J. CHEM. SOC. PERKIN TRANS. I 1994 Condensed I ,2,4-Triazines: Synthesis of 5-Benzyl-5H-imidazo[4,5-e]-1,284-triazine I -Oxides (9-Benzyl-6-azapurine 6-Oxides) Cherng-Chyi Tzeng,+Ba Dau-Chang Wei,a Long-Chih Hwang,a Ming-Chu Chengb and Yu Wangb a School of Chemistry, Kaohsiung Medical College, Kaohsiung City 807, Taiwan, Republic of China Department of Chemistry, National Taiwan University, Taipei City 107,Republic of China A number of 5-benzyl-5H-imidazo[4,5-e] -1.2,4-triazine 1-oxides, bioisosteric isomers of antiviral 9-benzylpurines, have been prepared. Oxidation of 6-amino-5-benzylamino-3-methylsulfanyl-l,2,4-triazine 1 with excess of m-chloroperbenzoic acid afforded 6-amino-5- benzylamino-3-methyl- sulfonyl-1.2.4-triazine 1-oxide 2 in 75% yield. The 3-methylsulfonyl group, which is a good leaving group, has been replaced with various nucleophiles to give 3-amino 4, 3-methoxy 5 and 3-hydrazino 8 derivatives.Oxidative dehydrazination of 8 with mercury(i1) oxide (HgO) in ethanol gave 6-amino-5-benzylamino-1.2.4-triazine 1-oxide 9 in a moderate yield. The 1,2,4-triazine 1-oxides were then cyclized with triethyl orthoformate (TEOF) to afford the title compounds in 28-88% yields. A number of 9-benzylpurines have been synthesized and tested for antirhinovirus activity.'-3 One of the most active com- pounds against rhinovirus serotype 1B was 6-dimethylamino-2- trifluoromethyl-9-benzylpurine which had an ICs0 value of 0.04 pmol dm-3 .4 Structure-activity studies reveal that optimum activity against serotype 1B is associated with a lipophilic, electron-withdrawing group at the 2-position,' but none of these analogues has a uniform profile of potent antirhinovirus serotype activity.To study the effect of structural modification at the 6-position with respect to optimal antirhinovirus activity, a series of 6-substituted derivatives were prepared and evaluated for their potency. Among them, the 6-dimethylamino and 6-anilino derivatives proved to be two of the be~t.~,~ To establish further the structure-activity relationship, we initiated the present research programme involving the synthesis of a novel series of 9-benzylpurine analogues with an N-oxide substituted at the 6-position. The bioisosteric replacement of an enolizable carbonyl or amino group with an N-oxide group leading to the discovery of potential therapeutical agents has been previously Results and Discussion Oxidation of 6-amino-5-benzylamino-3-methylsulfanyl-1,2,4-triazine 1l2 with 4.4 mol equiv. of m-chloroperbenzoic acid (MCPBA) gave the N-oxide product whose structure is tenta- tively assigned as 6-amino-5-benzylamino-3-methylsulfonyl-1,2,4-triazine 1-oxide 2 from the 13CNMR spectra, elemental analyses, and mass spectrum (in addition to the molecular ion peak at m/z 295, a peak of M -16 was also detected).Several papers 3-'6 have dealt with the N-oxidation of 1,2,4-triazines with the conclusion that the oxidation of 3-amino and 3- substituted amino 1,2,4-triazines affords the 2-oxides as the major products while oxidation at N-1 occurs when C-3 is either unsubstituted or is substituted by a methoxy or phenoxy group.However, the reaction of 1 with MCPBA is more complicated, as it involves not only the N-oxidation but also an in situ S-oxidation. From the spectral data it appears that N-oxidation is likely to occur at N-1. However, we were reluctant to make this critical structural assignment founded only on this evidence and therefore we sought a more definitive answer; an X-ray crystallographic analysis of 5-benzyl-3-methylsulfonyl-5H-imidazo[4,5-e]- 1,2,4-triazine 1 -oxide 3 which was prepared by the ring closure of compound 2 with triethyl orthoformate C(12) Fig. 1 ORTEP drawing of compound 3 (TEOF).'7-1 A view of a single molecule of 3 is given in Fig.1. As can be seen from the figure, the oxidation occurs at