N-methyl Analogues Research Articles

Keto acids in the pyrrole series

The spectral properties of o-(2-pyrrolylketo)benzoic acid and its N-methyl and N-benzyl analogs were investigated in order to detect ring-chain tautomerism. It is shown that the investigated acids exist in the open keto form. The corresponding derivatives involving the carbonyl group were obtained. The preparation of derivatives of the cyclic lactol form of the 2-pyrrolylketobenzoic acids is described.

ChemInform Abstract: SYNTHETIC STUDIES OF AZAFLAVONOIDS. II. SYNTHESIS OF 6‐AZAFLAVONOIDS

AbstractNach Acetylierung der Pyridone (I) mit Acetanhydrid (II) erhält man mit Anisaldehyd (IV) das Azaflavanon (V).

Anorectic and motor activity effects of some 1-benzylcycloalkylamines in the rat.

1. A series of 1-benzylcycloalkylamines with cycloalkyl rings of five, six or seven carbons and with various benzyl ring substituents (3-Cl, 4-Cl, 4-F, 3-CF3) was prepared and tested for anorectic and motor activity effects in rats. 2. Two potent, non-stimulant, anorectics were found: 1-(3-chlorobenzyl)-cycloheptylamine, and its N-methyl analogue. The activity of these compounds resembled that of chlorphentermine.

Synthetic studies of azaflavonoids. II. Synthesis of 6-azaflavonoids.

The syntheses of 5-hydroxyl-4'-methoxy-7-methyl-6-azaflavanone (Ia) and 5-hydroxy-4'-methoxy-7-methyl-6-azaflavone (IIa) from 4-hydroxy-6-methyl-2 (1H)-pyridone (IVa), and the syntheses of Ib and IIb, N-methyl analogues of Ia and IIa respectively, and of IIc, N-methyl-4'-demethoxy analogue of IIa, starting with N-methyl analogue (IVb) of IVa, were described.

Bromination of 4-hydroxypyrazolo[3,4-d]pyrimidines

The bromination of 4-hydroxypyrazolo[3,4-d] pyrimidine and its N-methyl analogs leads to the corresponding 3-bromo derivatives. Inhibition of the reaction by 4-hydroxypyrazolo[3,4-d] pyrimidine was observed during a study of the bromination kinetics; this is explained by complexing.

ChemInform Abstract: NARCOTIC ANTAGONISTS. SYNTHESIS AND EVALUATION OF SOME SUBSTITUTED 1,2,3,4,5,6‐HEXAHYDRO‐1,4‐2,6‐DIMETHANO‐3‐BENZAZOCINES

AbstractDas aus ö‐Hydroxytropinon erhaltende Ketal (I) wird nach Oxidation zu (II) mit p‐Methoxyphenylmagnesiumbromid in das Addukt (III) übergeführt, aus dem dann nach Dehydratisierung, katalytischer Hydrierung und saurer Hydrolyse das Tropinon (IV) erhalten wird.

ChemInform Abstract: 10‐HYDROXY‐4‐METHYL‐2,3,4,5,6,7‐HEXAHYDRO‐1,6‐METHANO‐1H‐4‐BENZAZONINE DERIVATIVES (HOMOBENZOMORPHANS) AS ANALGESICS

Abstract7‐M.ethoxy‐1‐tetralon (I) liefert mit Li‐acetonitril das Addukt (II), aus dem durch Reduktion die Amine (IIIa) und (IIIb) zugänglich sind.

10-Hydroxy-4-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine derivatives (homobenzomorphans) as analgesics.

Six 10-hydroxy-4-methyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine derivatives 17a-f have been synthesized as potential analgesics. The synthesis of these compounds involved conversion of 4-(2-dimethylaminoethyl)-6-methoxy alpha tetralone derivatives 12a-f to their N-methyl analogues and the subsequent intramolecular mannich reaction with formaldehyde to give the 7-keto C-ring homobenzomorphans 14a-f from which 17a-f, respectively, were obtained. Compounds 17a-f are as potent as morphine as analgesics (mice).

The effect of N-alkyl groups of substituted phenyl-N-alkyl carbamates on the inhibition of human plasma cholinesterase.

The inhibition constants for human plasma cholinesterase (dissociation, carbamylation, decarbamylation, overall bimolecular rate constants) were determined for two series of substituted phenyl-N-alkyl carbamates. N-propyl carbamates were found to be better inhibitors than the corresponding compounds carrying smaller N-alkyl groups. In both series the carbamylation constants of N-ethyl carbamates were lower than those of the N-methyl and N-propyl analogues, whereas the decarbamylation constants of the former were found to be higher than those of the latter carbamates. The experimental results obtained with human plasma cholinesterase are compared with published inhibition constants determined for several types of acetylcholinesterases.

