Synthesis of Tacrine Analogues and Their Structure-Activity
Relationships G.R. Proctor 1 and A.L. Harvey, *2 Department of 1 Pure and Applied Chemistry and 2 Physiology and Pharmacology, and Strathclyde Institute for Drug Research, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR Abstract: Three man synthetic routes to analogues of tacrine are described: reaction of anthranilonitriles with cyclohexanone and other ketones, reaction of various anilines with -cyanoketones, and reactions involving anilines and cyclic -ketoesters. Although tacrine has a wide range of pharmacological effects, it is best known as an inhibitor of cholinesterase enzymes. Many of the analogues that have been made have not been tested against acetylcholinesterase or butyrylcholinesterase activity. Consequently, there is limited information from which a detailed understanding of structure- activity relationships can be derived. However, some halogenated derivatives are not only more potent acetylcholinesterase inhibitors than tacrine, they are also more selective for acetylcholinesterase than for butyrylcholinesterase. Chemistry of Tacrine and its Congeners N C NH 2 b a A B C 1 2 3 4 5 6 7 8 Tacrine 1 Tacrine, which is 9-amino-1,2,3,4- tetrahydroacridine, was formerly known by some authors as one of the polymethylene quinoline group, namely 4-amino-2,3-tetramethylene quinoline. The generally accepted scheme of numbering is that shown in Fig. (1). We define congeners in the present context as derivatives of tacrine which have:- Fig. (1). The structure of tacrine, indicating the sites of different bond-disconnections (a, b, c). a) Substituents or ring annelations (fusions) in ring A, Route 1: Bond-disconnection a b) Substituents on the amino group at C 9 , c) Ring contractions or expansions in ring C, Reaction of anthranilonitrile (2) with cyclohexanone (3) in the presence of zinc chloride gives a complex (4) which can be converted to tacrine (1) by aqueous alkali treatment (Fig. 2) [1]. Recently, it has been shown that BF 3 /etherate is a suitable alternative for ZnCl 2 [2]. d) Heteroatom substitutions in rings A or/and C, e) Annelations of rings on to ring C f) Substitutions in ring C. Fluoro-substituted anthranilonitriles (5) and (6) (Fig. 3) have been employed in similar fashion with cyclohexanone [3,4], cyclopentanone [5], cycloheptanone [5] and other ketones [5] such as the three methylcyclohexanones and compound (7) [11] (Fig. 3). Bridged ketones (8)-(11) (Fig. 3) have featured in reactions with several substituted anthranilonitriles (12; X= 6-OMe, 4-Cl, 5-Cl, 6-Cl, 4-Me, 6-Me, 5-NO 2 , 4-CF 3 , 5-CF 3 , for example) [5]. A fair number of heterocyclic ketones are known participants in reactions with anthranilonitriles: in this way the representative structures shown in Fig. (4) have been reported. In contemplating viable syntheses for tacrine and its congeners, one is attracted to three possibilities for bond-disconnection. These are designated as a, b and c in Fig. (1). All have found use in practice: which approach is employed depends, as always, on the precise structural requirements for any particular project. *Address correspondence to this author at Physiology and Pharmacology, and Strathclyde Institute for Drug Research, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR; Tel: 0141 553 4155; Fax: 