N. V. Klimova

Synthesis and pharmacological activity of phenothiazine derivatives containing the adamantyl radical

The introduct ion of a bulky and highly lipophilic rad ica l into the molecule of a physiological ly act ive substance leads, in a num ber of ca ses , to a cons iderab le change in the magnitude and c h a r a c t e r of i ts b io logical act ivi ty . This has been shown for compounds which have hypoglycemic [1, 2], c u r a r e l i k e [3, 4, 5], hormona l [6], and o ther f o r m s of pha rmaco log ica l ac t iv i t ies [7]. In th i s connection it was of i n t e re s t to a s ce r t a in how the introduct ion of adarnantyl r ad i ca l s af fec ts the act ivi ty of compounds of the phenothiazine s e r i e s , whose 10-dia lkylaminoalkyl de r iva t ives have neurolept ic p r o p e r t i e s [8], while the 10-d ia lkylaminoacyl de r iva t ives d isplay ac t iv i ty with r e s p e c t to the ca rd iovascu l a r s y s t e m [9].

ADAMANTYLPYRIDINES AND THEIR BIOLOGICAL ACTIVITIES

A wide range of pharmacological activities, including anti-anginal and hypertensive [13, 14], vasodilator [15, 16], antioxidant, and psychotropic activities [3-6, 12] are found in compounds belonging to the class of substituted pyridines. Adamantane derivatives such as the psychotropic and antidepressant compounds gludantan [6] and adapramine [2], and immunotropic compounds of the adamantyl-phenothiazine and -aniline series also possess a variety of pharmacological properties. Adamantane derivatives are also known to exhibit positive inotropic action resulting from blockage of the calcium channels [17]. The wide spectrum of biological activities exhibited by these classes of compounds provides a perspective for investigations in the synthesis and study of the pharmacological activities in the adamantylpyridine series. With the goal of studying the effects of introducing the pyridine group on the pharmacological spectrum of adamantane derivatives, the directed syntheses of several adamantylpyridines were undertaken. Using the Leuckart reaction, adamantan-2-one and aminopyridines were condensed to yield 3-(adamant-2-ylamino)pyridine (I) and 4(adamant-2-ylamino)pyridine (II) [8]. For comparative pharmacological studies on the effects of esterification of primary, secondary and tertiary alcohol derivatives of adamantane, adamantyl esters of nicotinic and 5-bromonicotinic acids (III-VI) were synthesized. N-acylation of 1and 2-aminoadamantanes with the acid chloride of 5-bromonicotinic acid yielded the amides VIIIX. Condensation of the ethyl ester of 5-aminonicotinic acid with the acid chloride of 1-adamantancarboxylic acid yielded amide X. In carrying out the acylation of 4-amino-3-hydroxy-2-ethyl-6-methylpyridine with 1-adamantanecarboxychloride in toluene in the presence of triethylamine at 35-40~ a mixture of Nand O-acylated compounds was obtained (XI-XII). Under more stringent conditions such as reflux the reaction yielded a single product 4adamantoylamino-3-adamantoyloxy-6-methyl-2-ethylpyridine (XII). Under mild conditions such as conducting the reaction at 0~ with an equimolar quantity of the acid chloride only the N-acyl compound was obtained (XI). In the alkylation of l-(N-methylamino)adamantane with 4-bromomethyl-3-hydroxy-2-ethyl-6methylpyridine (XIII) under reflux in toluene in the presence of an HBr acceptor the compound XIV was obtained. The starting material XIII was obtained from the action of hydrobromic acid on 4-acetoxylmethyl-2-ethyl-6-methyl3-acetoxypyridine. The psychotropie properties of the substituted adamantylpyridines were studied. We examined the effects in mice of the compounds on spontaneous activity, prevention of development of triftazine catalepsy, and on physical working efficiency (swimming with weights of up to 10% of body weight). The acute toxicities of the compounds were determined. A significant positive effect on spontaneous motor activity was shown by compounds I, III, and V. Statistically significant increases in the duration of swimming by weighted mice was shown by compounds V, VII, and VIII. It is interesting to note that an increase in the working efficiency was brought about, as a rule, by compounds containing a bromine atom in the pyridine ring.

