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The concept of bioisosterism between benzimidazole and catechol was applied to the design and synthesis of benzimidazole analogues of norepinephrine, (R,S)-1-[5(6)-benzimidazolyl]-2-aminoethanol (2), and of isoproterenol, (R,S)-1-[5(6)-benzimidazolyl]-2-isopropylaminoethanol (4). Compound 2 was shown to be a partial bioisostere of norepinephrine, with direct agonist activity at the alpha-adrenergic receptor. The ED50 for 2 in contracting the guinea pig isolated aortic strip was determined to be 8.0 x 10(-6) M. Compound 4 was shown to be a partial bioisostere of isoproterenol, with direct activity as a beta-adrenergic agonist. The ED50 values for positive chronotropic and inotropic effects of 4 on the isolated guinea pig atrial preparation were determined to be 6.2 x 10(-6) and 3.8 x 10(-6) M, respectively. The ED50 for 4 on the isolated guinea pig tracheal preparation was determined to be 1.6 x 10(-6) M. These results indicate that 4 shows greater selectively for the beta-2 adrenergic receptor than does isoproterenol. The chemical stability of benzimidazole, compared with that of catechol, suggests that benzimidazole bioisosteres of catecholamines may be of value as adrenergic drugs.

Ethyl -Phthalimidoocetoacetate Ethylene Thioketal.-Ester II (5 g, 0.018 mol) and 2.7 g (0.028 mol) of ethanedithiol were dissolved in CHC13 and 5.8 ml of BF3-etherate was added. The solution was stirred 3 hr at 25°, then was washed with NaHCOg solution, dried, and concentrated. After long standing it partly crystallized from ¿-Pr20, 3.1 g, mp 71-72°. Anal. (CieHuXOJSa) C, , N, S.Pyrrolidine-2,4-dione 4-Ethylene Ketal (XIV).-NaOMe (0.32 g, 0.006 mol) wTas added to a solution of 2 g of XI (0.006 mol) and 0.23 g (0.007 mol) of NH2OH in MeOH. The solution turned pale yellow', then bright yellow, orange and, after 15 min, red. Shortly afterwards a solid precipitated. After 16 hr, the solid Xa salt of Ar-hydroxyphthalimide (0.6 g) was filtered, the filtrate was diluted with a large volume of i-Pr20 and more Na salt (0.25 g) was removed. The filtrate was concentrated giving 1.5 g of crude XIV, as an oil. This material slowly recrystallized and was then sublimed in vacuo and recrystallized from f-Pr20, to give 0.7 g of XIV, mp 98-101°. The compound shows a typical lactam absorption in the ir at 5.92 µ. Anal. (CeHgNOs) C, , N.