0141 552 8376; E-mail: sidr@strath.ac.uk 0929-8673/00 $19.00+.00 2000 Bentham Science Publishers B.V. 296 Current Medicinal Chemistry, 2000, Vol. 7, No. 3 Proctor and Harvey CN NH 2 O N NH 2 ZnCl 2 N NH 2 + ZnCl 2 NaOH H 2 O / 2 3 4 1 Fi g. (2). Synthesis of tacrine from anthranilonitrile (2) and cyclohexanone (3). CN NH 2 5 F CN NH 2 6 F F O O O O 7 8 9 10 O N N O O O NH 2 OH NH 2 CN NH 2 X 11 12 13 14 15 Fi g. (3). Various substituents incorporated into tacrine analogues via bond-disconnection a. N N Ph NH 2 N N NH 2 CH 3 N O NH 2 N S NH 2 Ref (6) Ref (6) Ref s(3, 7) Ref (5) N S F NH 2 N S MeO NH 2 N N NH 2 N N NH 2 Cl Ref (5) Ref (5) Ref (2) Ref (5) F N NH NH 2 N NH NH 2 N H N NH 2 Ref (2) Ref (2) Ref (46) Fi g. (4). Representative tacrine analogues prepared using the route from bond disconnection a. Synthesis of Tacrine Analogues Current Medicinal Chemistry, 2000, Vol. 7, No. 3 297 N HN N NH 2 N N N NH 2 OH N S NH 2 N N NH 2 N O NH 2 N S NH 2 O Ref (13) Ref (14) Ref (3) Ref (4) Ref (4) Ref (15) PhCH 2 Fi g. (5). Analogues of tacrine, modified in Ring A (figure 1). Reactions of 1,3-diones with anthranilonitriles have been much studied by the Hoechst-Roussel group [8- 12]. The clinically tested compound (13) [velnacrine] is obtained by reduction of the ketone (14), itself arising from reaction of anthranilonitrile with cyclohexan-1,3- dione (15) (Fig. 3). Many variants of this reaction have been reported [8]. The only significant limitation on this type of synthesis is the accessibility of anthranilonitriles, which are not always easily made. A partial solution involved use of isatins [21]. The latter (e.g. 23) which are commonly obtained from anilines by reaction with chloral and hydroxylamine [22], when heated with cyclohexanone and ammonia gave, for example, 24 (R=Br, OMe) [21] (Fig. 6). Hofmann degradation then gave the amino compounds 25(R-Br,OMe, H) (Fig. 6). Heterocyclic analogues of anthranilonitrile such as the pyrazole (16) [13] have been used to react with cyclic ketones. In this way, several Ring A modified structures have been made (Fig. 5). It has long been known [36] that heating anthranilic acid with cyclohexanone led to 1,2,3,4- tetrahydroacridone (26, X=H, n=2) (Fig. 7). Utilisation of the latter will be discussed later. However, work carried out in Russia [23-25] showed that N-substituted tacrine and related analogues could be obtained by condensing anthranilamides (27) with cyclic ketones (5-, 6- and 7-membered) and then heating the products with PCl 5 and POCl 3 . In this way amides 27 (X=H, 3-Me, 5-Me, 3-Cl, 5-Cl, 5-OMe, 5-Br: R=Me, Et, Bu, aryl) were There appears to be scope for further work in this section since methods are known for synthesis of other -aminonitriles of potential use, for example (17), (18), ( 19) and (20) [16-18] (Fig. 6). Carbocyclic partly saturated -aminonitriles (e.g. 21) [19] were used to produce for example amiridin (22) by reaction with cyclohexanone [20]. N N H CN NH 2 O CN NH 2 CH 3 N CN NH 2 CH 3 CO 2 Et N CN NH 2 Ph CO 2 Et N Aryl CN NH 2 Aryl 16 17 18 19 20 CN NH 2 21 NH 2 N H O O N R CONH 2 R N R NH 2 22 23 24 25 HCl Fi g. (6). Various -aminonitriles and their likely end-products. 298 Current Medicinal Chemistry, 2000, Vol. 7, No. 3 Proctor and Harvey N H (CH 2 ) n O X N (CH 2 ) n NHR' X CONHR' NH 2 X N (CH 2 ) n NMe 2 R 26 27 28 29 Fi g. (7). Tacrine analogues prepared from anthranilic acid. converted to the analogues 28 (n=1, 2, 3) [23-25]. Methyl anthranilate [26] has also been shown to be useful: when heated with HMPT (hexamethylphosphoric triamide) plus a catalytic amount of PPA (polyphosphoric acid) and cyclohexanone, it gave the N,N-disubstituted tacrine 29 (R=H,
