Zwitterion Structure in Some 1-Carboxymethylimidazoles and Their Analgetic Activity

The ratio (R) of zwitterions to neutral molecule was determined for the derivatives of 1-carboxymethylimidazole. 1-Carboxymethylimidazole (I) and its 2-methyl derivate (III) were found to be entirely in the form of zwitterion. Of the two 1-carboxymethyl- 2-methyl-nitroimidazoles (V and VII) the 4-nitroisomer (V) possesses no zwitterionic structure, but the 5-nitroisomer (VII) was found to be about 65Q/o in the zwitterionic form. The results obtained are discussed in view of the significant analgetic and sedative effect observed with tlie compounds having a zwitterionic structure

Study of Cyclization Mechanism of N-Substituted-2-amino- benzophenones into 1,4-Benzodiazepines; B-Participation of an Vinylogous Amide Nitrogen

2-(N-B-Bromoalkyl)-amino-5-substiJtuted ben:oophenones 28, 32, 33 .and 38 have been i:nduced by treatment in ethanolic solution of hexamethyleintetramine or rammonia ·to ring c1osure into 1,4-beinzcidiazepiines 39-46. Deuterium B-labe1ed compound 28 gave on cyclization two 1,4-benzodfazepiines (39 and 40) in the rntio 45/55, reveal1ng B-par!ticipation of :nitrogen atom. The neighbouri:ng grnup participa·tion was further investigated by deternniniing the ratio and configuration of the 2- and 3-substituted chiral 1,4-benzodi. azepines 1resulting on ring closure: 32 gave (S)-41 and (S)-42 (ratio 82/18), 33 gave (S)-43 and {S)-44 ~rntio 92/8), 38 gave 45 and 46 (ratio 58/42). High regioselectiviity was also 1observed for recyclization of aziridines 36 in (S)-41 and (R)-42 (rntio 63/37), and 37 in (S)-43 and (R)-44 (ratio 76/24), respectively. Arn opposite stereochemical course of formaition of 42 and 44 f.rom 32 and 33, as :Dram 36 and 37 is observed. Absolute configurntfon of (-)- and ( + )-42 and 44 was determined by comparison of their CD spectra with those of (S)-50, and mecha1nistic scheme is offered accountLng for all exper-imental results

Syntheses of the New Indole Derivatives Related to Indomethacin

Syntheses and properties of the new indole derivatives 18-33, being potential antiinflammatoric agents, are described. 1-p-Chlorobenzoyl- 2-methyl-3-(2\u27-methyl-4\u27-nitroimidazol-1\u27-yl)-5-methoxyindole (32) have been found to possess pronounced antiinflammatoric activity and very low ulcerogenity. Attempting preparation of N-benzoylindole derivative 38 via sigmatropic rearrangement of the open chain precursor 35, as a model procedure for the new synthesis of indomethacin, very low yields on the desired cyclic product 38 have inevitably been obtained

Chiral 1,4-Benzodiazepines. VIII. Concerning the Rate of WD Exchange and Optical Stability of the Chiral Centre C(3).

Various chiral substituted 1,4-benzodiazepin-2-ones with 3- -acyloxy (general formula I), 3-hydroxy- and 3-alkoxy (general formula II), 3-alkyl (general formula III) and 3-quaternary ammonium (general formula IV) groups as substituents were subjected to C(3)-H-D exchange rate measurements in order to obtain information on the optical stability of the chiral centre and on the mechandsm of racemization. Only type IV compounds (IVa-j) exhibited H/D exchange, but acid catalyzed racemization took place in type I and II compounds, indkating some other mechani. sms in this process. Type III compounds as free bases (IIIa-c), N4-protonated acids, or N4-oxides (III, e; f) underwent no H/D exchange and are optically sfable as well. In cases whe,re deprotonation- reprotonation mechanism of racemization can be excluded two other mechanisms are discussed, i. e. acid-\u27catalyzed ring-chain tautomerism and identity substitution with alkoxide ion

