Subject(s)
Physical Exertion , Sleep Stages/physiology , Animals , Fatigue , Male , Rats , Rats, Inbred StrainsABSTRACT
A series of 33 N-(2-chloroethyl)-N-nitrosocarbamoyl derivatives of N-substituted glycosylamines has been prepared and tested for antitumor activities. The compounds were obtained by reaction of glycosylamines with isocyanate, followed by nitrosation with N2O4. Structure-activity relationships of these trisubstituted nitrosoureas were investigated by varying the N-substituents and disaccharide groups and by comparing them with the corresponding disubstituted analogues. A large number of the nitrosoureas bearing a maltosyl group exhibited strong antitumor activities against leukemia L1210 and Ehrlich ascites carcinoma, and 60-day survivors against leukemia L1210 were found at the optimal dose for these derivatives. In contrast, the lactosyl and the melibiosyl derivatives were almost inactive. The most interesting compound in this series, the 3-isobutyl-3-maltosyl derivative (37), was tested against leukemia L1210 by single and multiple treatment. Its therapeutic ratio (96.3) obtained by multiple treatment is 3 times larger than that (31.5) obtained by single treatment, suggesting a possible clinical utility of 37 by multiple treatment. The favorable effect of a maltosyl moiety in this class of compounds is discussed.
Subject(s)
Antineoplastic Agents/chemical synthesis , Nitrosourea Compounds/chemical synthesis , Animals , Carcinoma, Ehrlich Tumor/drug therapy , Chemical Phenomena , Chemistry , Leukemia L1210/drug therapy , Lomustine/therapeutic use , Male , Mice , Nitrosourea Compounds/pharmacologySubject(s)
Circadian Rhythm , Sleep/physiology , Work Schedule Tolerance , Work , Adult , Electroencephalography , Female , Humans , Male , Nurses , Security MeasuresSubject(s)
Occupational Medicine , Sleep , Activities of Daily Living , Adult , Biological Clocks , Humans , Middle Aged , Occupations , Time FactorsSubject(s)
Occupational Medicine , Work , Absenteeism , Adult , Age Factors , Humans , Male , Middle Aged , Occupational Diseases/epidemiology , Time FactorsSubject(s)
Fatigue , Nursing Staff, Hospital/organization & administration , Personnel Management , Personnel Staffing and Scheduling , Adult , Body Temperature , Female , Flicker Fusion , Hospital Bed Capacity, 300 to 499 , Hospitals, University , Humans , Posture , Rest , Sleep , Time Factors , WorkABSTRACT
A series of 53 1-phenyl-6-azabicyclo[3.2.1]octanes (1) has been tested for their analgetic and narcotic antagonist activities. Structure-activity relationships were investigated by varying the structural parameters. The most interesting compound in this series, the 1-(3-hydroxphenyl)-6,7-dimethyl derivative 8, shows the profile of a well-balanced antagonist-analgesic agent with a very mild physical dependence capacity. The absolute stereochemistry of its active enantiomer [(+)8] was established by the x-ray study and the chemical transformation to the phenylmorphan [(+)-II]. (+)-8 was stereochemically correlated also with the active enantiomer of the 7-demethyl derivatives [(+)-7] by chemical transformation and CD measurement. Certain structural and stereochemical correlations between these compounds (7 and 8) and other known antagonist-analgetics are discussed.