n=2) (Fig. 7): Several other congeners (29; n=3, R=9-Cl, 9-I and 9-CH 3 ) were also made [26]. Ar=C 6 H 5 -,p-FC 6 H 4 - -, p-OMeC 6 H 4 -, p-BrC 6 H 4- -) and (37) into tacrine analogues (38; X=H, OMe, Br, F) (Fig. 9). Thus, in making a choice between routes 1 and 2, it may be a question of whether it would be easier to synthesise a relatively inaccessible anthranilonitrile- type component for ring A of tacrine or to make an - cyanoketone component of ring C. Route 3: Bond-disconnection c Route 2: Bond-disconnection b This method depends upon displacement of a leaving group (X in 39) by an amino nucleophile. Much use has been made of this approach. Leaving groups are most frequently halogen, particularly chlorine. More esoteric was the use of CF 3 SO 3 - as leaving group in the synthesis of compound 40 [35]. Phosphate appears to have been involved as the leaving group in the case of 29 [26]. It is quite surprising that, until recently, this approach was seldom employed. Lamant [27,28] was responsible for introducing the protocol shown in Fig. (8). More recently [29], it has been demonstrated that a wide variety of anilines (e.g. 30, 2-, 3-, 4-Cl, 2-, 3-, 4-F, 2-, 4-Me, and all possible diF) participates in these reactions and that TiCl 4 is a convenient alternative to AlCl 3 . It is noted that methoxy-substututed anilines have a tendency to demethylate during the second step of the procedure. Not surprisingly, nitroanilines failed [30] at the second stage. Virtually all of compounds 39 were obtained from acridones (e.g. 26, n=2) [36] or similar structures. Two methods are, in general, available: C 9 of the acridine structure is either carried on the component forming ring A or on that forming ring B. The original synthesis [36] was of the first type utilising anthranilic acid or, later, its esters [37]. This approach has limitations, for although indanone and cycloheptanone [38] reacted fruitfully with anthranilic acid, cyclopentanone did not [39]. Accordingly the route (Fig. 10) involving reactions of anilines (30) with cyclic -keto esters (e.g. 41) became more popular [38-40]. Many workers have chosen this route [37, 41-45]. Activation of most substances (26) is usually brought about by POCl 3 [25, 38, 40, 41] to give 39 (X=Cl) [50,51], although some workers favour a mixture of POCl 3 with PCl 5 [23,27]. Introduction of the CF 3 SO 2 - group was achieved by The scope of this approach hinges on the availability of the -cyano-ketone (31 e.g.). While - cyanocyclanones of 5 to 8 membered rings are easily made by the Thorpe-Ziegler [31-32] reaction employing , -dinitriles, the synthesis of bicyclic - cyanoketones requires several steps from the corresponding ketones. For example, to make - cyanotetralone (34) (Fig. 9) from -tetralone, it is necessary to proceed in several steps via the fused isoxazolo dihydronaphthalene (35) [33]. This approach does not work for indanones. The latter, however, can be converted via fused pyrazolo derivatives (36; NH 2 