A. S. Saratikov

Amide- and urea-based synthetic anticonvulsants, antihypoxics, and inducers of the hepatic monooxygenase system. VII. Effect of benzhydrylureas on the cytochrome P-450-dependent liver monooxygenase system

54. D. M. Sedlock, R. A. Dobson, D. M. Deuel, et al., Antimicrob. Agents Chemother., 34, No. 4, 568-575 (1990). 55. S. Segeu, A. Barrilai, N. Rosen, and E. Rubinstein, Antimicrob. Agents Chemother., Abstract No. 385 (1988). 56. S. Segeu, A. Barrilai, N. Rosen, et al., Arch. Intern. Med., 149, No. 6, 1314-1316 (1989). 57. C. Siporin, et al. (eds.), The New Generation of Quinolones, New York-London (1990). 58. J. T. Smith and C. S. Levin, The Quinolones, V. T. Andriole (ed.), London (1988). 59. M. Soliati, D. Basetti, B. Datto!i, et al., Congress of Chemotherapy, Tokyo, pp. 1797!798 (1985). 60. R. Stahlman, Drugs Today, 24, 529-536 (1988). 61. R. W. Strunk, J. C. Gratz, R. Moserati, and W. M. Schell, Antimicrob. Agents Chemother., 28, 428-432 (1985). 62. P. van der Auwera, P. Grenier, Y. Glupczynki, and D. Picard, J. Antimicrob. Chemother., 2~, 209-219 (1989). 63. J. Vanderdouckt, A. Hellebrand, and R. Cordier, Curr. Ther. Res., 43, 82-91 (1988). 64. A. Vellucci, G. Bernardini, A. M. Battaglia, and P. Battaglia, Int. J. Clin. Pharmacol. Ther. Toxicol, 25, 279-281 (1987). 65. M. R. Wentland, The New Generation of Quinolones, C. Siporin, et al. (eds.), New York, Basel (1990), pp. 1-45. 66. W. J. A. Wijnands, A. J. A. Van Griethuysen, T. B. Vree, et al., J. Antimicrob. Chemother., i_88, 719-727 (1986). 67. W. J. A. Wijnands, T. B. Bree, A. M. Baars, et al., J. Antimicrob. Chemother., 21, 67-77 (1988). 68. L. S. Young, Ann. Intern. Med., 106, 144-146 (1987).

Quantitative relationship between anticonvulsant activity in N-benzhydrylamides and N-benzhydrylureas, their structures, and13c NMR spectra

In order to establish quantitative relationships between anticonvulsant activity and the structures of compounds containing the common amide grouping Ph2CHNHCOR, we have synthesized the N-benzhydrylamides (I-V) and N-benzhydrylureas (VI-XX), and measured their 13C NMR chemical shifts and anticonvulsant activity as expressed by the anticorazole index. Ph~HNHCOR RC6H~H(Ph) NHCONH2 I--VI VII--XX R=H (I), Me (II), Et (liD, Pr (IV), i-Pr (V), NH2 (VI). o-F (VII), m~ (VIII), p-F (IX), o-Cl (X), m-Cl (XI), wCI (XII), o-Br (XIII), m-Br (XIV), p-Br (XV), o-I (XVI), m4 (XVII), o-Me (XVIII), m-Me (XIX), p-Me (XX). The s y n t h e s i s o f b e n z h y d r y l f o r m a m i d e ( I ) was e f f e c t e d by a m o d i f i e d L e u c k a r t r e a c t i o n f rom benzophenone and f o r m i c a c i d , u s i n g t h e more r e a d i l y a v a i l a b l e u r e a in p l a c e o f t h e more u s u a l formamide [ 5 ] . Compounds ( I I V ) were o b t a i n e d by a c y l a t i n g b e n z y h y d r y l a m i n e w i t h t h e a p p r o p r i a t e a c i d c h l o r i d e s . The N b e n z h y d r y l u r e a s were o b t a i n e d by s t a n d a r d methods f rom t h e a p p r o p r i a t e b e n z h y d r y l a m i n e s and u r e a [ 1 ] . The c o n s t a n t s o f t h e p r o d u c t s (I-XX) a r e g i v e n in T a b l e s 1 and 2.

