Comparison of the hypolipidemic activity of cyclic vs. acyclic imides

Two series of nitrogen-substituted cyclic and acyclic imides were examined for hypolipidemic activity in mice after dosing for 16 days at a dose of 20 mg/kg per day. The hypolipidemic activity of the unsubstituted, N-butyl, N-3-oxobutyl, and N-2-carboxyethyl derivatives of diacetimide and succinimide were compared as well as the unsubstituted and N-substituted dibenzimide and diphenimide. It was shown that an imide functionality incorporated into a ring was not necessary for hypocholesterolemic activity. Good hypocholesterolemic activity was observed in both series of acyclic and cyclic imides. However, a cyclic imido structure was a necessary requirement for good hypotriglyceridemic activity. A decrease in hypotriglyceridemic activity was noted when comparing the cyclic imides to their respective acyclic congeners.     

Synthesis of new aminoalkanol derivatives of benzofuran with potential beta-adrenolytic activity

Two routes of synthesis of 2-acetyl-7-hydroxy-6-methoxy-3-methylbenzofuran and some of its aminoalkanol ethers are described. Six compounds proved to exert the expected antiarrhythmic and hypotensive effects.     

Analgesic activity of cyclic imides: 1,8-naphthalimide and 1,4,5,8-naphthalenediimide derivatives

In early studies, we have reported the synthesis and biological activities of several cyclic imides. The present study describes the analgesic activity of 1,8-naphthalimide and 1,4,5,8-naphthalenediimide derivatives in a standard murine model of analgesia. The pharmacological results show that all compounds studied, given intraperitoneally, produced significant inhibition of acetic acid-induced abdominal constrictions. At the ID50 (micromol/kg) level, these cyclic imide derivatives were about 40-270-fold more potent in this assay than aspirin and acetaminophen, two well-known and widely used analgesics. These results extend previous studies on the analgesic activity of cyclic imides.     

Synthesis and hypolipidemic activity of 2-substituted isobutyric acid derivatives

A series of 2-substituted isobutyric acid derivatives have been synthesized and evaluated as hypolipidemic agents. Compounds 11 and 20 were found to decrease the level of plasma total cholesterol in experimental hyperlipidemic rats to a greater extent than clofibrate (CF) and to increase the level of plasma high-density lipoprotein cholesterol to the same extent as gemfibrozil (GF). Increase in liver weight caused by these compounds were less than those with CF and GF.     

Synthesis of flavones with hypolipidemic activity

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 23, No. 11, pp. 1353–1356, November, 1989.     

Synthesis,and hypolipidemic and cholagogic activity of cinnamic acid derivatives

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 25, No. 8, pp. 38–41, August, 1991.     

Synthesis of p-menthane derivatives with potential biological activity

The synthesis of amino ketones and amino alcohols in p-menthane series is presented. These compounds were obtained in Mannich reaction, starting from the unsaturated ketone p-mentha-6,8-dien-2-one and its saturated analogue p-menthan-2-one. The structures of the compounds obtained were established by means of chemical transformations and elemental and spectral (IR, 1H NMR) analysis. The compounds obtained were subjected to the pharmacological investigations.     

Amnesia-reversal activity of a series of cyclic imides

A series of dihydro-1H-pyrrolizine-3,5(2H,6H)-diones were synthesized and evaluated for their ability to reverse electroconvulsive shock (ECS) induced amnesia in mice. Among the structure-activity relationships explored were the effects of ring size, the presence of heteroatoms (sulfur) in the ring system, and the introduction of alkyl substituents. The optimal ring size for the bicyclic system was 5.5 with dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (3), although some activity was present in the corresponding 5.6 [hexahydro-3,5-indolizinedione (7)] and 6.6 [tetrahydro-2H-quinolizine-4,6(3H,7H)-dione (9)] analogues. Replacement of the C-1 carbon atom in compound 3 with a sulfur [dihydropyrrolo[2,1-b]thiazole-3,5(2H,6H)-dione (10)] abolished activity, and the introduction of methyl groups resulted in poorer biological profiles except when the substitution was made at the 7a position [dihydro-7a-methyl-1H-pyrrolizine-3,5(2H,6H)-dione (4)]. In several instances, hydrolysis of the parent bicyclic compound was carried out to furnish the corresponding lactam acids, which were further derivatized. Several exhibited interesting activity, especially the 5-oxo-2-pyrrolidinepropanoic acid derivatives such as 5-oxo-2-pyrrolidinepropanoic acid (12), 5-oxo-2-pyrrolidinepropanoic acid phenylmethyl ester (17), 5-oxo-2-pyrrolidinepropanoic acid (3-chlorophenyl)methyl ester (20), N-4-pyridyl-5-oxo-2-pyrrolidinepropanoic acid amide (25), and N-(2,6-dimethylphenyl)-5-oxo-2-pyrrolidinepropanoic acid amide (27). Compound 3 (CI-911; rolziracetam) was also observed to improve performance on a delayed-response task in aged rhesus monkeys and was selected for evaluation in cognitively impaired human subjects on the basis of its biological profile and a wide margin of safety in animals.     