N-1. Selected bond lengths and bond angles are presented in Tables 1 and 2, respectively. Treatment of compound 2 or 3 with liquid ammonia gave 3,6-diamino-5-benzylamino-1,2,4-triazine 1-oxide 4 in 80%yield. When the reaction was carried out under the same conditions except that methanolic ammonia (saturated at 5 "C) was used instead of liquid ammonia, the desired compound 4 was not obtained. The 'H NMR spectrum of the sole product isolated showed a sharp singlet at 6 3.73, ascribable to 3-OMe, along with absorptions at 6 4.62, 6.15 and 8.14 corresponding to ArCH,, 6-NH2, and SNH, respectively. The I3C NMR spectrum supported the 'H NMR spectrum in confirming the presence of one methoxy carbon, resonance appeared at 6 54.43, and three heteroaromatic carbons, resonances at 6 127.50, 150.60 and 158.06, respectively.The elemental analysis was in accord with the molecular formula C, 1H13Ns02 which, taken together with spectral evidence, suggests a structure of 6-amino-5-benzyl- amino-3-methoxy- 1,2,4-triazine 1 -oxide 5. Ring closure of Table 1 Selected bond lengths (A) of compound 3 Atoms Distance ~ ~~ 1.247( 3) 1.355(4) 1.357(4) 1.334(4) 1.802(3) 1.319(4) 1.324(4) 1.362(4) 1.377(4) 1.463(4) 1.316(4) 1.359(4) I .395(4) Table 2 Selected bond angles (") of compound 3 O( 1 W(2) 118.2(3) O(1)-N( 1)-C(7a) 122.7(3) N(2)-N( 1)-C(7a) 119.1(3) N( 1)-N(2)-C( 3) 115.8(3) C( 3 )-N( 4)-C( 4a) 109.4( 3) C(4a)-N( 5)-C( 6) 106.1(3) C(4a)-N( 5)-C(9) 125.4( 3) C(6kN(5)-C(9) 128.4(3) C(6-N(7)-C(7a) 102.4( 3) S-C(3)-N(2) 112.24(23) S-C(3)-N(4) 116.10(23) N(2)-C( 3)-N(4) 13 1.7(3) N(4)-C(4a)-N(5) 129.3(3) N(4)-C( 4a)-C( 7a) 126.6(3) N(5)-C(4a)-C(7a) 104.1(3) N(5FC(6)-N(7) 114.3(3) N( l)-C(7a)-N(7) I29.5( 3) N( 1)-C(7a)-C(4a) 117.3(3) N(7)-C( 7a)-C(4a) 113.2(3) N( 5)-C( 9)-C( 10) 113.3(3) compound 5 with triethyl orthoformate (TEOF) under acidic conditions afforded 5-benzyl-3-methoxy-5H-imidazo[4,5-el-1,2,4-triazine 1 -oxide 7in 88% yield.Ring closure of compound 4 with TEOF under acidic conditions was not successful due to the poor solubility of 4 in TEOF. To circumvent this situation, a mixed solvent of equal volumes of TEOF and dimethylform- amide (DMF) was used instead of neat TEOF.The cyclization product thus obtained was a mixture of 3-amino-5-benzyl-5H- imidazo[4,5-e]- 1,2,4-triazine 1 -oxide 6 and its 3-formamido derivative which were very difficult to separate and purify. Therefore, the initial product was treated with methanolic ammonia to furnish pure compound 6 in 45% yield (Scheme 1). According to Lee and Paudler,20 a hydrazino group sub- stituted on the C-3 of a 1,2,4-triazine can be eliminated by oxidation. A similar reaction of compound 2 with hydrazine in ethanol gave 6-amino-5-benzylamino-3-hydrazino-I ,2,4-tri-azine 1-oxide 8 which was oxidized with mercury(rr) oxide in ethanol to give 6-amino-5-benzylamino- 1,2,4-triazine 1-oxide 9.Ring closure of 9 with TEOF afforded 5-benzyl-5H-imidazo- [4,5-e]-1,2,4-triazine 1-oxide 10 in 65% yield (Scheme 2). Experimental M.p.s were determined with a Thomas-Hoover apparatus and are uncorrected. The UV spectra were determined in 0.1 mol dm-3 HC1 (pH I), methanol and 0.1 mol dm-3 NaOH (pH 13) with a Hitachi U-2000 spectrophotometer. NMR ('H and 13C) spectra were recorded on a Varian VSR-300s spectrometer. Samples were dissolved in C2H,]dimethyl sulfoxide, and the J. CHEM. soc. PERKIN TRANS. I 1994 0 0t t CHpPh 1 2 3 0 0 4 6 2or3 -I 0 0I t t 6H2Ph CHpPh 5 7 Scheme 1 Reagents: i, MCPBA; ii, CH(OEt),; iii, NH,; iv, NH,-MeOH 0 t 2-i fx:," H2NHN 1 CH2Ph 8 1 ii 0 0 t t CH2Ph CH2Ph 9 10 Scheme 2 Reagents: i, NH,NH,; ii, HgO; iii, CH(OEt), chemical shifts are expressed in ppm with respect to tetra- methylsilane (TMS) as an internal standard.J-Values are given in Hz. The progress of the reactions was followed by thin-layer chromatography (TLC) on silica gel 60 F-254 plates purchased from E. Merck. Mass spectra were determined with a Quattro VG-5022 mass spectrometer in the electron-impact (EI) mode. Crystal Data.