General Papers ARKIVOC 2003 (xv)

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1 General Papers AKIVOC 00 (xv) 07-4 Heterocycles of biological importance: Part 7. ynthesis of biologically active pyrimido[,-b]benzothiazoles from acetylenic acids and -aminobenzothiazoles Helene Wahe a,b, Joseph T. Mbafor b, Augustin E. kengfack b, Zacharias T. Fomum b, afael A. Cherkasov a, Olov terner c, and Dietrich Doepp* d a Department of Chemistry, Kazan tate University, Kremlovskaya str. 8, Kazan , ussia. b Department of Organic Chemistry, University of Yaounde, P.O. Box 8, Yaounde, Cameroon. c University of Lund, Lund Institute of Technology, Chemical Centre, Organic Chemistry, -00 Lund, weden, d Institut fuer Chemie, Universitaet Duisburg-Essen, D Duisburg, Germany doepp@uni-duisburg.de (received 06 Oct 0; accepted Dec 0; published on the web Jan 04) Abstract Conjugate addition of the imino nitrogen of -aminobenzothiazoles to the alkyne β-carbon atom of acetylenic acids followed by ring closure gives rise to novel H-pyrimido[,-b]- benzothiazol--ones in good yield. Keywords: Michael addition, amidines, fused nitrogen heterocycles, cyclocondensation Introduction Condensed pyrimidine compounds have been shown to exhibit interesting pharmacological properties and a number of synthetic methods - has been reported for their preparation. As a part of an ongoing study of the syntheses of heterocyclic compounds of potential biological activity from allenic and acetylenic compounds, - we have shown recently 4 that substituted and unsubstituted H-pyrimido[,-b]benzothiazol--ones are a new group of GABA A / benzodiazepine receptor ligands. In this paper we wish to present the preparation of these compounds. esults and Discussion I Page 07 AKAT UA, Inc

2 General Papers AKIVOC 00 (xv) 07-4 The conjugate addition of -aminobenzothiazole to the acetylenic acids in butanol, followed by cyclocondensation, gave the corresponding H-pyrimido[,-b]benzothiazol--ones 6-8 in 68 86% yield (cheme ). H COOH a-c C H O C C OH H O OH H COOH H 5 4 H O 6,7,8 4 O,6,7,8 a H H a, 6a-d H b Me Me b, 7a-d -Pentyl c H OMe c, 8a-d Ph d H OEt cheme The structures of these compounds were established beyond any doubt by their H-M and C-M spectra and by additional COY, HMQC (Heteronuclear Multiple-Quantum Correlation) and HMBC (Heteronuclear Multiple-Bond Correlation) experiments. When -aminobenzothiazoles a d were allowed to react with phenyl propiolic acid (c), 4-phenyl-H-pyrimido[,-b]benzothiazol--ones 