The proofs of the structures proposed for the Chlorobi~rnl pheophorbides 650, fractions 1-3, and for the Chlorobizrn~ pheophorbides 660, fractions 5 and 6, are completed and the degradational evidence, where parallel, confinned through the synthesis of derived porphyrins.The photosynthetic bacteria Clllorobizim thioszilfatoplzilum, strain L and strain VN, contain Chlorobium chlorophyll 650 and Chlorobiz~nz cl~loropl~yll 660 respectivelj., the numbers indicating the wavelength of their absorption maxima in the red. These are magnesium complexes of farnesyl (not phytyl) esters of the Chlorobium pheophorbides 650 and 660. Like ordinary chlorophyll, both these cl~lorophylls are mixtures, for their pheophorbides can be resolved into several con~ponents, which are termed fractions: Cl~lorobium pheophorbide 650, fractions 1-6, and Chlorobium pheophorbide 660, fractions 1-6.These fractions (pheophorbides) are more closely related to the pyrropheophorbide a than to the pheophorbide a from cl~lorophyll a , for they lack the 10-carbomethoxy group of the latter. All were shown to be homologues of 2-(a-hydroxyethy1)-2-desvinyl-pyrropheophorbide a (I, R1 = E t , R2 = Me, R3 = H) (Reaction Scheme 1) and were forinulated (2,3) as shown in Table I , wherein the structures of the related porphyrins as well as soine chlorophyll a derivatives are also indicated. I t will be noted that some trivial names such a s pyrroporphyrin (strictly pyrroporphyrin l5), phylloporphyrin, and desoxo-phylloerythrin are used in two senses. Without qualification, they refer to the prototypes derived from chloropl~yll a ; otherwise, they refer to the homologues of these, derived fro111 the Cizlorobium chlorophylls.The analytical and degradational evidence (2, 3) did not coillpletely prove these structures for, in the absence of special features, it could only reveal the pairs of substituents on positions 1-8 but not their order. In both the 650 and 660 series other structures in which the substituents on any of the pyrrole rings 1, 2, or 4 n-ere reversed in order (e.g. 7-methj~l-8-propionic acid) were equally compatible with it. The indicated structures 1 1 ere preferred, because they \\-ere Inore obviously related to pheophorbide a .In the G50 series, there was no direct evidence concerning the nature of R2 in fractions 3 , 5 , and 6, for citraconimide had not been detected among their oxidation products.In the 660 series, improved analytical methods revealed the natures of R2 in all fractions.However, in the absence of adequate models, the nuclear magnetic resonance evidence xvhich placed the R3 groups on the 6-positions xvas not conclusive (3, 4)
18 65 87 93 100 0.3'* Cunen X 10_,! ' M for 50% inhibition of MAO activity of scintillation fluid and the radioactivity was measured. A blank contg boiled enzyme was carried through the entire procedure. The reported results are the averages of replicates and the average variation in the same experiment was ± ó %. The 1.0 was derived from a graph of the log conen/per cent inhibition. Chemistry.I.-The N-nitrosoamines were prepd by the method of Hartman and Roll.13 HC1 was replaced by AcOH, the reaction was carried out under N2 (HONO is lost by reaction with O»), and the mixt was heated to 60-70°after the addn of the NaN()2 soln. The compds were distd and anald, but can be used crude in the redns. The nmr spectra show split Me and CH2 peaks.
An approach to the design of potential combined antithrombotic-antihypertensive agents is described. A series of 1,4-dihydropyridines bearing a 1H-imidazol-1-yl or pyrid-3-yl substituted side chain in the 2-position were synthesized and tested for antihypertensive activity in spontaneously hypertensive rats and for inhibition of TXA2 synthetase in rabbit platelets, in vitro. 1,4-Dihydro-2-(1H-imidazol-1-ylmethyl)-6-methyl- 4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl diester (1) was shown to be similar in potency to nitrendipine as an antihypertensive agent. Compound 1 inhibited TXA2 synthetase in rabbit and human platelets in vitro and reduced plasma TXB2 levels in rats at antihypertensive dose levels. The reductions in thromboxane production observed in vivo and in vitro were accompanied by enhanced levels of 6-KPGF1 alpha, reflecting diversion of the arachidonic acid cascade toward prostacyclin synthesis.
Access to a new class of indole derivatives was gained when Gray and Archer published their work on the pyridylethylation of indoles.1 The usefulness of this general reaction was enhanced by the finding that catalytic hydrogenation of indolylethylpyridines led to selective saturation of the pyridine ring.2 3 Alkylation of the resultant uidolylethylpiperidines gave products which displayed marked depressant effects on the central nervous system of mice and dogs. Certain
The role of α‐blockade in the treatment of hypertension can be reappraised in the light of a recently developed agent (indoramin) which overcomes the major drawbacks of earlier agents. The medicinal chemistry involved in the discovery and synthesis of indoramin is summarized. Highlights of the animal pharmacology of indoramin are outlined with reference to therapeutic utility as an antihypertensive agent. The mode of action of indoramin can be described as competitive post‐synaptic α‐adrenoceptor antagonism combined with myocardial membrane stabilization. Indoramin is an effective antihypertensive agent in man, without therapeutic problems associated with tachycardia, postural hypotension, tolerance, poor absorption, gastrointestinal disturbances, increased peripheral resistance or increased airways resistance. The pre‐clinical basis for these features has been reviewed.
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