Synthesis and stereochemistry of reduction of N-tert-butyl-5-methyl-3-piperidone

Two variations for the synthesis of N-tert-butyl-5-methyl-3-piperidone were described, and a study was made of the stereochemistry of its reduction, which proved to be mainly analogous to the stereochemistry of the reduction of the N-methyl analog. The corresponding epimers of the alcohols were isolated in the pure form.

Semisynthetic aminoglycoside antibacterials. Part IV. Synthesis of antibiotic JI-20A, gentamicin B, and related compounds

The application of the Lemieux-Nagabhushan reaction to the synthesis of antibiotic JI-20A and gentamicin B from a suitably protected garamine derivative is described. 3′-Deoxy-6′-N-methyl analogues of antibiotic JI-20A and gentamicin B have also been prepared from garamine intermediates. The transformation of 3′-deoxygentamicin X2 into the 6′-deoxy-6′-methylamino-derivative is discussed.

N-Methyl analogues of some peptide juvenoids

N-Methyl analogues of some peptide juvenoids

Regulation of phospholipid biosynthesis in isolated rat hepatocytes. Effect of different substrates.

The effects of choline, ethanolamine and its N-methyl analogs, different fatty acids, and L-methionine on phospholipid biosynthesis via the CDP-ester pathways and the methylation pathway were studied in rat hepatocytes. Phosphatidylethanolamine synthesis was stimulated severalfold by 0.02 to 0.1 mM ethanolamine, especially in the presence of long chain unsaturated fatty acids. At higher concentrations of ethanolamine, phosphorylethanolamine accumulated but the level of CDP-ethanolamine and the rate of phosphatidylethanolamine synthesis did not increase further. The rate of phosphatidylcholine synthesis via the CDP-ester pathway responded in a way analogous to that of phosphatidylethanolamine synthesis upon the addition of choline and fatty acid, except that a 10- to 20-fold higher concentration of choline was required for maximal stimulation, probably due to the rapid oxidation of choline to betaine. Phospholipids containing N-monomethyl- or N,N-dimethylethanolamine were efficiently formed from the corresponding free bases in the absence of ethanolamine and choline. Ethanolamine, but not other bases, inhibited completely phospholipid formation from N-monomethylethanolamine, probably as a result of competition at the level of CDP-ester formation. The data indicate that the cytidylytransferase reactions are rate-limiting steps in the synthesis of phosphatidylethanolamine and probably also phosphatidylcholine. In addition, the availability of diacylglycerol and its fatty acid composition may significantly affect the rate of phospholipid synthesis. The rate of phosphatidylcholine formation via phospholipid N-methylation approximately doubled when L-methionine was added at concentrations similar to that in rat plasma. Under these conditions the rate of phosphatidylcholine synthesis via this pathway was 20 to 40 percent of that via diacylglycerols and CDP-choline. The methylation of phosphatidylethanolamine to phosphatidylcholine remained essentially constant when the rate of phosphatidylethanolamine synthesis was varied 8-fold, but was significantly reduced when the formation of N-monomethyl- or N,N-dimethylphospholipid was stimulated by addition of the corresponding base. These phospholipids not only replaced phosphatidylethanolamine as the substrate for methylation but also increased the rate of phosphatidylcholine formation via this pathway. A method for the determination of nanomole amounts of different ethanolamine compounds is described.

Equilibrium studies. Complex formation of 4-azaheptane-1,7-diamine, 4,8-diazanonamine, and 4-aza-4-methylheptane-1,7-diamine with copper(II) ions and protons in aqueous solution

Equilibrium constants are reported for the protonation of the linear triamine, 4-azaheptane-1,7-diamine (4NH-hd), and its N-methyl analogues, 4,8-diazanonamine (4,8NH-nam) and 4-aza-4-methylheptane-1,7-diamine (4NH-4Me-hd),I= 0.1M(NaCl), 25°C. Formation constants and spectrophotometric data are presented for the complexes [CuL(H2O)]2+ and [CuL(OH)]3+ formed by each ligand. Data are compared with those for analogous triamines.

A New Synthesis of 5-Phenyl-2,3-dihydro- and 2,3,4,5-Tetrahydro-1H-2-benzazepin-1-ones

It was shown that 3-phenyl-3-(2-aminoethyl)phthalide (6, R = H) and its N-methyl analog (6, R = CH3) existed in the amino lactone form in solution at room temperature. In the absence of solvents, however, these compounds underwent a spontaneous transformation into the 5-phenyl-2,3,4,5-tetrahydro-1H-2-benzazepin-1-ones (8, R = H, CH3) which suffered dehydration in sulfuric acid with the formation of 5-phenyl-2,3-dihydro-1H-2-benzazepin-1-ones (9, R = H, CH3).This benzazepine synthesis can be considered to be analogous to the known (12–15) conversion of 1-aminomethylphthalides (11) to 4-hydroxy-3,4-dihydroisocarbostyrils (13).