Synthesis and pharmacological properties of benzimidazoline-3-acetic acid n-adamantylamides

Among benzimidazole derivatives, compounds with various biological activities were found, including adaptogenic activity [5]. Thus, for example, dibasole, a representative member of this series, increases the resistance of the human organism to the action of unfavorable factors [7]. In producing such adaptogenic agents, it must be considered that in many cases, their possession of psychostimulating action is important.

Synthesis of diadonium

31. D. M. Burness, Organic Synthesis, Vol. 40, M. S. Narman (ed.), New York (1960), pp. 2930. 32. Chemistry of Acetylenes, E. D. Viehe (ed.), New York (1969). 33. N. Clauson-Kaas and N. Elming, Acta Chem. Stand., ~, 23-26 (1955). 34. D. L. Coffen, Encyclopedia of Chemical Technology, Vol. 24, 3rd edn., M. Grayson and Do Eckroth (eds.), New York (1984), pp. 94-107. 35. J. W. Copperhawer and J. W. Bigelow, Acetylene and Carbon Monoxide Chemistry, New York (1949), p. 357. 36. J.W. Cornforth and J. Cornforth, J. Chem. Sot., No. i, 93-98 (1953). 37. A. Dornow, Chem. Bet., 93, Noo 9, 1998-2001 (1960)o 38. R. A. Firestone, E. E. Harris, and W. Rewter, Tetrahedron, 23, No. 2, 943-955 (1967) o 39. R. E. Geiger, M. Lalonde, H. Stoller, and H. Schleich, Helv. Chim. Acta, 67, No. 5B, 1274-1282 (1984). 40. E. Harris, R. Firestone, K. Pfister III, et al., J. Org. Chem., 27, No. 7, 2705-2706 (1962). 41. H. K6nig and W. B611, Chem. Ztg., i00 , No. 3, 105-111 (1976). 42. H. K6nig, E. Craf, and V. Weverndorfer, Justus Liebigs Ann. Chem., No. 4, 668-682 (1981). 43. Io Maeda, Mo Takehara, K. Togo, et alo, Bull. Chemo Soco Jpn., 42, No. 5, 1435-1437 (1969). 44. I. Maeda, K.. Togo, and R. Yoshida, Bull..Chem. Soc. Jpn., 44, 1407-1410 (1971). 45. D. T. Mowry and J. M. Butler, Organic Synthesis, Vol. 30, A. C. Cope~(edo), New York (1950), pp. 46-48. 46. M. Murakami and M. lwanami, Bull. Chem.

Analysis and standardization of the new domestic antiarrhythmic drug bradizol

oc. Jpn., 41, No. 3, 726-727 (1968). 47. C. A. Parnell and K. P. C. Vollhardt, Tetrahedron, 41, No. 24, 5791-5796 (1985). 48. S. Shimada and M. Oki, Chem. Pharm. Bull., 32, No~ I, 38-43 (1984). 49. T. Shono, Y, Matsumura, K. Tsubata, and J. Takata, Chem. Lett., 1121-1124 (1981).

Analysis and Standardization of the New Psychotropic and Immunotropic Drug Ladasten

As is known, the class of 2-mercaptobenzimidazole derivatives contains substances possessing adaptogen, cardiotropic, gastroprotective, and anxiolytic properties [1 – 4]. A new original domestic drug, bradizol, also belonging to this class, produces antiischemic and antiarrhythmic action [5]. Now bradizol is in the stage of clinical investigation as a specific antibradycardic drug. The chemical structure of bradizol corresponds to 2-[2-(diethylamino)ethylthio]-5-ethoxybenzimidazole dihydrochloride:

N-Adamantyl Derivatives of Aromatic Amines. Part II. Synthesis and Neurotropic Activity of N-(5-R- or 6-R-Adamant-2-yl)arylamines

