed as major metabolites in human and rat after oral administration. These structures were characterized on the basis of MS and NMR spectra. Metabolite 1 isolated from human urine was estimated as a hydroxylated metabolite at the propyl side chain of Pratosartan. A similar hydroxlated metabolite was also reported for Losartan.2) Metabolite 2 and 3 isolated from rat bile were estimated as 8-and 5-hydroxylated metabolites on the cycloheptane ring of Pratosartan, respectively. In this paper, we describe the synthesis of these metabolites to identify their structures and to study their pharmacological properties. ChemistryMetabolite 1 was synthesized as shown in Chart 2. Protection of 2-propyl-3H-cycloheptimidazol-4-one 4 3,4) with chloromethyl methyl ether (MOMCl) gave 5, which was treated with N-bromosuccinimide (NBS) to give the brominated product 6. The bromo group was converted to an acetoxy group using sodium acetate to yield 7. Removal of the MOM group and subsequent ester exchange of the acetate gave the corresponding alcohol 9. Hydrogenation of 9 provided 10, and it was alkylated with 11 5) to afford the desired intermediate compound 12. N-Alkylation of 3H-cycloheptimidazol-4-one in the presence of K 2 CO 3 in N,N-dimethylformamide (DMF) gave an N3-alkylated compound preferentially similarly to the biphasic reaction condition 6) and the regioisomer was separated easily by silica gel column chromatography. The N-benzylic proton of compound 12 and 20 was observed at lower field characteristically (0.4-0.5 ppm) compared to their regioisomers, which was caused by the anisotropic effect of the C4-carbonyl group. For the purpose of optical resolution, the racemic trityl compound 12 was converted to a-methoxy-a-(trifluoromethyl)phenylacetate (MTPA) 13 with (ϩ)-MTPA-Cl. 7) Each diastereomer could be separated by silica gel column chromatography. Hydrolysis of the isolated single isomer 13a gave an optically active hydroxy intermediate, and finally (ϩ)-1 was obtained by the successive deprotection of MTPA and trityl groups. Enantiomer (Ϫ)-1 was obtained from 13b in the same manner.In order to confirm the structure, the human main metabolite was led to MTPA ester (Chart 3). The human main metabolite was protected with trityl chloride to give trityl compound 12, and then it was converted to MTPA est...

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“…In a previous paper, we reported that imidazoles that had hydroxymethyl and carboxy groups at the 4- and 5-positions, respectively, possessed potent antagonistic activity, which would be caused by hydrogen bonding or hydrophilicity of the hydroxymethyl group. Here we report on the synthesis of the imidazole antagonists possessing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position, their biological evaluation (SAR), and stereochemical comparison with the C-terminal pentapeptide of AII.…”

Section: Introductionmentioning

confidence: 99%

Nonpeptide Angiotensin II Receptor Antagonists: Synthesis, Biological Activities, and Structure−Activity Relationships of Imidazole-5-carboxylic Acids Bearing Alkyl, Alkenyl, and Hydroxyalkyl Substituents at the 4-Position and Their Related Compounds

et al. 1996

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A series of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds were prepared and evaluated for their antagonistic activities to the angiotensin II (AII) receptor. Among them, the 4-(1-hydroxyalkyl)-imidazole derivatives had strong binding affinity to the AII receptor and potently inhibited the AII-induced pressor response by intravenous administration. Various esters of these acids showed potent and long-lasting antagonistic activity by oral administration. The most promising compounds were (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (CS-866) and (pivaloyloxy)-methyl esters of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[(2'-1H-tetrazol-5- ylbiphenyl-4-yl)-methyl]imidazole-5-carboxylic acid (26c). A study involving stereochemical comparison of 26c with the acetylated C-terminal pentapeptide of AII was also undertaken.

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Angiotensin II receptor antagonists: imidazoles and pyrroles bearing hydroxymethyl and carboxy substituents

Cited by 8 publications

References 13 publications

A convenient and practical synthesis of olmesartan medoxomil methyl ether

A convenient and practical synthesis of olmesartan medoxomil methyl ether

Synthesis and Pharmacological Activity of the Metabolites of Pratosartan

Nonpeptide Angiotensin II Receptor Antagonists: Synthesis, Biological Activities, and Structure−Activity Relationships of Imidazole-5-carboxylic Acids Bearing Alkyl, Alkenyl, and Hydroxyalkyl Substituents at the 4-Position and Their Related Compounds

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