Effects of atropine on avoidance condition: interaction with nicotine and comparison with n-methyl-atropine.

Atropine, when given to rats shortly before acquisition of a conditioned avoidance response, increases the number of correct responses both in that session and in a retention session performed 5 days later; when the drug is given at a longer pre-trial interval, it has, instead, a depressant action. The depressant action is not observed when the performance of a previously well established conditioned response is measured, instead of the acquisition of a new one. Furthermore, the depressant action does not seem to interfere with the previously reported enhancing action of post-trial atropine on memory consolidation. It does, however, block the enhancing effects of nicotine on learning. The stimulant effect of atropine at short pre-trial intervals is mimicked by N-methyl-atropine at moderate doses; the depressant effect of atropine is shared by high doses of the N-methylated analog. The effects of N-methyl-atropine are not time-dependent, as those of the parent compound.

Studies on the toxicity of dimethoate analogs and their hydrolysis by sheep liver amidase

Various O,O-dialkyl, N-alkyl and N,N-dialkyl analogs of dimethoate [ O,O-dimethyl S-( N-methylcarbamoylmethyl) phosphorodithioate] were synthesized and their toxicity to mice and houseflies was determined. Of the N-alkyl analogs tested, the N-methyl analog of the diethyl ester was the most toxic to mice and houseflies. In the N,N-dialkyl series, N,N-dimethyl was the most toxic to mice, while the N,N-dimethyl, -diethyl, and di- n-propyl were equally toxic to houseflies. The relative rate of hydrolysis of these compounds by a purified sheep liver amidase was also examined. Substrate specificity with dimethoate showed that structural changes in the O,O-dialkyl portion of the phosphorodithioate as well as modifications in the branching indicate a critical size is required for hydrolysis. No direct correlation was found between their toxicity and the rate of hydrolysis by the enzyme. Three amide-containing organophosphorus insecticides, dimethoxon, Bidrin, and Azodrin, were not hydrolyzed by this amidase but they inhibited the enzyme. This finding explains in part the reason for the high mammalian toxicity as well as the inability to find substantial quantities of the corresponding carboxylic acid derivatives in vivo.

Some steroidal p-aminophenyl ethers and their N-methyl and NN-dimethyl analogues.

The synthesis of the 3-O-p-amino-, -p-methylamino-, and -p-dimethylamino-phenyl derivatives of oestrone and oestradiol, and of the p-dimethylaminophenyl ethers of 3β-hydroxyandrost-5-en-17-one and 3β-hydroxypregn-5-en-20-one, from the corresponding p-nitrophenyl ethers, is described.

Structural preferences for the double bond position in some unsaturated 3,3-diphenylpyrrolidines

The reaction between 3,3-diphenyl-3-cyano-1-methylpropyl isocyanate and ethyl magnesium bromide leads to 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline rather than the isomeric 2-ethylidenepyrrolidine. The protonated N-methyl analogue (identical with a major metabolite of methadone) retains the 1-pyrroline structure, but the free base is a cis-trans mixture of the corresponding 2-ethylidenepyrrolidines; the cis Me/Ph isomer preponderates and is the sole product (obtained as a quaternary salt) when the mixture is treated with methyl iodide. 5-Methyl-2-methylene-3,3-diphenylpyrrolidine, a lower homologue of the methadone metabolite, isomerizes to a 1-pyrroline derivative when protonated or methylated. All structural conclusions are based on i.r. and p.m.r. spectroscopic evidence.

Alkaloid studies. Part LXI. The structure of twelve new alkaloids from Aspidosperma cylindrocarpon

Twelve new alkaloids have been isolated from Aspidosperma cylindrocarpon; six (IX, X, and XIV–XVII) belong to a new series of aspidospermine-type with 20-hydroxy- and 21-carboxymethyl groups. These compounds differ in the nature of their N-acyl substituents (formyl, acetyl, benzoyl, cinnamoyl, and dihydrocinnamoyl). The demethoxy (VIII), N-formyl (V), N-benzoyl (VI), and N-methyl (VII) analogues of cylindrocarpidine (III) were also found, together with the unsubstituted compound which is now named ‘cylindrocarine’(IV) to facilitate the nomenclature of its derivatives. In addition N-formyl (XIX) and N-acetyl (XX) cylindrocarpinol were characterized.