ABSTRACT
Ethyl 3-chloro-6-(4-chlorophenyl)-pyridazine-4-carboxylate [VII] was cyclized with some nucleophilic reagents (hydrazine hydrate or N-monosubstituted hydrazines) to the new derivatives of pyrazolo[3,4-c]pyridazine [IXa-d]. The structures of the novel compounds were confirmed by elemental and spectral analyses. The effect of several synthesized derivatives on the central nervous system was studied.
Subject(s)
Central Nervous System Agents/chemical synthesis , Pyridazines/chemical synthesis , Amphetamine/antagonists & inhibitors , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacology , Body Temperature/drug effects , Central Nervous System Agents/pharmacology , Central Nervous System Agents/toxicity , Central Nervous System Stimulants/antagonists & inhibitors , Female , Lethal Dose 50 , Male , Mice , Motor Activity/drug effects , Pyridazines/pharmacology , Rats , Rats, WistarABSTRACT
Several new alpha-aminoderivatives of gamma-(p-chlorophenyl)-tetrahydrofuran-2-one were synthesized. alpha-Aminoderivatives of beta-(p-chlorobenzoyl)-propionic acid 2-13 were used as the substrates. After the reduction with NaBH4 at 10-12 degrees C and cyclization the compounds were converted into the appropriate derivatives of tetrahydrofuran-2-one 16-26. In pharmacological tests compounds 9 and 26 abolished the aggressiveness in isolated mice while compound 8 showed antiinflammatory activity.
Subject(s)
Aggression/drug effects , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Blood Pressure/drug effects , Furans/pharmacology , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents , Anticonvulsants/pharmacology , Blood Pressure/physiology , Dopamine Antagonists , Female , Furans/chemical synthesis , Furans/toxicity , Magnetic Resonance Spectroscopy , Male , Mice , Rats , Rats, Inbred Strains , Reserpine/antagonists & inhibitors , Serotonin Antagonists/pharmacology , Spectrophotometry, InfraredABSTRACT
Using 3-cyano-5-(p-chlorophenyl)-tetrahydrofuran-2-one 4, 3-aminomethyl derivatives of 5-(p-chlorophenyl)-tetrahydrofuran-2-one were synthesized. The starting material under alkaline hydrolysis yielded 5-(p-chlorophenyl)-tetrahydrofuran-2-one-3-carboxylic acid 5, which was transformed, via an acid chloride, into amide 6. From acid 5 by aminomethylation compounds 7-12 were obtained. Some of them (7, 8, 12) in reactions of ammono-, amino-, and hydrazinolysis yielded corresponding derivatives of 2-aminomethyl-4-(p-chlorophenyl)-4-hydroxybutyric acid 13-20. In pharmacological tests compounds 10 displayed analgesic activity while compounds 2 and 3 revealed anxiolytic properties.
Subject(s)
Central Nervous System Depressants/chemical synthesis , Furans/chemical synthesis , Phenylbutyrates/chemical synthesis , Analgesics , Animals , Anticonvulsants , Apomorphine/antagonists & inhibitors , Blood Pressure/drug effects , Chemical Phenomena , Chemistry , Female , Furans/pharmacology , Magnetic Resonance Spectroscopy , Male , Mice , Phenylbutyrates/pharmacology , Rats , Rats, Inbred Strains , Reserpine/antagonists & inhibitors , Seizures/prevention & control , Serotonin Antagonists , Stereotyped Behavior/drug effectsABSTRACT
Several new aziridine derivatives of propionic acid were synthesized (10-15, 19, 20). o-, m-, p-Chloroanilide of chloroacetic acid 1-3 and chloride of 3-/p-chlorobenzoyl/acrylic acid 16 were the substrates. The compounds 1-3 in reaction with nicotine aldehyde or p-chlorobenzaldehyde were transformed into appropriate anilides of 2,3-epoxypropionic acid 4-9. These, in turn reacted with ethylenimine giving the appropriate 3-aziridine derivatives 10-15. Acid chloride 16 in reaction with amines gave the appropriate amides 17 and 18 which formed 2-aziridine derivatives 19 and 20 when under the influence of ethylenimine. Pharmacological analysis revealed that the aziridine derivatives 12-15, 19 and 20 modulate some immunological reactions with the prevailing effect of the suppressive component (PFC, RFC, IgM level, cellular response to SRBC). The stimulatory effect was observed with some compounds on the level of circulating IgG and GvH reaction. The mechanism of these compounds consists in their interference with the activity of Ts cells and mediators of the immunological reactions.