8a-8d were obtained. The M spectra of the 8-methoxy compound 8c and the 8-ethoxy compound 8d showed singlets at δ 6.0 ppm and δ 6.5 ppm, respectively, attributed to -H, and doublets at δ 6.0 ppm and δ 5.96 ppm, respectively, for 6-H. The shielding effects observed for the 6-H in the compounds 8a-8d is due to the diamagnetic effect of the phenyl group attached to C-4. I Page 08 AKAT UA, Inc

3 General Papers AKIVOC 00 (xv) 07-4 The above data exclude the formation of the isomeric -phenyl-4h-pyrimido[,-b]benzothiazole-4-ones 9 which should exhibit a deshielded proton (6-H) near δ 9 ppm resulting from the anisotropic effect of the carbonyl group 5. Further evidence for the formation of the -one derivatives was obtained from the fact that no shielding effect was noticed in compounds 6a-d and 7a-d where the phenyl group was replaced by H or -pentyl, respectively. The reaction of -aminobenzothiazoles with acetylenic acids is rationalized as shown (cheme ), whereby the alkynoic acid is first attacked at the β-carbon atom by the ring nitrogen atom of the benzothiazole. An attack of the -amino group of on the β-carbon of which eventually would generate the isomeric product 9 definitely does not occur 5, 6 (cheme ). H COOH O 4 9 cheme Experimental ection General Procedures. All the melting points were determined with a eichert Thermovar microscope and are uncorrected. Electron impact mass spectra (direct inlet, 70 ev) were recorded with a Jeol JM-X0 spectrometer. The Ultraviolet (UV) spectra were determined in an ethanol-chloroform mixture (:) on a Perkin Elmer 554 instrument and the Infrared (I) spectra were recorded with a Varian Cary 90 and Perkin Elmer 98 spectrometers. H-M (500 MHz) and C-M spectra (5 MHz) were recorded at room temperature with a Bruker instrument using an inverse 5 mm probe equipped with a shielded gradient coil. Chemical shifts (δ) are given in ppm and coupling constants (in brackets) are reported in Hz. COY, HMQC and HMBC experiments were performed with gradient enhancements using sine shaped gradient pulses, and for the D heteronuclear correlation spectroscopy, the refocusing delays were optimised for J CH = 45 Hz and J CH = 0 Hz. The raw data were transformed and the spectra were evaluated with the standard Bruker UXM software (rev. 9400). Combustion analyses were performed with CH + O/ elemental analyser CALO EBA model 06. The purity of the samples was checked routinely by TLC. ynthesis of H-pyrimido[,-b]benzothiazol--ones 6a-d, 7a-d and 8a-d The alkynoic acid a-c (0 mmol) and the appropriate -aminobenzothiazole (a-d, 0 mmol) were heated to reflux in -butanol (50 ml) for 48 hours. Evaporation of solvent under reduced pressure gave the crude product which was crystallized from hexane/ethyl acetate to give the Hpyrimido[,-b]benzothiazol--ones. I Page 09 AKAT UA, Inc