X CN O N CN X N NH 2 X + -H 2 O AlCl 3 130-150 o 30 31 32 33 Fi g. (8). Synthesis of tacrine analogues via bond-disconnection b. Synthesis of Tacrine Analogues Current Medicinal Chemistry, 2000, Vol. 7, No. 3 299 N O O CN H N N H Ar CN NHAryl N NH 2 X N (CH 2 ) n X N N 40 39 38 37 36 35 34 Fi g. (9). Various reagents and products of bond-disconnection b. quite mild treatment of 26 (X=H, n=2) with (CF 3 SO 2 ) 2 O and Na 2 CO 3 in CH 2 Cl 2 [35]. X=Cl, Br, Me, OMe, H; n=1,2,3). However, it should be said that if primary amino compounds are required, routes 1 and 2 are certainly preferable. Amination of 39 (X=Cl, n=1) using ammonia in hot (180 0 C) phenol gave the phenoxy compound [40] (39, X=OPh, n=1): the amino compound (39, X=NH 2 , n=1) was obtained when alcoholic ammonia in presence of traces of copper salt was applied in sealed tubes at 220-240 o C [40]. Later workers [41] demonstrated that heating several examples of 39 (X=Cl, n=3) with ammonia in hot cresol gave both cresoxy compounds (39, X=OCres, n=3) and amines (39, X=NH 2 , n=3). On the other hand, route 3 may be the method of choice if the final products are secondary or tertiary amines (e.g. 28, R=alkyl or aryl or 29). Since most primary and secondary amines are liquids, it is relatively easy [25, 37, 42] to bring them into reaction with the halo compounds (e.g. 39, X=Cl, Br) either in traditional solvents (e.g. benzene [37] or phenol [42,44,49]). A catalytic amount of an acidic catalyst has been found advantageous. Many substances of general formula 42 (R 2 =Alkyl NH, aryl NH or alkyl 2 N) (Fig. 11) have been reported [44, 47-49]. Most of these contributions were not undertaken in connection with Alzheimers disease. To overcome the difficulties encountered using gaseous ammonia, Konshin and coworkers [47] reacted various chloro compounds (39) with urea (NH 2 CONH 2 ) followed by hydrolysis. In this way a good variety of amino compounds was obtained (28; R=H, X NH 2 O CO 2 Et N H O X + 26 (n = 1) 41 30 Fi g. (10). Production of tacrine analogues via bond-disconnection c. 300 Current Medicinal Chemistry, 2000, Vol. 7, No. 3 Proctor and Harvey N (CH 2 ) n R 2 42 R 1 site. This conclusion is reinforced by the findings that tacrine could still influence acetylcholinesterase which had its active site blocked by the organophosphorus anticholinesterase sarin [62], and that tacrine has only slight effects on binding of propidium to the peripheral active site [64]. Unfortunately, however, the study of Wu and Yang did not extend to similar measurements of the effect of tacrine on pseudocholinesterase or a comparison of tacrine with structurally related analogues. Fig. (11). General formula of tacrine analogues typically produced by route 3. N-Acyltacrine analogues have been obtained from the amino compounds using anhydrides [(alkylCO) 2 O] in the usual way [6]. Similarly, condensation of various aldehydes with the primary amino compounds by heating in toluene with water removal, led to imine compounds (42; R 2 = -N=CHR) [52]. The enzyme from Torpedo californica has been co- crystallised with tacrine [65], which provided evidence that there are aromatic interactions between tacrine and tryptophan and phenylalanine residues within the catalytic site of the enzyme. The first structure-activity study involving tacrine analogues and