Subject(s)
Aziridines/metabolism , Azirines/metabolism , Graft vs Host Reaction/drug effects , Immunosuppressive Agents , Propionates/metabolism , Animals , Aziridines/pharmacology , Aziridines/toxicity , Interleukin-1/metabolism , Mice , Mice, Inbred BALB C , Molecular Conformation , Propionates/pharmacology , Viral Plaque AssayABSTRACT
Several new amides and anilides of alpha-aziridinyl-beta-/p-chlorobenzoyl/-propionic acid were synthetized. The beta-/p-chlorobenzoyl/-acrylic acid 2 was used as the substrate. This compound was converted by reaction with appropriate amine into amides and anilides of beta-/p-chlorobenzoyl/-acrylic acid (3-10). These compounds react with ethylenoimine giving appropriate amides and anilides of alpha-aziridinyl-beta-/p-chlorobenzoyl/-propionic acid (11-18). When pharmacologically analyzed, they appeared to possess marked immunotropic activity. The derivatives in question modulated both humoral as well as cellular immune response, the effect being related to the type of substitutent in the amide group.
Subject(s)
Aziridines/toxicity , Azirines/toxicity , Immunity/drug effects , Animals , Aziridines/chemical synthesis , Chemical Phenomena , Chemistry , Chlorobenzoates/chemical synthesis , Chlorobenzoates/toxicity , Edema/immunology , Graft vs Host Reaction/drug effects , Hemolytic Plaque Technique , Hypersensitivity, Delayed/immunology , Lethal Dose 50 , Mice , Mice, Inbred BALB C , Propionates/chemical synthesis , Propionates/toxicity , Rosette Formation , Sheep/immunologyABSTRACT
Several new aziridinyl derivatives of beta-/p-chlorobenzoyl/propionic acid were synthesized (3, 5, 7, 14-18). The gamma-/p-chlorophenyl/-dihydrofuran-2-one 2 and beta-/p-chlorobenzoyl/acrylic acid 4 were used as the substrates. Compound 2 reacts with ethylenimine yielding aziridinylamide of beta-/p-chlorobenzoyl/-propionic acid 3. The sodium salt of acid 4 and methyl ester 6 were converted by reactions with ethylenimine into appropriate alpha-aziridinyl derivatives 5 and 7. The acid 4 in the reaction with phosphorus pentachloride gives the acid chloride 8 which is transformed under the influence of appropriate amines into corresponding amides 9-13. These amides react with ethylenimine giving the appropriate alpha-aziridinyl derivatives of beta-/p-chlorobenzoyl/-propionic acid 14-18. Pharmacological analysis revealed that the compounds studied possessed immunotropic activity; they modulate both humoral as well as cellular immune response. Their effect has been shown to be related to chemical structure and to substituents of the carboxyl group in particular.
Subject(s)
Adjuvants, Immunologic/chemical synthesis , Aziridines/chemical synthesis , Azirines/chemical synthesis , Chlorobenzoates/chemical synthesis , Propionates/chemical synthesis , Acrylates/chemical synthesis , Acrylates/pharmacology , Acrylates/toxicity , Animals , Antibody Formation/drug effects , Aziridines/pharmacology , Aziridines/toxicity , Chlorobenzoates/pharmacology , Chlorobenzoates/toxicity , Graft vs Host Reaction , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred Strains , Propionates/pharmacology , Propionates/toxicity , Rosette Formation , Spectrophotometry, Infrared , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/immunologyABSTRACT
beta-Phenyltetrahydrofuran-2-one-alpha-carboxylic acid 1 was transformed in the Mannich reaction into alpha-aminomethyl derivatives of beta-phenyltetrahydrofuran-2-one 2-6. The obtained alpha-aminomethyllactones, in reaction of ammono- and hydrazinolysis yield alpha-aminomethyl-beta-phenyl gamma-hydroxybutyric acid derivatives 7-12. Compounds 4, 5, 8, 9, and 10 depress the central nervous system, and compound 12 shows analgesic properties.