4 General Papers AKIVOC 00 (xv) 07-4 H-Pyrimido[,-b]benzothiazol--one (6a). From a and a, Yield: 68 %; colourless crystals mp 7 75 C [Lit 4 : mp 7 75 C]; I: ν/cm - 60 (C=O), 58 (C=), 5 (C=C). UV (EtOH/CHCl :) λ max (nm), (log ε): 60 (4.0), 00 (4.). M data: δ H (CDCl ) 6. (H, d, J,4 7.7 Hz, -H), 7.46 (H, dd, J 7,6 = J 7,8 8.0 Hz, 7-H), 7.58 (H, dd, J 8,7 = J 8,9 8.0 Hz, 8- H), 7.98 (H, d, J 9,8 7.9 Hz, 9-H), 8.0 (H, d, J 6,7 8. Hz, 6-H), 8.86 (H, d, J 4, 7.7 Hz, 4-H). δ C (CDCl ) 0.8 (C-),.9 (C-9a),.7 (C-6), 6. (C-9), 7. (C-7), 8.8 (C-8), 4.8 (C-4), 5.0 (C-5a), 6.6 (C-0a), 66.9 (C-). M (EI): m/z 0.0 (M +, 00 %, C 0 H 6 O requires 0.00) 76 (), 74 (64), 50 (5), 48 (); Anal. Calcd. for C 0 H 6 O: C, 59.4; H,.97;,.86; O, 7.9;, Found: C, 59.49; H,.0;,.78;, ,8-Dimethyl-H-pyrimido[,-b]benzothiazol--one (6b). From b and a, Yield: 75%; colourless crystals, no melt below 00 C. I: ν/cm (C=O), 67 (C=), 570 (C=C). UV (EtOH/CHCl :) λ max (nm), (log ε): 65 (4.6), 76 (4.), 07 (4.6). M data: δ H (CDCl ).0 (H, s, 8-CH ),.5 (H, s, 7-CH ), 6.4 (H, d, J,4 7.7 Hz, -H), 7.5 (H, s, 9-H), 7.7 (H, s, 6-H), 8.4 (H, d, J 4, 7.7 Hz, 4-H); δ C (CDCl ) 9.7 (7-CH ), 0. (8-CH ),.5 (C-),. (C-6), 0.6 (C-9a),.5 (C-9),. (C-5a),. (C-4), 6. (C-8), 7.0 (C-7), 64. (C-0a), 68.5 (C-). M (EI): m/z 0.05 (M +, 00 %, C H 0 O requires 0.054) 04 (0), 0 (5), 89 (8), 87 (5). Anal. Calcd. for C H 0 O: C, 6.6; H, 4.5;,.7; O, 6.96;,.9. Found: C, 6.7; H, 4.9;,.;,.8. 8-Methoxy-H-pyrimido[,-b]benzothiazol--one (6c). From c and a, Yield: 80%; colourless crystals; no melt below 00 C (Lit 4 : > 00 C). I: ν/cm - 66 (C=O), 49 (C=), 47 (C=C). UV (EtOH/CHCl :) λ max (nm), (log ε): 4 (4.7), 77 (4.), (4.). M data: δ H (CDCl ).8 (H, s, 8-OCH ), 6.9 (H, d, J,4 7.7 Hz, -H), 7.6 (H, dd, J 7,6 9. Hz and J 7,9.6 Hz, 7-H), 7.64 (H, d, J 9,7.6 Hz, 9-H), 7.95 (H, d, J 6,7 9. Hz, 6-H), 8.8 (H, d, J 4, 7.7 Hz, 4-H); δ C (CDCl ) 55.9 (8-OCH ), 08.0 (C-9), 0.6 (C-),.5 (C-7), 4.4 (C-6), 4. (C-9a), 8.6 (C-5a), 5.0 (C-4), 57.6 (C-8), 6. (C-0a), 66.7 (C-). M (EI): m/z.09 (M +, 00 %, C H 8 O requires.006) 06 (8), 04 (), 9 (0), 89 (7). Anal. Calcd. for C H 8 O : C, 56.90; H,.45;,.07; O,.79;,.79. Found: C, 