acetylcholinesterase activity was by Kaul [57]. Tacrine was compared with tetrahydroacridine, 4-aminoquinoline, 4-aminopyridine, and 9-(N-butyl)-amino-1,2,3,4-tetrahydroacridine. The N-butyl substituent seemed to reduce activity, and there was little correlation between potency and basicity. Subsequently, a more extensive series of analogues was compared by Steinberg et al. [66]. From the relatively small effects of additional substituents on the amino nitrogen, it was concluded that the planar ring system interacted with the enzyme. The saturated ring could be reduced to five carbons or increased to seven carbons without dramatic effects on potency, and the benzene ring could be converted to a saturated form without affecting potency. However, activity was lost when the saturated ring was replaced by methyl groups or small alkyl chains. Given the weak blocking activity of 4-aminoquinoline, it may be thought that tacrine binds to acetylcholinesterase through its 4- aminoquinoline portion with the cyclohexyl ring being important in blocking the catalytic site of the enzyme. Pharmacological Effects of Tacrine and its Analogues Since tacrine was synthesised in 1945 [53], many analogues have been made and tested for a variety of pharmacological effects. Tacrine itself was produced during an investigation of the antibacterial properties of acridine derivatives, and although it lacks antibacterial effects it has several other actions. Tacrine was found to antagonise the respiratory depression caused by morphine [54] before it was known to inhibit both acetylcholinesterase [55] and butyrylcholinesterase [56]. Additional actions of tacrine were discovered later: block of monamine oxidase activity [57], inhibition of neuronal uptake of 5-HT and dopamine [58], blockade of certain potassium ion channels [59], interaction with muscarinic acetylcholine receptors [60]. It is still not clear whether the therapeutic effect of tacrine in Alzheimers disease results from its effects on acetylcholinesterase activity or on some of its additional pharmacological properties. Several other early studies involved different analogues of tacrine, but these were not tested for activity on acetylcholinesterase. Examples include Plotnikoff et al. [67], Patnaik et al. [43], Lee [68], and Bindra et al. [44]. The synthesis of some of these analogues has been described earlier in this review. However, inhibition of acetylcholinesterase activity is one of tacrines most potent effects, and most of the work on tacrine analogues has concentrated on effects on this enzyme. Tacrine has complex effects on acetylcholinesterase, producing reversible but non- competitive inhibition (e.g. 61, 62, 63). A meticulous examination of tacrines interaction with acetylcholinesterase was published by Wu and Yang [64]. Tacrine was found to change the circular dichroism spectrum of purified Torpedo acetylcholinesterase, and this was used to monitor the interaction of tacrine with the enzyme in the presence of other drugs. Evidence was obtained to support the suggestion that tacrine binds to the anionic site in the substrate binding region of the enzyme with a large contribution from hydrophobic binding, rather than directly to the esteratic site, or to the peripheral anionic More recent structure-activity work concerned with inhibition of acetylcholinesterase