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A study aimed at further elucidation of the relationship between hypotensive activity and structure among analogs of the protoveratrines is reported. A series of synthetic protoverine tetraesters, which differ from each other only in the nature of the acid residue affixed at C15, have been prepared and subjected to preliminary pharmacological evaluation. The results indicate that alteration in the structure of the ester affixed at C15in analogs of the protoveratrines profoundly affects hypotensive potency.

Desoxycholic acid and 3α,12α-dihydroxypregnane were transformed to the corresponding Δ9(11)-12-oxo compounds. These steroids and their NaBH4reduction products were then hydrogenolyzed with AlCl3–LiAlH4to provide Δ9(11)-compounds in good yield.

A correlation between the infrared absorption spectra and the structure of 13 N-mono- and N-di-substituted trichloroacetamidines is presented. N-Alkyl- and N-aryl-trichloroacetami-dines associate strongly in the liquid and solid phases, and exist only in the imino form in non-polar solvents. They can be characterized by a strong band (amidine II band) at 1510–1525 cm−1and 1570–1580 cm−1respectively which is attributed to the deformation vibration of the secondary amino group. The degree of association of N-substituted trichloroacetamidines changes in the following order of substitution:

The infrared spectra of 14 trichloro- and trifluoro-acetamidine hydrochlorides were studied. It was concluded that protonation occurs at the imino nitrogen atom of the N-substituted amidines. Both nitrogens of the amidine grouping, C(=N)N, become electron-deficient due to resonance leading to the single structure (III), regardless of which of the tautomers is present in the equilibrium mixture, and of the number and type of substituents on the amidine nitrogen atoms. These findings predestine to failureany attempts to isolate the two amidine tautomers, whenever amidinium salts are involved as intermediates.

Trichloroacetonitrile reacts with primary and secondary aliphatic and primary aromatic amines to give N-substituted trichloroacetamidines. A series of N-mono- and N-di-substituted trichloroacetamidines, and was prepared by carrying out the reaction in water, in water–methanol solutions, or in the absence of solvents.

The scope of the reaction of halogen-substituted nitriles and amines was extended by including trifluoro- and dichloro-acetonitrile. Trifluoroacetonitrile reacts easily with primary and secondary aliphatic, primary aromatic, and heterocyclic amines to give the corresponding amidines. N-Mono- and N-di-substituted dichloroacetamidines were prepared from dichloro-acetonitrile and amines, Trichloroacetonitrile also affords N-substituted amidines with heterocyclic amines.

A correlation between the infrared spectra and the structure of some N-mono- and N-disubstituted trifluoroacetamidines is presented. It was found that there was a considerable similarity between the infrared spectra of trifiuoroacetamidines and those of the corresponding trichloroacetamidines. Additional information of the existence of these amidines in the imino form, CF3—C(=NH)NHR, was provided by the infrared study of N,N-dideuterioamidines.

In view of the significant pharmacological differences between protoveratrine A and protoveratrine B when the substances are administered orally, and of our recent revelation that the structures of the two compounds differ only in the nature of the acid moiety of the ester at C3, a series of analogs of the protoveratrines have been prepared and subjected to preliminary pharmacological evaluation. The results indicate that considerable alterations can be made in the structure of the ester affixed at C3without greatly altering hypotensive potency.

It has been shown by infrared spectroscopic study that the alleged N-aryl-nitroacetamidines are in fact the salts of nitroacetonitrile with aromatic amines.