56.85; H,.5;,.07;, Ethoxy-H-pyrimido[,-b]benzothiazol--one (6d). From d and a, Yield: 8%; colourless crystals (8 %); no melt below 00 C. I: ν/cm (C=O), 585 (C=), 500 (C=C). UV (EtOH/CHCl :) λ max (nm), (log ε): 40 (4.0), 78 (4.), (4.). M data: δ H (CDCl ).5 (H, t, J 6.9 Hz, 8-OCH CH ), 4.09 (H, q, J 6.9 Hz, 8-OCH CH ), 6.9 (H, d, J,4 7.7 Hz, -H), 7.5 (H, dd, J 7,6 9.0 Hz and J 7,9.4 Hz, 7-H), 7.6 (H, d, J 9,7.4 Hz, 9-H), 7.9 (H, d, J 6,7 9.0 Hz, 6-H), 8.80 (H, d, J 4, 7.7 Hz, 4-H). δ C (CDCl ) 4.5 ( 8-OCH CH ), 64.0 (8-OCH CH ), 08.4 (C-9), 0.6 (C-),.5 (C-7), 4.8 (C-6), 4. (C-9a), 8.5 (C- 5a), 5.0 (C-4), 56.8 (C-8), 6. (C-0a), 66.7 (C-). M (EI): m/z (M +, 00 %, C H 0 O requires ) 8 (), 9 (), 90 (55), 65 (0). Anal. Calcd. for C H 0 O : C, 58.54; H, 4.06;,.8; O,.0;,.0. Found: C, 58.65; H, 4.04;,.8;,.0. I Page 0 AKAT UA, Inc

5 General Papers AKIVOC 00 (xv) Pentyl- H-pyrimido[,-b]benzothiazol--one (7a). From a and b, Yield 75%; colourless crystals, mp 8-40 C. I: ν/cm - 64 (C=O), 576 (C=), 500 (C=C). UV (EtOH/CHCl :) λ max (nm), (log ε): 5 (4.47), 6 (4.), 9 (4.06), 0 (4.08). M data: δ H (CDCl ) 0.86 (H, t, J 5,4 7. Hz, 5 -H),. (H, m, 4 -H),.4 (H, m, -H),.70 (H, tt, J, 8 Hz and J, 8 Hz, -H),.0 (H, t, J, 7.5 Hz, -H), 6. (H, s, -H), 7.6 (H, dd, J 8,7 9 Hz and J 8,9 8 Hz, 8-H), 7.4 (H, dd, J 7,6 9.0 Hz and J 7,8 8 Hz 7-H), 7.6 (H, d, J 9,8 7.8 Hz, 9-H), 7.74 (H, d, J 6,7 8.6 Hz, 6-H). δ C (CDCl ).7 ( C-5 ),. (C-4 ), 6.5 (C- ), 0.7 (C- ),.5 (C- ), 0.7 (C-), 6.0 (C-6),. (C-9), 4. (C-9a), 6 (C-7), 6.9 (C-8), 5.6 (C- 5a), 5.5 (C-4), 64.8 (C-0a), 67. (C-). M (EI): m/z (M +, 97 %, C 5 H 6 O requires 7.098) 0 (9), 6 (54), 88 (4), 87 (4), 76 (00), 46 (6). Anal. Calcd. for C 5 H 6 O: C, 66.8; H, 5.88;, 0.9; O, 5.88;,.76. Found: C, 66.0; H, 5.8;, 0.5;,.76. 7,8-Dimethyl-4-pentyl-H-pyrimido[,-b]benzothiazol--one (7b). From b and b, Yield: 77%, Colourless needles; mp 78-8 C. I: ν/cm (C=O), 570 (C=), 500 (C=C). UV (EtOH/CHCl :) λ max (nm), (log ε): (4.4), 74 (4.06), 07 (4.4); M data: δ H (CDCl ) 0.87 (H, t, J 5,4 7. Hz, 5 -H),.5 (H, tq, J 4, 8.0 Hz and J 4,5 7.0 Hz, 4 -H),.44 (H, m, - H),.70 (H, tt, J, 8.0 Hz and J, 8.0 Hz, -H),.8 (H, s, 7-CH ),. (H, s, 8-CH ),.98 (H, t, J, 7.6 Hz, -H), 6.0 (H, s, -H), 7. (H, s, 9-H), 7.46 (H, s, 6-H). δ C (CDCl ).7 (C-5 ), 9.4 (8-CH ), 0.6 (7-CH ),. (C-4 ), 6.7 (C- ), 0.8 (C- ),.5 (C- ), 0.6 (C-), 6.8 (C-6),. (C-9a),. (C-9),.9 (C-5a), 5.5 (C-7), 6.0 (C-8), 5. (C-4), 65.0 (C-0a), 67. (C-). M (EI): m/z (M +, 00 %, C 7 H 0 O requires 00.96) 58 (6), 44 (9), 6 (6), 