has been published by Morita and colleagues [6] and Shutske and colleagues [7, 8, 10, 11, 12, 15, 37, 52]. Among the synthetic variations were different substitutions of the amino nitrogen, replacement of the aromatic ring, and incorporation of additional heterocyclic functions into the rings. However, there seems to have been no systematic improvement in potency against acetylcholinesterase. Synthesis of Tacrine Analogues Current Medicinal Chemistry, 2000, Vol. 7, No. 3 301 Another study concentrated on variations around the cyclohexyl ring of tacrine: alterations of ring size, bridging the ring, fusing a benzene ring, and introducing additional heteroatoms [2]. Tacrine itself is about three times more active against butyryl- than acetylcholinesterase, and it was found that the cycloheptyl compound was even more potent against butyrylcholinesterase. Increasing the ring size to cyclooctyl resulted in a 100-fold decrease in potency against both enzymes, presumably as a result of the increased bulk and flexibility of the saturated ring. Introduction of a methylene bridge across the cyclohexyl ring also resulted in a dramatic loss of activity. Similarly, fusing a benzene ring to the alicyclic ring generally gave compounds that were less active than tacrine against the cholinesterase enzymes. However, when a benzene ring was fused to the cyclopentyl ring, the compound (6-amino-4,5-benzo- 5H-cyclopenta [1,2-b]quinoline) was 10-fold more active against acetyl- than butyryl-cholinesterase [2]. Overall, it appears that it is possible to prepare analogues of tacrine with increased activity against acetylcholinesterase and with increased selectivity for acetyl- over butyryl-cholinesterase. However, none of these more active and selective acetylcholinesterase inhibitors appears to have been tested in vivo. Therefore it is not known whether the enhanced anticholinesterase activity will translate into more powerful effects on learning and memory or less side effects than found with tacrine. Acknowledgements The authors thank the British Technology Group, Strathclyde Institute for Drug Research, and Tanabe Seiyaku Co. Ltd. for financial support for some of their work described in this review. References Other studies have explored the consequences of introducing a halogen atom into the benzene ring of tacrine or its cyclopentyl analogue [5, 69]. It seemed to be difficult to improve on the potency of the parent analogue (9-amino-2,3-dihydro-[1H]-cyclopenta-[1,2- b]-quinoline) against acetylcholinesterase. Addition of Cl at position 6 (9-amino-6-chloro-2,3-dihydro-[1H] cyclopenta [1,2-b]-quinoline) gave a 6-fold increase in potency, while the corresponding 6F compound was equiactive as the parent. F or Cl substitutents at other positions caused small (8Cl; 8F; 7F; 5F) or marked (7Cl; 5Cl) losses in potency against acetylcholinesterase. A bromo-substituent (7Br) had only weak activity against acetylcholinesterase (IC 50 10M). [1] Moore, J.A; Kornreich, L.D. Tetrahedron Lett., 1963, 20, 1277. [2] McKenna, M.T; Proctor, G.R; Young, L.C; Harvey, A.L. J. Med. Chem., 1997, 40, 3516. [3] Desai, M.C. W.O. Patent 8902739 (1989), Chem. Abstr., 1989, 111, 153657e. [4] Desai, M.C. Eur. Patent 311303 (1989), Chem. Abstr., 1989, 111, 153658f. [5] Kawakami, H; Ohuchi, R; Kitano, M; Ono, K. Eur. Patent, 268871 (1988), Chem. Abstr. 