Zwitterion Structure in Some 1-Carboxymethylimidazoles and Their Analgetic Activity

The ratio (R) of zwitterions to neutral molecule was determined for the derivatives of 1-carboxymethylimidazole. 1-Carboxymethylimidazole (I) and its 2-methyl derivate (III) were found to be entirely in the form of zwitterion. Of the two 1-carboxymethyl- 2-methyl-nitroimidazoles (V and VII) the 4-nitroisomer (V) possesses no zwitterionic structure, but the 5-nitroisomer (VII) was found to be about 65Q/o in the zwitterionic form. The results obtained are discussed in view of the significant analgetic and sedative effect observed with tlie compounds having a zwitterionic structure

N 1-Substitution in 2-Methyl-4(5)-Nitroimidazole. II.

During the syntheses of some new derivatives of 2-methyl-4(5)nitroimidazole with potential antitrichomonal activity, we have noticed that the substitution on N 1 did not always depend on the pH of the medium, as it has been stated by Pyman1- 4 and Grimison et al.5- 8 • Therefore, we have approached the syste matic investigations of the influence of pH on the formation of t h e 4-nitro and 5-nitroisomers of N1- s ubstituted 2-methyl-4(5)-nitroimidazole. The results obtained indicate that the conclusion of Pyman1- 4 is valid only when strongly alkylated agents are applied, e. g. dialkylsulphates and alkyl tosylates9, since, with other alkylated agents this conclusion could be applied only with restrictions· In addition, we have measured pK:i constants for some isomer pairs prepared, in order to apply the statem ent of Grimison et al.6 that the tautomer ratio, calculated from pKa values, determines the ratio of the isomers in the product mixture . In spite of the fact that the pKa measurements were in goo d accordance with some earlier perform e d6 ,10,15, N 1-substitution with a number of alkylating agents indicate that the statement of Grimison et al.5- 8 is of importance only for alkylation with dimethylsulphate under strictly d e termined conditions

Chiral 1,4-Benzodiazepines. X. Further Investigations of Configurational Stability of the Chiral Centre C(3)

For various at C(3)-chiral 1,4-benzodiazepin-2-ones rate determinations of racemisation (ka.- for C(3)-0CH3 derivative ( + )-1), degenerate nucleophilic exchange (k0 - for rac. 1 and rac. 2), and solvolysis (k5 - for C(3)-hemisuccinyl derivative 4) have been performed. These investigations revealed; (a) retention of .configuration during methanolysis of ( + )-3, (b) slow racemisation of ( + )-1 during solvolytic degenerate nucleophilic substitution (kefko. - - 4), (c} no participation of SNl retentive reaction, possible via intramolecular transfer of the methoxy group within intermediary compounds 4-6, (d) thermodi:namic parameters for racemisation of ( + )-1 between 20-40 °c; liH"" = 18.0 ± 0.8 kcal/moll**, liS"" = = - 7.2 ± 2.5 e. u.*** Mechanistic scheme is offered which accounts for all experimental results. The effect of the electrocyclic equilibrium on the electronic structure of N(4) protonated benzodiazepines, and its possible consequences for their mechanisms of biological activity on the central nervous system (CNS), have briefly been discussed