Synthesis and potential anticonvulsant activity of new aryl sulfonyl semicarbazide derivatives

In the present study on the development of new anticonvulsants, twelve new aryl sulfonyl semicarbazide derivatives were synthesized and tested for anticonvulsant activity using maximal electroshock (MES), subcutaneous pentylenetetrazole screens. Their neurotoxicity was determined by the rotorod test. The most active compound 5i showed the MES-induced seizures with ED₅₀ value of 7.3 mg/kg and TD₅₀ value of 402.3 mg/kg after intraperitoneally injection to mice, which provided compound 5i with a protective index (TD₅₀/ED₅₀) of 55.1 in the MES test.     

Hypolipidemic activity of phthalimide derivatives V: Reduced and hydrolytic products of simple cyclic imides

A series of cyclic imides and related compounds have previously been shown to possess hypolipidemic activity at the low dose level of 20 mg/kg/d. Hydrolytic and reduced products of the cyclic imides were synthesized and examined to discern if possible metabolic products were the active chemical species of these hypolipidemic agents. Phthalimide proved to be the most active cyclic imide tested. Unfortunately, the new products did not, in general, improve hypolipidemic activity in rodents. The exceptions were piperidine which demonstrated improved hypotriglyceridemic activity, and 3,4,5,6-dibenzohomopiperidin-2-one, which demonstrated improved hypocholesterolemic activity compared to phthalimide.     

Synthesis of new N-substituted cyclic imides with potential anxiolytic activity. XXV. Derivatives of halogenodibenzo[e.h]bicyclo[2.2.2]octane-2.3-dicarboximide

The preparation of a number of derivatives of dibenzo[e.h]bicyclo[2.2.2]octane-2.3-dicarboximide with an expected anxiolytic activity.     

Synthesis of some indole derivatives with potential antiinflammatory activity

2-Methylindole-3-acethydrazide (1) was reacted with arylisothiocyanate to give the corresponding 4-arylthiosemicarbazides 2a-d. Cyclization of the latter gave the corresponding 3-mercapto-5-[3-(2-methylindolyl)methyl]-1,2,4-triazoles 3a-d. Compounds 3a-c reacted with chloroacetic acid to give the corresponding indolyl-1,2,4-triazolythioglycolic acids 4a-c. The methylmercapto derivative 5 was also obtained from 3a and methyliodide. The hydrazide 1 was also reacted with carbon disulfide to give the corresponding indolymethyl-1,3,4-oxadiazole-2-thione (6) which was condensed with piperidine and formaldehyde to give the corresponding Mannich base 7. Condensation of 1 with aromatic aldehydes gave the corresponding hydrazones 8a-c which were converted into the corresponding oxadiazolines 9a-c.     

Synthesis of isothiazole derivatives with potential biological activity.

The synthesis of acyl and ureido derivatives of substituted amides of 3-methyl-5-aminoisothiazole-4-carboxylic acid is presented. The structures of the compounds obtained were established on the basis of IR, 1H NMR and elemental analysis. The influence on the circulatory system of the derivatives was investigated. All structures of the compounds obtained were fully confirmed by IR and 1H NMR as well as by elemental analysis (Table).     

Synthesis of new n-substituted cyclic imides with potential anxiolytic activity. XXIII. Derivatives of 2'-chlorodibenzo[e.h]bicyclo[2.2.2]octane-2,3-dicarboximide

The preparation of a number of derivatives of dibenzo[e.h]bicyclo[2.2.2]octane-2,3-dicarboximide with an expected anxiolytic activity is described.     

Hypocholesterolemic and hypolipidemic activity of some novel morpholine derivatives with antioxidant activity

In this investigation, we study the synthesis and the evaluation of antioxidant and hypocholesterolemic activity of a number of 2-biphenylyl morpholine derivatives, which are structurally similar to some substituted morpholines possessing antioxidant activity, as well as to hypocholesterolemic 3-biaryl-quinuclidines. The novel derivatives are found to inhibit the ferrous/ascorbate induced lipid peroxidation of microsomal membrane lipids, the most potent derivative, 2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol (compound 7), having an IC(50) value of 250 microM. In addition, these compounds demonstrate hypocholesterolemic and hypolipidemic action. The most active compound (7) decreases total cholesterol, low density lipoprotein, and triglycerides in plasma of Triton WR-1339 induced hyperlipidemic rats by 54%, 51%, and 49%, respectively, at 28 micromol/kg (ip). The above results indicate that the new molecules may be proven useful as leads for the design of novel compounds as potentially antiatherogenic factors.