The synthesis of 1 -aminoalkylphosphonous acids, isosteres of the protein amino acids, by addition of hypophosphorous acid to diphenylmethylimines is described. These analogues of glyche, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, methionine, cysteine, cystine, glutamic acid, lysine, ornithine, arginine, and proline have been prepared and the analogues of alanine, valine, leucine, phenylalanine, and methionine resolved. Tha alanine, valine and methionine analogues have interesting antimicrobial activity and the alanine analogue has plant growth inhibiting properties. Oxidation of the appropriate 1 -aminoalkylphosphonous acids gave tRe 1 -aminoalkylphosphonic acid analogues of ( Ifr ) -alanine, ( -) -alanine, ( & ) -valine, ( -) -valine, ( + ) -serine, ( & )threonine, (-t )-lysine, (-)-leucine, and (+)-ornithine.

1 The pharmacological properties of CGP 37849 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid; 4-methyl-APPA) and its carboxyethylester, CGP 39551, novel unsaturated analogues of the Nmethyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonopentanoate (AP5), were evaluated in rodent brain in vitro and in vivo. 2 Radioligand binding experiments demonstrated that CGP 37849 potently (K1 220 nM) and competitively inhibited NMDA-sensitive L-[3H]-glutamate binding to postsynaptic density (PSD) fractions from rat brain. It inhibited the binding of the selective NMDA receptor antagonist, [3H]-( ±)-342-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), with a Ki of 35 nm, and was 4, 5 and 7 fold more potent than the antagonists ((±)-cis-4-phosphonomethylpiperidine-2-carboxylic acid) (CGS 19755), CPP and D-AP5, respectively. Inhibitory activity was associated exclusively with the trans configuration of the APPA molecule and with the D-stereoisomer. CGP 39551 showed weaker activity at NMDA receptor recognition sites and both compounds were weak or inactive at 18 other receptor binding sites. 3 CGP 37849 and CGP 39551 were inactive as inhibitors of L-[3H]-glutamate uptake into rat brain synaptosomes and had no effect on the release of endogenous glutamate from rat hippocampal slices evoked by electrical field stimulation. 4 In the hippocampal slice in vitro, CGP 37849 selectively and reversibly antagonized NMDA-evoked increases in CAI pyramidal cell firing rate. In slices bathed in medium containing low Mg2+ levels, concentrations of CGP 37849 up to 10pM suppressed burst firing evoked in CAl neurones by stimulation of Schaffer collateral-commissural fibres without affecting the magnitude of the initial population spike; CGP 39551 exerted the same effect but was weaker. In vivo, oral administration to rats of either CGP 37849 or CGP 39551 selectively blocked firing in hippocampal neurones induced by ionophoreticallyapplied NMDA, without affecting the responses to quisqualate or kainate. al., 1988). Many studies have demonstrated that activation of the NMDA receptor is involved in the generation of epileptiform activity and in hypoxic-ischaemic neuronal damage, and conversely that NMDA receptor antagonists are anticonvulsant and cerebroprotective in animal models of epilepsy and stroke (see reviews by Meldrum, 1985;Rothman & Olney, 1986;Choi, 1988;Patel et al., 1988;Iversen et al., 1989;Albers et al., 1989 (Meldrum, 1985;Rothman & Olney, 1986;Albers et al., 1989;.Antagonism of NMDA receptor mechanisms potentially may be achieved by a number of different approaches. In addition to the transmitter recognition site, the NMDA receptor complex comprises an allosteric regulatory site and a channel binding domain (Foster & Fagg, 1987b), and possibly also sites defined by the actions of Zn2", polyamines, tricyclic antidepressants, ifenprodil and CGP 31358 (see Lodge, 1989;Baud et al., 1989). At present, however, the two most well characterized sites are (1) the transmitter recognition site, at which substances such as ...

Reaction of pentafluoropyridine with tetrafluoroethylene and caesium fluoride in dimethylformamide produces, inter alia, perfluoro-4-ethyl-, -2,4-diethyl-, -2,4,5-triethyl-, -2.3.4.6-tetraethyl-, and -pentaethyl-pyridines. In perfluoro-n-pentane solution, the last compound is isomerized by U.V. light to pentakis(pentafluoroethy1)-1 Lazabi-cycl0[2,2,0] hexa-2.5-diene. which in turn forms the corresponding 1 -azatetracyclo[2,2,0,02~s,0S~] hexane. These valence-bond isomers show substantial thermal resistance to rearrangement ; in hexafluorobenzene solution, the half-life at 170°C of the hexadiene is 104 h and that of the hexane is 1.1 h.PHOTOCHEMICAL isomerization of benzene derivatives provides a convenient route to the non-planar valencebond isomers , para-bonded benzenes (bicyclo[2,2 ,O] hexa-2,5-dienes) , benzvalenes (tricyclo[3 , 1 ,O ,02,6] hex-3-enes) , and prismanes (tetracyclo[2,2,0,02~6,03~5]hexanes). Perfluoroalkylation leads to increased thermal stability, and the hexakis-trifluoromethyl and -pentafluoroethyl derivatives are the most stable examples known.2Little is known concerning the valence-bond isomers of six-membered nitrogen heterocycles. N-Methyl-2pyridone forms a $am-bonded isomer upon U.V. irradiation in solution,3 the isomeric picolines and lutidines are photochemically in t erconver tible in the gas phase , possible via prismane intermediates: and it has recently been reported that pyridine is isomerized to an unstable $am-bonded isomer (Scheme 1) which decays back to SCHEME I pyridine with a half-life of 2.5 min at 25 oC.6Nucleophilic displacement of fluoride in peduoroaromatic compounds by perfiuorocarbanions (from fluoro-olefins and casium fluoride in aprotic solvent) provides a convenient route to perfluoroalkyl derivatives.6 Pentafluoropyridine has been reported to react with tetrafluoroethylene to give low yields of pentakis-(pent aff uoroet hyl)pyridine,6* together with perfluoroethylpyridines, C,F,(C,F,),,N(n = 1 4 ) .7 We find 1 (a) Part 111, M.

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NN-Dimethylthioformamide is a superior reagent in the Vilsmeier reaction. Examples of its use are described.