A. A. Bakibaev

Amide- and urea-based synthetic anticonvulsants, antihypoxics, and inducers of the hepatic monooxygenase system. IX. Synthesis and search for inducers of the liver cytochrome P-450-dependent monooxygenase system among carbamide-containing heterocyclic compounds

Heterocyclic compounds based on carbamide fragments generally have wide spectra of biological activity. Some members of this class of compounds have been used clinically as tranquilizers (e.g., mebicar) [6] and anticonvulsants (benzonal, diphenin) [7]. Phenobarbital, benzene, and diphenin are powerful inducers of the microsomal oxidation and metabolism of xenobiotics [i0, 12, 13]. However, there have thus far been no systematic and directed studies of liver monooxygenase system inducers among carbamyl-containing heterocyclic compounds.

SYNTHESIS AND ANTICONVULSIVE ACTIVITY OF FLUORINE-SUBSTITUTED BENZHYDRYLAMIDES

In the previous work [1] we have studied the anticonvulsive properties of a series of N-benzhydrylamides and established that some of these compounds produce pronounced anticonvulsive effects. Taking into account that introducing fluorine atoms into aromatic nuclei frequently leads to increase in biological activity compared to that of the base compounds [2], we have synthesized a series of N-benzhydrylamides (I V) containing fluorine substituents in the aromatic fragments and characterized them with respect to anticonvulsive activity.

Electrochemical Determination of the Antioxidant Activity of 1,4-Benzodiazepine

Organic compounds containing 1,4-benzodiazepine fragments are widely used in clinical practice as psychotropic agents [1]. We have studied the antioxidant properties of nozepam, a classical tranquilizer of the 1,4-benzodiazepine group (Fig. 1, compound I), and its oxidation product 7-chloro-5-phenyl-1H-1,4-benzodiazepine-2,3-dione (Fig. 1, compound II). As is known, the seven-member cycle of 1,4-benzodiazepines is stable with respect to oxidation [2]. Indeed, our attempt to provide conditions for the electrochemical oxidation of nozepam failed: the compound was stable in the entire range of electrode oxidation conditions (see the experimental part below). Since the tranquilizer effect of 1,4-benzodiazepines can be related to their transformation into biologically active metabolites in the animal and human organism, we used phenyliodosotrifluoroacetate (PITFA) to oxidize nozepam I so as to retain the 1,4-benzodiazepine framework. PITFA acts upon nozepam as a soft regioselective oxidizing agent [3]. The reaction of I with PITFA in acetonitrile at room temperature usually leads to the formation of compound II with a 79% yield (Fig. 1). In recent years, chemotherapy involving preparations possessing antioxidant properties, has found increasing use in the treatment and prophylaxis of some disorders. We suggest that both nozepam and its oxidation product II, containing NH groups in the 1,4-benzodiazepine core (Fig. 1), may possess antioxidant properties. In order to check for this hypothesis, we have studied the antioxidant properties of both compounds using a rapid and sensitive method of cathode voltammetry (CVA) [4]. A model reaction was the electroreduction of oxygen proceeding by the mechanism analogous to that involved in oxygen reduction in living cells of the organism:

Antihypoxic properties of organic compounds (A review)

A current and important problem of modem pharmacology is the synthesis and biolo#cal characterization of substances capable of increasing the resistance of the organism with respect to hypoxia (or preventing development of this disorder) and accelerating normalization of the cell function during the recovery period. At present, antihypoxic compounds are recogniTed as anindependent class of pharmacolo~cally active substances [1]. In recent years, there has been a steady increase in investigations into the antihypoxic properties of organic compounds, mostly synthetic, belonging to various classes. By now, no reviews were published in the literature that would generalize numerous experimental data on the antihypoxic properties of synthetic preparations and, which is especially important, on the relationship between the antihypoxic effect and the structural and other characteristics of these compounds.

Synthetic anticonvulsants, antihypoxics, and inducers of the liver monooxygenase system based on amides and ureas. XVI. Studies of the antihypoxic properties of bicyclic bis-ureas

Previous studies [2] have demonstrated that the bicyclic bis-ureas include compounds with neuroleptic, antidepressant, and pychostimulatory activities, and one tetramethyl derivative (Mebicar) has found application as a tranquilizing agent [3]. The same report [2] showed that Mebicar has no anticonvulsant activity, but has antihypoxic properties. Our previous studies [4, 5] have shown that the bicyclic his-ureas include compounds with high levels of enzyme-inducing activity [4]; the most active of these induced the cytochrome P-450-dependent monooxygenase system of the liver [5]. In order to obtain more data on the biological properties of the bicyclic bis-ureas, we have studied the antihypoxic activity of carbamide-containing heterocyclic compounds I-X, whose synthesis and physicochemical properties have been reported previously [1]. O O

