Lindley A. Cates

Phosphorus GABA Analogues as Potential Prodrugs.

Analogues of γ-aminobutyric acid (GABA), wherein a P=O moiety is separated by three carbon atoms from an amino group, were incorporated into Schiff bases as potential acid-labile carrier molecules. These include 3-aminophenylphosphonic acid, its dimethyl ester and its previously unreported N,N′-diisopropylphosphonodiamide. A benzophenone derivative of GABA was also synthesized.A study of the degrees of in vitro hydrolysis of four Schiff bases indicated that lability of the C=N bond is determined by electronic influences of ring substituents.All new products were tested for abilities to inhibit maximal electroshock- and subcutaneous pentylenetetrazol (Metrazol)-induced seizures in mice.Activity was found only in the former system with moderate inhibition displayed by two dimethyl ester and the GABA Schiff bases.

Phosphinic acid analogues of methylaspartic and methylglutamic acids as antibacterials

DL-l-Amino-l-methyl-3-carboxypropanephosphinic acid, a bioisostere of α-methylglutamic acid, was synthesized. This compound, the corresponding α-methylaspartic acid analogue and their precursors were tested for antibacterial activity. The methylaspartic acid analogue gave a MIC of 400 and 800 µg/ml against B. subtilis and P. aeroginosa, respectively.

P-N COMPOUNDS 28. PHOSPHAMINIMIDES 3. 4-NITROBENZYLATION OF PHOSPHINYL-1, 1-DIMETHYL HYDRAZIDES AND FORMATION OF A UNIQUE HYDRAZINIUM INNER SALT1

Abstract The treatment of diethoxyphosphinyl-1,1-dimethylhydrazide with 4-nitrobenzylbromide at 82–90°C resulted in the loss of EtBr and the formation of EtO(−O)P(O) NHN+(CH3)2CH2-4-NO2Ph, a novel type of phosphaminimide. At lower temperatures the diethoxyhydrazide gave the hydrazinium bromide which slowly underwent loss of EtBr to yield the same product. The diphenoxy compound similarly lost HBr at high, but not lower, temperature with production of the normal phosphaminimide. The diphenyl derivative yielded the expected hydrazinium bromide which was dehydrobrominated to the usual phosphaminide with NaOH. The reaction between all three hydrazides and iodomethane, followed by dehydroiodination, gave the usual phosphaminimides.

ADDITION OF HYPOPHOSPHOROUS ACID TO α,β-UNSATURATED AMIDES

Abstract The reaction between hypophosphorous acid and acrylamide gave 2-carbamylethylphosphinic acid. Similar reactions involving methacrylamide and crotonylamide were not successful.

P-N COMPOUNDS 32. PHOSPHAMINIMIDES 6. PHOTOISOMERIZATION TO 1H-1,2 DIAZEPINES1

Abstract Photoinduced ring enlargement of diethoxy, diphenoxy and diphenyl pyridinophosphaminimides resulted in the formation of the corresponding 1-phosphinyl-1H-1,2-diazepines.

P-N COMPOUNDS 29. PHOSPHAMINIMIDES 4. SYNTHESIS COMPARISONS WITH CARBONYL AND SULFONYL COMPOUNDS

Abstract General preparatory methods for carbonyl and sulfonylaminimides were examined for application to phosphaminimides. Three routes to these agents were investigated and one, the reaction between phosphoric or phosphinic chlorides and aminopyridinium salts, was successful. A further anomaly involving the hydrazinium salt dehydrohalogenation procedure was also found.

Phosphorus–Nitrogen Compounds. 31. N-Phosphinylamino-1,2,5,6-tetrahydropyridines: Analgesic Activity and Effect on Blood Glucose

The present research describes the preparation of an additional phosphinyl compound and the results from testing it, and two previously reported agents of this nature, for analgesic, hypoglycemic, and hyperglycemic properties. For purposes of comparison, three analogous carbonyl compounds, which were reported to have these activities, were resynthesized and similarly tested

P-N COMPOUNDS 33. PHOSPHAMINIMIDES 7. N-METHYL-N-PHOSPHINYLAMINO-1,2,5,6- TETRAHYDROPYRIDINIUM INNER SALTS

Abstract Phosphinylaminopyridinium inner salts were reduced and methylated to yield N-methyl-N-phosphinylamino-1,2,5,6-tetrahydropyridinium iodides. Dehydroiodination of these intermediates gave the title compounds.