1988, 109, 110275v. [6] Morita, S.; Saito, K.; Ninomiya, K.; Tobe, A.; Nitta, I.; Sugano, M. Eur. Patent 319429 (1989), Chem. Abstr., 1989, 111, 232602m. [7] Shutske, G.M.; Effland, R.C., Eur. Patent 287977 (1989), Chem Abstr., 1989, 110, 154283w. Most of the monohalogen derivatives were less active than the parent cyclopentyl analogue against butyrylcholinesterase: only the 6F compound was as active as the parent. Therefore, the selectivity for acetylcholinesterase in preference to butyrylcholi - nesterase activity (the B/A ratio) was increased in these derivatives. The most selective compounds were the 8F, 6Cl, 7F, 5Cl and 8Cl derivatives, which had B/A ratios of 19, 13, 6.2, 4.1 and 3.8, respectively (B/A ratio of the cyclopentyl parent was 0.93). [8] Shutske, G.M.; Pierrat, F.A.; Kapples, K.J.; Cornfeldt, M.L.; Szewczak, M.R.; Huger, F.P.; Bores, G.M.; Haroutunian, V.; Davis, K.L. J. Med. Chem., 1989, 32, 1805. [9] Puri, S.K.; Hsu, R.; Ho, I.; Lassman, H.B. Curr. Ther. Res., 1988, 44, 766-80, Chem. Abstr. 1989, 110, 68926b. [10] Shutske, G.M.; Pierrat, F.A.; Cornfeldt, M.L.; Szewczak, M.R.; Huger, F.P.; Bores, G.M.; Haroutunian, V.; Davis, K.L. J. Med. Chem. 1988, 31, 1278. [11] Shutske, G.M., US Patent 4762841 (1988). Chem. Abstr. 1989, 110, 8059m. Addition of a second F substituent tended to reduce potency against both forms of cholinesterase, with the effect on potency against butyrylcholinesterase activity being more pronounced than that against acetylcholinesterase. Only 6,7-diF derivative was more active than the corresponding mono F derivatives. Thus, the B/A ratios were higher for the diF derivatives than for the monoF derivatives: 286 for 6,7 diF, 36.6 for 7,8-diF, 16.3 for 5,7-diF, 11.7 for 6,8-diF, and 10.2 for 5,8-diF. [12] Shutske, G.M.; Pierrat, F.A. Eur Patent 179383 (1986). Chem. Abstr. 1986, 105, 172311e. [13] Deeb, A.; Elmobayed, M.; Essawy, A.N.; Elhamid, A.A.; Elhamid, A.M.A. Coll. Czech. Chem. Commun., 1990, 55, 728. [14] Gatta, F.; Pomponi, M.; Marta, M. J. Heterocycl. Chem., 1991, 28, 1301. [15] Shutske, G.M.; Kapples, K.J. US Patent 4753950 (1988). Chem. Abstr. 1988, 109. 128990j. 302 Current Medicinal Chemistry, 2000, Vol. 7, No. 3 Proctor and Harvey [16] Corsaro, A.; Perrini, G.; Puglisi, G.; Purrello, G. J. Chem. Res. 1989(S), 246, M1772. [43] Patnaik, G.K.; Vohra, M.M.; Bindra, J.S.; Garg, C.P.; Anand, N. J. Med. Chem. 1966. 9, 483. [17] Dave, C.G.; Shah, P.R.; Upadhyaya, S.P. Indian J. Chem. Sect. B., 1988, 27, 1046. [44] Bindra, J.S.; Rastogi, S.N.; Patnaik, G.K.; Anand, N.; Rao, K.G.G.; Dwivedi, P.C..; Rao, C.N.R. Indian J. Chem. B., 1987, 26, 318. Chem. Abstr. 1988, 108, 112192u. [18] Verma, S.S.; Taneja, P.; Prakash, L.; Mital, R.L. J. Indian Chem. Soc. 1988, 65, 798. [45] Stephen, J.M.L.; Tonkin, I.M.; Walker, J. J. Chem. Soc. 1947, 1034. [19] Vieillescazes, C.; Coen, S.; Ragonnet, B.; Roggero, J. Heterocycles 1985, 23, 927. [46] Gatta, F.; Delgiudice,; Pomponi, M.; Marta, M. Heterocycles, 1992, 34. 991. [20] Upadysheva, A.V.; Grigoreva, N.D.; Znamenskaya, A.P.; Sarkisyan, D.A.; Metkalova, S.E.; Antonyan, S.G.; Fleiderman, S.N.; Lavretskaya, E.F. Khim. Farm. Zh. 1977, 11, 40. Chem Abstr. 1977, 86, 189676q. [47] Konshin, M.E.; Uvarov, D.I.; Abramochkin, E.S.; Zaks, A.S.; Kapitonenko, T.A. Khim-Farm. Zh. 1974, 8, 17, Chem. Abstr. 