04 (85), 89 (), 74 (). Anal. Calcd. for C 7 H 0 O: C, 68.00; H, 6.67;, 9.; O, 5.;, Found: C, 68.00; H, 6.70;, 9.6;, Methoxy-4-pentyl-H-pyrimido[,-b]benzothiazol--one (7c). From b and c, yield: 80%; colourless crystals; mp C. I: ν/cm - 60 (C=O), 574 (C=), 507 (C=C). UV (EtOH/CHCl :) λ max (nm), (log ε): (4.4), 85 (4.0), 08 (4.). M data: δ H (CDCl ) 0.90 (H, t, J 5,4 7. Hz, 5 -H),.7 (H, tq, J 4, 8.0 Hz and J 4,5 7.0 Hz, 4 -H),.45 (H, m, H),.7 (H, tt, J, 8.0 Hz and J, 8.0 Hz, -H),.0 (H, t, J, 7.6 Hz, -H),.85 (H, s, 8-OCH ), 6.5 (H, s, -H), 6.97 (H, dd, J 7,6 9.4 Hz and J 7,9.7 Hz, 7-H), 7. (H, d, J 9,7.7 Hz, 9-H), 7.65 (H, d, J 6,7 9.4 Hz, 6-H). δ C (CDCl ).8 (C-5 ). (C-4 ), 6.5 (C- ), 0.9 (C- ),.5 (C- ), 55.8 (8-OCH ), 07. (C-9), 0.6 (C-), 4.0 (C-7), 7.0 (C-6), 5.9 (C- 9a), 9.6 (C-5a), 5. (C-4), 57.5 (C-8), 64.5 (C-0a), 67. (C-). M (EI): m/z 0.07 (M +, 00 %, C 6 H 8 O requires 0.089) 74 (6), 60 (), 46 (), 8 (0), 06 (8), 9 (). Anal. Calcd. for C 6 H 8 O : C, 6.57; H, 5.96;, 9.7; O, 0.60;, Found: C, 6.55; H, 5.95;, 9.7;, Ethoxy-4-pentyl-H-pyrimido[,-b]benzothiazol--one (7d). From b and b, yield 84%; colourless crystals; mp 5-54 C. I: ν/cm (C=O), 605 (C=), 580 (C=C); UV (EtOH/CHCl :) λ max (nm), (log ε) : 9 (4.5), (4.5), 87 (4.9), 0 (4.). M data: δ H (CDCl ) 0.90 (H, t, J 5,4 7. Hz, 5 -H),.6 (H, tq, J 4, 8.0 Hz and J 4,5 7.0 Hz, 4 -H),.4 I Page AKAT UA, Inc

6 General Papers AKIVOC 00 (xv) 07-4 (H, t, J 7.0 Hz, 8-OCH CH ),.45 (H, m, -H),.7 (H, tt, J, 8.0 Hz and J, 8.0 Hz - H),.00 (H, t, J, 7.6 Hz, -H), 4.05 (H, q, J 7.0 Hz, 8-OCH CH ), 6.5 (H, s, -H), 6.95 (H, dd, J 7,6 9.4 Hz and J 7,9.6 Hz, 7-H), 7.09 (H, d, J 9,7.6 Hz, 9-H), 7.6 (H, d, J 6,7 9.4 Hz, 6-H). δ C (CDCl ).8 (C-5 ), 4.6 (8-OCH CH ),. (C-4 ), 6.5 (C- ), 0.9 (C- ),.5 (C- ), 64. (8-OCH CH ), 07.6 (C-9), 0.5 (C-), 4.0 (C-7), 7.0 (C-6), 5.9 (C-9a), 9.4 (C-5a), 5. (C-4), 56.9 (C-8), 64.5 (C-0a), 67. (C-). M (EI): m/z 6.56 (M +, 00%, C 7 H 0 O requires 6.45) 87 (9), 74 (), 60 (8), (0), 0 (55), 9 (8). Anal. Calcd. for C 7 H 0 O : C, 64.56; H, 6.;, 8.86; O, 0.;, 0.. Found: C, 64.9; H, 6.9;, 8.75;, Phenyl-H-pyrimido[,-b]benzothiazol--one (8a). From a and c, yield: 76%, colourless needles; mp 6-8 C (Lit 4 : 7-8 C). I: ν/cm (C=O), 600 (C=), 585 (C=C); UV (EtOH/CHCl :) λ max (nm), (log ε): 0 (4.5), 4 (4.9), 00 (4.). M data: δ H (CDCl ) 6.0 (H, d, J 6,7 8.6 Hz, 6-H), 6.6 (H, s, -H), 6.95 (H, dd, J 7,6 8.0 Hz and J 7,8 8.0 Hz 7-H), 7. (H, dd, J 8,7 8.0 Hz and J 8,9 8.0 Hz, 8-H), 7.8 (H, d, J, 7.4 Hz, -H, 6 -H), 