Quantitative relationships between structure and dissociation constants of enzyme - substrate complexes of microsomal cytochrome p-450 with derivatives of urea, diphenyl, diphenylmethane, and carbamide-containing heterocycles

Cytochrome P-450 is a key component in the monooxygenase system of liver, which is responsible for the metabolism of many xenobiotics [1]. The cytochrome P-450 dependent monooxygenase system serves a universal chemical receptor and chemical analyzer sensitive to a wide circle of compounds [2, 3]. Interaction of a substance with P-450 ferricytochrome, leading to the formation of an enzyme substrate complex, is the first stage in the process of oxidation of this substance. The formation and character of the enzyme substrate complexes can be studied by spectroscopic methods, for example, by monitoring the differential absorption spectra [4, 5]. The mechanisms of interaction in these complexes can be elucidated by studying the quantitative structureactivity relationships (QSAR), in particular, using the dissociation constant K s of the substratecytochrome P--450 complex as the measure of biological activity. In the previous works [6-8] , we used spectroscopic techniques to determine the K s values for the complexes of phenobarbital-induced microsomal cytochrome P-450 with some substrates reported [9] as activators of the liver monooxygenase system in rat liver. As is known, the shape of the differential absorption spectra of these complexes can be used to classify all ligands as belonging to subsmites of types I and H [ 10]. In this work, we have analyzed data on the K s values for cytochrome P-450 complexes with 15 substrates of type I and 37 substrates of type II. As a result, quantitative relationships offering high predicting ability were established between the structure and dissociation constants of these complexes.

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.

Amide- and urea-based synthetic anticonvulsants, antihypoxics, and inducers of the hepatic monooxygenase system. VIII. Effect of benzhydrylureas and m-chlorobenzhydrylureas on the rat liver monooxygenase system

Studies of the enzyme-inducing properties of a series of benzhydrylureas have established that the most active compounds are benzhydrylurea (I) and its m-chloro-substituted derivative (II), which produce pronounced reductions in the duration of hexobarbital sleep in mice, with parallel increases in the microsomal hemoprotein content [2]. Cytochrome P450 induction of the phenobarbital type was proposed to occur in mice receiving I and II. We report here our further studies on the effects of these compounds on the monooxygenase system of rat liver.

Synthesis and anticonvulsant activity of benzhydrylamines

The benzhydryl group forms part of many biologically active compounds, which include benzhydrylamines with high anticonvulsant activity [7-9]. We have established [9] a quantitative relationship between the structures of benzhydrylureas and their anticonvulsant activity and :sC NMR spectra. A limited amount of information on the anticonvulsant activity of benzhydrylamides is available in the literature [4, 6]. In order to compare the effects of substituents of the same type in the benzhydryl group in benzhydrylureas (reported in [9]) and benzhydrylformamides on pharmacological activity (compounds I-XVI) and also to study the anticonvulsant effects of various pharmacophoric amide groups in the benzhydryl moiety, we have synthesized and measured the anticonvulsant activity of compounds (I-XLVII). The benzhydrylformamides (I-XVI) were obtained by a modified Leuckart reaction from the benzophenones in formic acid, using the more readily accessible urea in place of the formamide usually employed [2]:

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.

Synthesis and study of anticonvulsive properties of phenylcycloalkylmethyl ureas

Phenylcycloalkyimethyl ureas I V . 0. I mole of the corresponding amine was added to a solution of0.11 mole of nitrourea in 150 ml of water, and the reaction mixture was heated at 70~ for I h. The precipitate formed is filtered off, washed with warm water, and recrystallized from a mixture of ethanol water (2 : 1 ). The yields and characteristics of synthesized compounds I V are given in Table 1.

Synthetic anticonvulsants, antihypoxics, and liver monooxygenase system inducers based on amides and urea. XI. Synthesis of alkyl- and arylalkylureas and their effects on the liver monooxygenase system

During studies on the search for and synthesis of new compounds able to induce the liver cytochrome--P-450-dependent monooxygenase system, we have produced a series of urea derivatives (I-XVIII) and we have evaluated their enzyme-inducing activities using the hexobarbital sleep test. Alkyland arylalkylureas I-XVIII were prepared by combining the corresponding alkyland arylalkylamines with nitrourea in aqueous solution as described in [1]. The yields, physicochemical properties, and spectral characteristics (IR, 1H, and 13 C NMR) of compounds I-XVIII are given in Tables 1-3, and their enzyme-inducing activities are shown in Table 4.

Synthesis of arylmethylureas and the influence of structure on their antispasmodic activity

We earlier determined the quantitative relationship between the antispasmodic activity, structure, and ZaCNMR spectra for series of benzhydrylureas [4]. In the development of these studies we synthesized 30 derivatives of arylmethylurea, determined their antispasmodic activity, and measured their chemical shifts in the IHNMR and 13CNMR spectra, and also carried out a search for a quantitative relationship between activity, structure, and spectral characteristics of the synthesized compounds I-XXXIV. The anticonvuisant constants of some arylmethylureas were published earlier in [3], and in the present work the series of arylmethylureas is expanded and new parameters are determined for all synthesized compounds.