Subject(s)
Central Nervous System Depressants/chemical synthesis , Furans/chemical synthesis , Methylamines/chemical synthesis , Animals , Central Nervous System Depressants/pharmacology , Central Nervous System Depressants/toxicity , Furans/pharmacology , Lethal Dose 50 , Methylamines/pharmacology , RatsABSTRACT
Several new derivatives of 5-aminomethyl-6-/p-chlorophenyl/-4, 5-dihydro-2H-pyridazin-3-one have been obtained. The substrates, beta-aminomethyl-beta-/p-chlorobenzoyl/-propionic acid derivatives 1-5, were converted by reactions with hydrazine hydrate or monosubstituted hydrazines, i.e. phenylhydrazine and N-/beta-hydroxyethyl/-hydrazine into appropriate derivatives of 5-aminomethyl-6-/p-chlorophenyl/-4,5-dihydro-2H-pyridazin-3-one 6-18. Compounds 7, 8, 11, 12, 14, 15, and 18 show depressant activity on CNS, while compounds 7a, 9a, 10, 11, 14, 15 possess cytostatic and immunosuppressive activities.
Subject(s)
Pyridazines/pharmacology , Animals , Brain/drug effects , Cell Division/drug effects , Immunosuppressive Agents , Pyridazines/chemical synthesisABSTRACT
Several new 2-substituted derivatives of 5-aminomethyl-6-/p-chlorophenyl/-4,5-dihydro-2H-pyridazin-3-one were synthesized. The derivatives of 5-aminomethyl-6-/p-chlorophenyl/-4,5-dihydro-2H-pyridazin-3-one (1-4) were used as the substrates. These compounds were converted by the reactions of cyanoethylation, hydroxymethylation and aminomethylation into appropriate 2-substituted derivatives of 5-aminomethyl-6-/p-chlorophenyl/-4,5-dihydro-2H-pyridazin-3-one (5-28). Some of these compounds (5, 9 and 16) show anticonvulsant activity, while compounds 6, 7, 11-13 and 20 possess immunosuppressive activity.
Subject(s)
Pyridazines/chemical synthesis , Animals , Anticonvulsants , Immunosuppressive Agents , Pyridazines/pharmacologyABSTRACT
Several new derivatives of beta-aminomethyl-gamma-(p-chlorophenyl)-gamma-hydroxybutyric acids have been obtained. The substrates, beta-aminomethyl derivatives of gamma-(p-chlorophenyl)-tetrahydrofuranone-2 1-4, were converted by the reactions of ammonolysis, aminolysis and hydrazinolysis into appropriate amides and hydrazides of beta-aminomethyl-gamma-(p-chlorophenyl)-gamma-hydroxybutyric acid. Compounds 10, 11, 16, 18, 19 and 20 show depressant activity on CNS, while compounds 6 and 8 demonstrate antiinflammatory action.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Central Nervous System Depressants/chemical synthesis , Hydroxybutyrates/chemical synthesis , Sodium Oxybate/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Mice , Sodium Oxybate/analogs & derivatives , Sodium Oxybate/pharmacologyABSTRACT
Several new D,L beta-aminomethyl derivatives of gamma-(p-chlorophenyl)-tetrahydrofuran-2-one have been synthesized. The derivatives of D,L beta-aminomethyl-beta-(p-chlorobenzoyl)-propionic acid 2-6 were used as the substrates. These compounds were obtained by the Mannich reaction from acid 1, cyclic secondary amines and formaldehyde. After the reduction with NaBH4, and cyclization, derivatives 2-6 were converted into the appropriate derivatives of tetrahydrofuran-2-one 9-13. Some of the obtained compounds (5, 6, 8, 11 and 12) showed depressant activity against the central nervous system.
Subject(s)
Central Nervous System Depressants/chemical synthesis , Furans/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Dihydroxyphenylalanine/pharmacology , Drug Interactions , Furans/pharmacology , Furans/toxicity , Lethal Dose 50 , Mice , Motor Activity/drug effects , Pentylenetetrazole/antagonists & inhibitorsABSTRACT
Proceeding with the studies on derivatives of pheyl-tetrahydrofuranone-2-carboxylic acids the authors have stated that the reaction of hydroxymethylation of ethyl ester of beta-phenyl-beta-cyanopropionic acid I gives transitionally beta-phenyl-beta-cyano-beta-hydroxymethylpropionic acid II which, after a long time, transforms into an amide of beta-phenyl-tetrahydrofuranone-2-beta-carboxylic acid (III). Amide III is tranformed, through acid IV, into acid chloride V that gives a number of derivatives: amide III, substituted amides (VI-IX), methyl ester X, ureide XI, and aminomethylamides (XII, XIII). The chemical structure of these compounds has been confirmed by elemental analysis and IR and PMR spectra. The compounds newly obtained were invested pharmacologically. It has been found that some of the derivatives (III, VI, VII, VIII, XII, XIII) exert a depressing action on the central nervous system.