1974, 81, 120411d. [21] Bielavsky, J. Coll. Czech. Chem. Commun. 1977, 42, 2802. [48] Prasad, M.; Rastogi, S.N.; Kar, K. Indian J. Chem. B., 1986, 25, 729, Chem. Abstr. 1987. 106, 196226c. [22] Perkin, Jnr. W.H.; Sedgewith, W.G. J. Chem. Soc., 1924, 2437. [49] Brian, W.P.; Souther, B.L. J.M. Chem., 1965, 8, 144. [23] Konshin, M.E.; Abramochkin, E.S. Khim. Getero. Soedin, 1970, 1667, Chem. Abstr., 1971, 74, 53475t. [50] Sargent, L.J.; Small, L. J. Org. Chem. 1946, 11, 359. [24] Konshin, M.E., Khim. Getero Soedin, 1973, 528. Chem. Abstr. 1973, 79, 42310n. [51] Basu, U.P.; Gupta, S.T. Indian Chem. Soc. 1937, 14, 468. [52] Shutske, G.M. European Patent 306825 (1989), Chem. Abstr., 1989, 111, 194612c. [25] Konshin, M.E.; Uvarov, D.I.. Khim. Getero. Soedin, 1973, 531, Chem. Abstr., 1973, 79, 42311p. [53] Albert, A.; Gledhill, W.J. J. Soc. Chem. Ind., 1945, 64, 169. [26] Osbirk, A.; Petersen, E.B. Acta Chem. Scand., 1979, B33, 313. [54] Shaw, F.H.; Bentley, G. Med. J. Aust., 1949, 2, 868. [27] Lamant, M, Ann. Chim. 1959, 4, 87. Chem. Abstr. 1960, 54, 14148c. [55] Shaw, F.H.; Bentley, G. Aust. J. Exp. Biol. Med. Sci., 1953, 31, 573 [28] Lamant, M. Bull. Soc. Chim. Fr., 1959, 782; 1958, 1064. [56] Heilbronn, E. Acta Chem. Scand., 1961. 15, 1386. [29] Harvey, A.L.; McKenna, M.; Mullins, S.J.; Proctor, G.R. UK. Patent 9524346-5 (1996). [57] Kaul, P.N. J. Pharm. Pharmacol., 1962, 14, 243. [58] Drukarch, B.; Leysen, J.E.; Stoof, J.C. Life Sci., 1988, 42, 1011. [30] Mullins, S.J., unpublished. [59] Halliwell, J.V.; Grove, E.A. Eur. J. Pharmacol., 1989, 163, 369. [31] Thorpe, J.F. J. Chem. Soc. 1909, 1901. [60] Perry, E.K.; Smith, C.J.; Court, J.A.; Bonham, J.R.; Rodway, M.; Atack, J.R. Neurosci. Lett., 1988, 91, 211. [32] Ziegler, K.; Eberle, H.; Ohlinger, H. Liebigs Ann. Chem., 1933, 504, 94. [61] Patocka, J.; Bajgar, J.; Bielvasky, J.; Fusek, J. Collect. Czech. Chem. Comm., 1976, 41, 816. [33] Johnson, W.S.; Shelberg, W.E., J. Am. Chem. Soc., 1945, 67, 1745. [62] Dawson, R.M. Neurosci. Lett., 1989, 227, 227. [34] Harvey, A.L.; MacTavish, J.; Mullins, S.J.; Proctor, G.R. J. Chem. Res. (S), 1997, 420. [63] Hunter, A.J.; Murray, T.K.; Jones, J.A.; Cross, A.J.; Green, A.R. Brit. J. Pharmacol., 1989, 98, 79. [35] Michalson, E.T.; Dandrea, S.; Freeman, J.P.; Szmuszkovicz, J. Heterocycles 1990, 30, 415. [64] Berman, H.A.; Leonard, K. Mol. Pharmacol. 1992, 41, 412. [36] Tiedke, H. Chem. Ber. 1909, 42, 621. [65] Sussman, J.L.; Harel, M.; Silman, I. Chemico-Biol. Interactions, 1991, 87, 187. [37] Shutske, G.M.; Helsley, G.C. Eur. Patent 282,959 (1998). Chem. Abstr. 1989 110, 212633y. [66] Steinberg, G.M.; Mednick, M.L.; Maddox, J.; Rice, R. J. Med. Chem. 1975, 18, 1056. [38] Blount, B.K.; Perkin Jnr., W.H.; Plant, S.G.B. J. Chem. Soc., 1929, 1975. [67] Plotnikoff, N.; Keith, J.; Heinemann, M.; Keith, W.; Perry, C. Arch. Int. Pharmacodyn. Ther. 1963, 146, 406. [39] Blount, B.K.; Plant, S.G.P. J. Chem. Soc. 1937, 376. [68] Lee, C.-M. J. Med. Chem., 1966, 9, 483. [40] Petrow, V. J. Chem. Soc., 1947, 634. [69] Proctor, G.R.; Harvey, A.L.; McKenna, M.T.; Mullins, S.J. International Patent Application, 1997, WO 97/19929. [41] Sigal Jnr, M.V.; Brent, B.J.; Marchini, P. US Patent 3,232,945 (1966). Chem. Abstr. 1966, 64, 14174g. [42] Joshi, K.C.; Dubey, K. Indian J. Chem. B. 1978, 16, 156. Chem. Abstr. 1978, 89. 43073f.