The synthesis and antihypertensive activity of a series of 2-amino-4-aryl-2-imidazolines are described. Although halogenated aryls and primary 2-amino or 2-methylamino groups are particularly suitable for good antihypertensive activity, an obvious correlation of physical parameters of the aryl substituents or amine groups with antihypertensive effects is not observed. Members of this series are potent adrenergic neuronal blocking agents; they also affect uptake and release of heart norepinephrine and prevent reserpine-induced ptosis. However, none of these biological effects correlate with antihypertensive activity in DOCA rats. One compound, 19, is particularly effective, after oral or subcutaneous administration, in several hypertensive models.We have synthesized a series of 2-amino4-aryl-2-imidazolines (V and VI) which incorporates the structural features of benzyl-and phenethylguanidines. These types of guanidines are believed to affect blood pressure by their actions at peripheral sympathetic nerve terminals.1"3 This series of imidazolines is also chemically related to 2-(2,6-dichloroanilino)-2-imidazoline (catapres), a potent hypotensive agent, which appears to act mainly by a central mechanism.4Many of the imidazolines (V and VI) are potent antihypertensive agents in hypertensive rat models, and we have attempted to relate some relevant biological actions and physical properties of these agents to their antihypertensive effects.Chemistry. The 2-amino4-aryl-2-imidazolines (Table I) were synthesized from ß-aminophenethylamines III as t Presented in part before the Division of Medicinal Chemistry, 163rd National Meeting of the American Chemical Society, Boston, Mass., April 10, 1972. shown in Scheme I. Primary amine derivatives V were obtained by cyclizing the ß-aminophenethylamines with cyanogen bromide (method 10). The 2-substituted amino compounds VI were obtained by cyclizing the primary ß-aminophenethylamines with carbon disulfide, followed by Smethylation with methyl iodide and displacement of methyl mercaptan with various amines (method 13). The hydrazones 37-40 were prepared by condensation of the hydrazine 36 with aldehydes or acetone (method 14).Infrared spectra of the 2-amino4-aryl-2-imidazolines are consistent with a delocalized guanidinium system. They exhibit strong NH absorption in the 3100-3400-cm"1 region rather than in the ammonium region. Their strong C=N absorption at 1680 and 1595 cm"1 is characteristic of the disubstituted guanidinium ion.5The ß-aminophenethylamine intermediates III (Table II)were prepared by several routes (A, B, and C) as shown in Scheme I. The unsubstituted diamine 51 and the 4-MeO de-140
As part of a continuing program of systematically modifying the structure of the class I antiarrhythmic drug changrolin, we synthesized 15 analogues in which the linkage between the two aromatic regions was altered. High antiarrhythmic activity and low parasympatholytic activity was found when the linkage region, designated region 3, contained a carbonyl moiety, including ketones, amides, and ureas. Secondary amides were superior to tertiary amides, while amide reversal resulted in no change in activities. One compound in this series, 7, 2,6-bis(1-pyrrolidinyl-methyl)-4-benzamidophenol (ACC-9358), is undergoing preclinical evaluations.
Novel [(arylcarbonyl)oxy]propanolamines were synthesized and investigated as potential ultrashort-acting beta-adrenergic receptor blockers. Many of these analogues exhibited good potency and short duration. The N-ureidoalkyl analogue 85 (ACC-9089) has a potency equal to propranolol and a duration of action of about 21 min in the dog. It has been selected as a candidate for further clinical study. Structure-activity relationships and structure-duration relationships for these new beta-blockers are also discussed.
Twenty-four structural derivatives of the antiarrhythmic drug changrolin were synthesized and tested for antiarrhythmic and parasympatholytic activities. It was found that while the bis(pyrrolidinylmethyl)phenol pattern of changrolin appeared to be optimal in this series, a wide latitude existed for the heteroaryl substituent for maintaining good antiarrhythmic activity. Further, the antiarrhythmic and parasympatholytic activities tended to exhibit parallel changes.
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