Synthesis and anticonvulsive activity of tricyclic analogs of benzhydrylurea

Ureas I V were obtained by the reaction of the corresponding amines with nitrourea in an aqueous medium under heating. The yields and characteristics of the compounds synthesized are given in Table 1. The data on anticonvulsive activity of l V obtained by Corazole titration and MES tests are also presented in Table 1. The studied compounds display a low toxicity (LD50 > 500 mg/kg). Replacement of one phenyl ring of benzhydrylurea in I by the cyclohexyl group (compound II) decreases the Corazole convulsion threshold, although pronounced anticonvulsive properties are retained for compound II when estimated by both procedures. In [3] we found the high conformational mobility of the benzhydryl group when studying the anticonvulsive properties of benzhydrylurea. The rather high anticonvulsive activity of phenylcyclohexylmethyl urea II is

Inducers of the phenobarbital type (a review)

Over 30 years ago, Conney suggested the possibility of clinical application o f inducers of the monooxygenase system of the liver (MOSL) [1]. Among numerous compounds with enzyme-inducing properties, inducers of the phenobarbital type (PB inducers) are currently attracting major attention. They are used to correct the antitoxic function of the liver in its various pathologies, and as homeostatic modulators [2]. In addition to increasing the rate of metabolism of a large range ofsubstrates, the PB inducers considerably less often, in comparison with other inducers of the methylcholanthrene type (MC type), cause the toxification of xenobiotics and their acquisition of mutagenic, carcinogenic, and teratogenic properties. This is apparently associated with the fact that the substrates whose metabolism is accelerated with induction of the PB type do not include many xenobiotics whose toxicity substantially grows upon microsomal biotransformation in the liver, e.g., because of K-region formation [3]. The prospects for new PB-type inducers depend primarily on the degree of their specificity for various species. Thus, 1,4-bis(3,5-dichloro-2-pyridyloxy)benzene is effective for the MOSL of mice, but is inactive in rats; whereas 2,4,6-triphenyl1,3-dioxane induces the MOSL in rats, but not in mice [4]. Phenobarbital is a standard PB inducer having no specificity for various species. The present review presents the results of analyzing the structure activity relation for PB-type inducers with the aim of singling out the most general structural criteria encompassing all known inducers of this type.

Synthetic anticonvulsants, antihypoxic agents, and inducers of the liver monooxygenase system. XIX. The synthesis, anticonvulsive, and antihypoxic properties of benzhydrylamine carboxylates

We have previously reported [1, 2] the anticonvulsive and antihypoxic properties of N-benzylhydralamides; we report here out studies on the anticonvulsant and antihypoxic properties of benzhydrylamine (compound I) carboxylates; these can formally be equated with the corresponding N-benzyhydrylamides. The benzhydrylamine carboxylates (compounds II-XX) and benzhydrylamine succinate (compound XXI) were synthesized by a previously described method using equimolar quantities of amine I and the appropriate carbonic acids in suitable solvents (see Chemical Methods section). We have previously described the conditions used for synthesis of benzhydrylamine I [2]. The yield and properties of the compounds studied here, i.e., compounds I-XXI, are shown in Table 1. The anticonvulsant activities of compounds I-XXI were studied using the maximum electric shock and corasol titration tests (Table 2); the neurotoxiciy of benzhydrylamine I and its carboxylates II, VII, and XII were assessed using a rotating bar test (Table 3), and antihypoxic activity was determined in experiments on acute hemic, histotoxic, and hypercapnic hypoxia (Table 4).

Synthetic anticonvulsants, antihypoxic agents, and inducers of the liver monooxygenase system. XII. The antihypoxic properties of n-benzhydrylamines

We have previously [2] studied the anticonvulsive properties of a number of benzhydrylamine derivatives, including N-benzyhydrylamides, with the aim of identifying relationships between structure and activity. A positive role was established for the benzhydryl pharmacophore group in determining biological activity. The relationship between the antihypoxic activity of benzhydrylamine derivatives and their chemical structure has not been described in the literature. We report here our studies on the antihypoxic activity of N-benzhydrylamides (compounds I-XX); the conditions used for their synthesis and details of their physicochemical properties have been described elsewhere [2]. The antihypoxic activities of these compounds are shown in Table 1.

Synthetic anticonvulsants, antihypoxics, and liver monooxygenase system inducers based on amides and urea. VI. Synthesis and search for liver monooxygenase system inducers among compounds containing the benzhydryl group

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