7.5 (H, dd, J, 7.0 Hz and J,4 8.0 Hz -H, 5 -H), 7.56 (H, d, J 9,8 8.0 Hz, 9-H), 7.58 (H, t, J 4, 8.0 Hz, 4 -H). δ C (CDCl ).9 (C-), 6. (C-6),.8 (C-9),.9 (C-9a), 5.9 (C-7), 6.0 (C-8), 8.0 (C-, C-6 ), 9. (C-, C-5 ), 0.7 (C-4 ),.8 (C- ), 5.0 (C-5a), 48.9 (C-4), 64.6 (C-0a), 66.8 (C-). M (EI): m/z (M +, 00 %, C 6 H 0 O requires ) 50 (67), 7 (7), 76 (64), 50 (), 48 (8), 0 (). Anal. Calcd. for C 6 H 0 O: C, 69.06; H,.60;, 0.07; O, 5.76;,.5. Found: C, 69; H,.60;, 0.0;,.56. 7,8-Dimethyl-4-phenyl-H-pyrimido[,-b]benzothiazol--one (8b). From b and c, yield 78%, colourless crystals; mp 8-0 C. I: ν/cm - 65 (C=O), 600 (C=), 565 (C=C). UV (EtOH/CHCl :) λ max (nm), (log ε): (4.5), 49 (4.8), 08 (4.). M data: δ H (CDCl ).89 (H, s, 7-CH ),.8 (H, s, 8-CH ), 5.79 (H, s, 6-H), 6.8 (H, s, -H), 7.9 (H, s, 9-H), 7.8 (H, d, J, 7. Hz, -H, 6 -H), 7.5 (H, dd, J, 7.0 Hz and J,4 8.0 Hz, -H, 5 -H), 7.6 (H, t, J 4, 7.5 Hz, 4 -H). δ C (CDCl ) 9.4 (8-CH ), 0. (7-CH ),.6 (C-), 7. (C- 6), 0.9 (C-9a),.9 (C-9), 8. (C-, C-6 ), 9. (C-, C-5 ), 0.6 (C-4 ),.0 (C- ),. (C-5a), 5. (C-7), 5.4 (C-8), 48.9 ( C-4), 64.9 (C-0a), 67.0 (C-). M (EI): m/z (M +, 00 %, C 8 H 4 O requires ) 78 (5), 65 (7), 04 (50), 89 (), 9 (6), 0 (7). Anal. Calcd. for C 8 H 4 O: C, 70.59; H, 4.57;, 9.5; O, 5.;, Found: C, 70.46; H, 4.56;, 9.7;, Methoxy-4-phenyl-H-pyrimido[,-b]benzothiazol--one (8c). From c and c, yield 8%, colourless crystals; mp C. I: ν/cm - 65 (C=O), 600 (C=), 580 (C=C). UV (EtOH/CHCl :) λ max (nm), (log ε) : 6 (4.48), 0 (4.48), 47 (4.5) 75 (4.), (4.9). M data: δ H (CDCl ).76 (H, s, 8-OCH ), 6.0 (H, d, J 6,7 9.4 Hz, 6-H), 6.0 (H, s, -H), 6.5 (H, dd, J 7,6 9.4 Hz and J 7,9.6 Hz, 7-H), 7.07 (H, d, J 9,7.6 Hz, 9-H), 7.4 (H, d, J, 7. Hz, -H, 6 -H), 7.54 (H, dd, J,4 8 Hz and J, 7.0 Hz, -H, 5 -H), 7.6 (H, t, J 4, 7.6 Hz, 4 -H). δ C (CDCl ) 55.7 (8-OCH ), 07.0 (C-9),.8 (C-),.5 (C-7), 7. (C-6), 5.6 (C-9a), 8. (C-, C-6 ), 9 (C-5a), 9. (C-, C-5 ), 0.8 (C-4 ),.9 (C- ), 48.8 (C- I Page AKAT UA, Inc

7 General Papers AKIVOC 00 (xv) ), 57.5 (C-8), 64. (C-0a), 67.0 (C-). M (EI): m/z (M +, 00 %, C 7 H O requires ) 80 (), 65 (8), 06 (54), 9 (5), 9 (5), 8 (), 7 (). Anal. Calcd. for C 7 H O : C, 66.; H,.90;, 9.09; O, 0.9;, 0.9. Found: C, 66.0; H,.97;, 9.4;, Ethoxy-4-phenyl-H-pyrimido[,-b]benzothiazol--one (8d). From d and c, Yield 86%, colourless crystals; mp - C. I: ν/cm (C=O), 600 (C=), 580 (C=C). UV (EtOH/CHCl :) λ max (nm), (log ε): 4 (4.44), 0 (4.4), 46 (4.), 74 (4.06), (4.6). M data: δ H (CDCl ). (H, t, J 7 Hz, 8-OCH CH ),.9 (H, q, J 7 Hz, 8-OCH CH ), 5.96 (H, d, J 6,7 9.4 Hz, 6-H), 6.5 (H, s, -H), 6.47 (H, dd, J 7,6 9.4 Hz and J 7,9.5 Hz, 7-H), 7.0 (H, d, J 9,7.5 Hz, 9-H), 7.8 (H, d, J, 7.4 Hz, -H, 6 -H), 7.5 (H, dd, J,4 8.0 Hz and J, 7.0 Hz, -H, 5 -H), 7.58 (H, d, J 4, 7.5 Hz, 4 -H). δ C (CDCl ) 4.4 (8-OCH CH ), 64.0 (8-OCH CH ), 07.4 (C-9),.6 (C-),.5 (C-7), 7. (C-6), 5.4 (C-9a), 8. (C-, C-6 ), 8.6 (C-5a), 9. (C-, C-5 ), 0.8 (C-4 ),.8 (C- ), 48.7 (C-4), 56.8 (C-8), 64. (C-0a), 66.9 (C-). M (EI): m/z.0777 (M +, 00 %, C 8 H 4 O requires.0776) 94 (), 66 (8), 0 (8), 9 (7), 9 (9), 9 (9). Anal. Calcd. for C 8 H 4 O : C, 67.08; H, 4.5;, 8.69; O, 9.94;, Found: C, 67.0; H, 4.4;, 8.6;, 9.9. Acknowledgements The authors are grateful to the University of Yaounde I research grants' committee for financial support. They are further grateful to Deutscher Akademischer Austauchdienst (DAAD) for financial support to Helene Wahe (through grant , A/0/840), to Fonds der Chemischen Industrie and to the administration of the University of Duisburg-Essen for technical and financial assistance. eferences. Part 6: Wahe, H.; Asobo, P. F.; Cherkasov,. A.; kengfack, A. E.; Folefoc,. G.; Fomum, Z. T.; Doepp, D.; accepted by AKIVOC.. Burger, A. Medicinal Chemistry rd Edition; Wiley- Interscience: ew York,. Y., 970, pp 7, 544 and 79.. Mosby, W. L. Fused 6/6 ring systems with one extra heteroatom In Heterocyclic systems with bridgehead nitrogen atoms, Part, Weissberger, A. Ed.; Wiley Interscience: ew York,. Y., 96, pp Al-Jallo, H..; Muniem, M. A. J. Heterocyclic Chem. 978, 5, Alamino,. J. J. Heterocyclic Chem. 97, 0, Dunwell, D. W.; Evans, D. J. Chem. oc. C 97, 094. I Page AKAT UA, Inc

8 General Papers AKIVOC 00 (xv) antagati, A.; antagati, M.; usso, F. J. Heterocyclic Chem. 988, 5, Wade, J. J.; Hegel,. F.; Toso, C. B. J. Org. Chem. 979, 44, Doad, G. J..; Okor, D.; chenmann, F. J. Chem. oc., Perkin Trans. 988, Acheson,. M.; Wallis, D. J. J. Chem. oc., Perkin Trans. 98, Landreau, C.; Deniaud, D.; Evain, M.; eliquet, A.; Meslin, J. C. J. Chem. oc., Perkin Trans. 00, 74.. Fomum, Z. T.; Asobo, P. F.; Ifeadike, P.. J. Heterocyclic Chem. 984,, 5.. Fomum, Z. T.; Ifeadike, P.. J. Heterocyclic Chem. 985,, Ai, J.; Wang, X.; Wahe, H.; Fomum, Z. T.; terner, O.; ielsen, M.; Witt, M.. Pharmacology 000, 60, Chan, C. K.; Ma, J. C..; Mak, T. C. W. J. Chem. oc., Perkin Trans. 977, Asobo, P. F.; Wahe, H.; Mbafor, J. T.; kengfack, A. E.; Fomum, Z. T.; opbue, E. F.; Doepp, D. J. Chem. oc., Perkin Trans. 00, 457. I Page 4 AKAT UA, Inc