Polyhedral viral disease of Leucoma salicis L. in Voivodina, Yugoslavia

U radu je dat kratak pregled pojedinih grupa insekatskih virusa. U ovom prvom delu rada poklonjena je veća pažnji Baculovirusima, koji su poznati samo kod insekata, a zatim su izneseni podaci o poliedarnom virusnom oboljenju (Bacilovirus) Leucoma salicis L. (Lepidoptera, Lymantriidae) jedne od značajnih štetočina topola, a naročito u drvoredima. Poliedarno virusno oboljenje L. salicis proučavano je na području SAP Vojvodine u reonu u kojem se topola gaji na znatnim površinama. U uslovima gajenja ove intenzivne šumske kulture L. salicis često oboleva od pomenutog virusnog oboljenja te se virusi ubrajaju među značajne faktore regulacije prenamnožene štetočine. Izneseni su rezultati proučavanja poliedara i infektivnosti virusa za različite stupnjeve starosti gusenica. L. salicis, kao i osetljivosti prema ovom virusu gusenica nekih drugih Lymantriidae. Ispitivan je uticaj vrste hrane na razvoj oboljenja u inficiranim gusenicama L. salicis, zatim infektivnost virusa različitih starosti kao i prenošenje virusa sa inficiranih roditelja na potomstvo.The paper deals with a nuclear polyhedral viral disease (Bacilovirus) of the brown tail moth (Leucoma salicis L., Lepidoptera, Lymantriidae) which is very often a pest of the poplar tree especially in Voivodina, Yugoslavia. The disease occurs in overcrowded populations of larvae. In our experiments a high percentage of the offspring of parents which survived the infection died with signs of the polyhedral disease (68.44 per cent). Polyhedral viruses of L. salicis stored in a relrigerator at 4-5 °C for four years caused death in 100 per cent of infected moths 17 days after infection. The same results were obtained with freshly isolated viruses. The mortality of the infected L. salicis larvae depends on the kind of feed. Unsuitable food causes a faster development of the disease. Younger larvae of L. salicis are more susceptible to the virus than the older ones. They become infected during the hatching if the surface of egg cluster is contaminated with the polyhedral virus

Study of Cyclization Mechanism of N-Substituted-2-amino- benzophenones into 1,4-Benzodiazepines; B-Participation of an Vinylogous Amide Nitrogen

2-(N-B-Bromoalkyl)-amino-5-substiJtuted ben:oophenones 28, 32, 33 .and 38 have been i:nduced by treatment in ethanolic solution of hexamethyleintetramine or rammonia ·to ring c1osure into 1,4-beinzcidiazepiines 39-46. Deuterium B-labe1ed compound 28 gave on cyclization two 1,4-benzodfazepiines (39 and 40) in the rntio 45/55, reveal1ng B-par!ticipation of :nitrogen atom. The neighbouri:ng grnup participa·tion was further investigated by deternniniing the ratio and configuration of the 2- and 3-substituted chiral 1,4-benzodi. azepines 1resulting on ring closure: 32 gave (S)-41 and (S)-42 (ratio 82/18), 33 gave (S)-43 and {S)-44 ~rntio 92/8), 38 gave 45 and 46 (ratio 58/42). High regioselectiviity was also 1observed for recyclization of aziridines 36 in (S)-41 and (R)-42 (rntio 63/37), and 37 in (S)-43 and (R)-44 (ratio 76/24), respectively. Arn opposite stereochemical course of formaition of 42 and 44 f.rom 32 and 33, as :Dram 36 and 37 is observed. Absolute configurntfon of (-)- and ( + )-42 and 44 was determined by comparison of their CD spectra with those of (S)-50, and mecha1nistic scheme is offered accountLng for all exper-imental results

Synthesen von em1gen pharmakologisch und stereochemisch interessanten Derivaten der Camphansaure

In der vorliegenden Arbeit wird die Herstellung von Camphansaurederivaten III-XIII beschrieben. Von den Verbindungen VVIII und XIII wurde eine tuberkulostatische Wirkung erwartet. In vitro Untersuchungen der Verbindungen V-VIII ergaben jedoch durchaus negative Resultate. Die Derivate XIV-XX wurden als potentiell brauchbare chirale Reagenzien zubereitet. Silbersalz XIV wurde erfolgreich filr die Trennung von 3-Hydroxyderivaten der 1,4-Benzodiazepin-2-onen durch die Ester XVII a, b verwendet, ebenso wie Camphansaure filr die Trennung von Enantiomeren des 2-Aminobutanol-1 durch ihre diastereomeren Salze (XXII a, b)