Ladasten is a white (or nearly white) crystalline powder that is virtually insoluble in water, slightly soluble in 95% ethanol, sparingly soluble in hexane, and readily soluble in chloroform, dioxane, acetone, and ether. The parent compound I was identified by methods of IR, UV, and H NMR spectroscopy and using the characteristic reaction. The IR spectra were recorded with a Perkin-Elmer Model 580 spectrophotometer (Sweden) using samples pelletized with KBr. The spectrum (Fig. 1) exhibits the following absorption lines (cm ): 3415 (secondary amino groups); 2852 – 2913 (stretching vibrations of CH adamantane fragments); 1450 – 1500 (C=C stretching in aromatic fragments); 1610 (characteristic NH bending vibrations); 809 (1,4-substituted benzene ring); 506 (C–Br vibrations). The H NMR spectrum (Fig. 2) was measured on a Bruker AC-250 spectrometer using a standard Bruker control microprogram package. The samples were dissolved in DMSO-d 6 . The proton chemical shifts relative to the internal standard (TMS) were as follows ( , ppm): 1.37 – 2.10 (m, 14H, Ad), 3.41 (m, 1H, 2-H, Ad), 5.75 (d, 1H, NH), 6.57, 7.15 (m, 4H, Ar). The UV absorption spectra of I were recorded using a Specord UV-VIS spectrophotometer (Germany). The optical density of an 0.001% solution of I in chloroform in a maximum at about 260 nm was poorly reproducible. Well reproducible values were obtained using solutions in 95% ethanol. Since I is only slightly soluble in this solvent, the parent compound was first dissolved in chloroform and then the solution was diluted with ethanol in a 1 : 100 ratio. The UV spectrum of this solution exhibits an absorption maximum at 260 2 nm related to the benzene ring and a broad band of lower intensity with a maximum about 310 nm (Fig. 3). In order to identify the parent compound I, we suggest using a qualitative reaction of the oxidation of ladasten to derivatives of oor m-quinone imine under the action of a mixture of concentrated sulfuric and nitric acids, which is accompanied by the appearance of a blue color. This is a characteristic reaction for ladasten. Under analogous reaction conditions, adamantan-2-one and p-bromoaniline give solutions of yellow and red color, respectively. The reaction procedure is as follows: to a solution of 0.05 g of I is added 1 ml of concentrated sulfuric acid and three drops of concentrated Pharmaceutical Chemistry Journal Vol. 37, No. 10, 2003

Anticataleptic activity of heterocyclic 2-aminoadamantane derivatives

The group of N-(adamant-2-yl)arylamines contains the drug bromantan – a highly active psychoand immunostimulant [1 – 5]. As is known, the main metabolites of adamantane derivatives contain a hydroxy group at the nodal position of the adamantane nucleus [6]. The aim of this study was to synthesize and characterize a series of previously unreported 2,5and 2,6-disubstituted adamantanes (Ia – Ih):

Bioavailability of Kemantan in rabbits

Adamantane derivatives (midantan, gludantan, memantine, bemantan, kemantane, etc.) are known to produce a therapeutic effect in patients with various types of Parkinsons syndrome [1, 2]. The interest in adamantane derivatives has been additionally stimulated in recent years, after some of these compounds were found to be capable of blocking the ion channel of glutamate receptors of the NMDA type. Taking into account the neurotoxicity of glutamate in the pathogenesis of a number of pathological states (parkinsonism, Alzheimers disease, Jakob Kreutzfeldt disease, multiple sclerosis, and neurogenic HIV infection), the adamantane derivatives can be considered as promising agents for inhibiting the development of these neurodegenerative disorders [3]. To date, quite a large number of new adamantane derivatives have been synthesized and pharmacologically studied as potential anti-parkinsonian drugs [ 1 ]. It should be noted that a significant part of these compounds contain substituents at the adamantane node position, although the results of tests performed for the screening of anti-parkinsonian agents show that higher activity at a lower toxicity may be inherent in 2-aminoadamantane derivatives [4]. From this standpoint, nitrogen-containing heterocyclic compounds representing adamantane derivatives substituted at the bridging position are still insufficiently studied. The purpose of this work was to synthesize a series of heterocyclic and alicyclic derivatives of 2-aminoadamantane and to perform their primary pharmacological characterization. The target products (Table 1) with the general formula

N-adamantyl derivatives of arylamides of α-azacycloalkanecarboxylic acids and their topical anesthetic activity

The bioavailability of Kemantan in rabbits when administered in tablets is compared with that of the substance when administered in gelatin capsules. We found that although plasma enzymes contribute to the biotransformation of Kemantan, a considerable amount of the active metabolite forms mainly at the expense of the liver enzymes. The relative bioavailability of Kemantan is shown to be higher in rabbits when introduced in the form of tablets. This points to the good biopharmaceutical properties of this drug form.