-Cl,Hl 'N503S, A4 = 305.25, monoclinic, a = 6.794(2), b = 14.834(2), c = 13.759(2)A, p = 104.04(2)", V = 1345.2(5)A3(by least-squares refinement on diffractometer angles for 25 automatically centred reflections, A = 0.710 69 A), space group P2,/n, 2 = 4, D, = 1.508 g ~m-~,crystal dimensions (distance to faces from centre) 0.20 x 0.25 x 0.35 mm,p(Mo-Ka) = 2.3 cm-'.Data collection and processing. CAD4 diffractometer, J. CHEM. SOC. PERKIN TRANS. I 1994 20 mode with 20 scan width = 1.4 + 0.7 tan 0, 28 scan speed 2.0-8.24 deg min-' , graphite-monochromated Mo-Ka radiation; 2412 reflections measured (1.5 d 6 d 25", f h,k, I), 2352 unique, giving 1524 with I 240. Structure analysis and reJnement. Direct methods were used followed by the full matrix least-squares refinements with all non-hydrogen atoms anisotropic and hydrogens in calculated positions. The weighting scheme w = l/a2(Fo) with 02(F,,) from counting statistics gave satisfactory agreement analyses. Final R and R, values are 0.041, 0.030.Programs used NRCVAX ,' on microvax computer. Atomic coordinates bond lengths and angles and thermal parameters have been deposited at the Cambridge Crystallo- graphic Data Centre.* 6-Amino-5-benzylamino-3-methylsulfonyl-1,2,4-triazine 1-Oxide 2.-To a solution of m-chloroperbenzoic acid (900 mg, 4.4 mmol) dissolved in chloroform (20 cm3) was added compound 1 '' (247 mg, 1.O mmol) in chloroform (20 cm3). The reaction mixture was stirred at room temperature for 2 h during which time the solution turned red. The solid thus formed was collected and crystallized from ethanol to give the title compound 2 (225 mg, 75%), m.p. 21 1-213 "C; R,,,/nm (pH 1) 326 (e/dm3 mol ' cm-' 15 300) and 237 (1 9 700); (methanol) 326 (19 000) and 236 (23 000); (pH 13) 309 (12 000) and 236sh (1 8 000); G,[(CD,),SO] 3.24 (s, 3 H, CH,), 4.71 (d, 2 H, CH,), 7.34-7.43 (m, 5 H, ArH), 7.24 (s 2 H, NH,) and 8.48 (br t, 1 H, NH); G,[(CD,),SO] 39.29 (SO,CH,), 44.93 (CH,), 127.66, 128.21, 128.70, 137.63 (Arcs), 132.63 (C-6), 148.51 (C-5) and 153.83 (C-3); m/z 295 (M+, 0.28%), 279 (5.0),278 (5.3), 200 (2.5) and 91 (100) (Found: C, 44.55; H, 4.2; N, 23.8.C, 1Hl,N,03S requires C, 44.71; H, 4.44; N, 23.73%). 5-Benzyl-3-methylsulfonyl-5H-imidazo[4,5-e]-1,2,4-triuzine 1-Oxide 3.---To a well stirred suspension of compound 2 (295 mg, 1.0 mmol) in triethyl orthoformate (25 cm3) was added concentrated hydrochloric acid (0.3 cm3). The reaction mixture was then heated at reflux for 1 h. After this period, the solution was allowed to stand at room temperature for 16 h.The solid was removed by filtration and the filtrate was evaporated to 20 cm3, allowed to cool and then kept at 4 "C for 16 h, the solid thus formed was collected and crystallized from chloroform to give the title compound 3 (86 mg, 28%) as needles, m.p. 216- 218 "C; imax/nm (pH 1) 310 (&/dm3 mol-' cm-' 11 500) and 237 (1 5 800); (methanol) 310 (12 500) and 237 (19 600); (pH 13) 326 (10900); d~[(cD~),So] 3.45 (s, 3 H, S02CH3), 5.57 (s, 2 H, CH,), 7.39-7.41 (m, 5 H, ArH) and 9.04 (s, 1 H, 6-H); G,[(CD,),SO] 40.49 (SO,CH,), 47.87 (CH,), 128.10, 128.48, 128.98, 135.15 (Arcs), 138.29 (C-7a), 148.73 (C-4a), 149.22 (C-6) and 159.75 (C-2); m/z 305 (M', 16%), 289 (5.6), 288 (4.3), 226 (6.6), 210 (15.6) and 91 (100) (Found: C, 47.1; H, 3.6; N, 22.85.Cl2H,,N5O3S requires C, 47.20; H, 3.63; N, 22.94%). 3,6-Diamino-5-benzylamino-1,2,4-triazine 1-Oxide 4.--A mixture of compound 2 (2.95 g, 10 mmol) and liquid ammonia (25 cm3) was heated in a stainless steel vessel at 80 "C for 2 days. The reaction mixture was allowed to cool to room temperature and then the excess ammonia was vented off, and the residual solid was suspended in water (2 x 10 cm3). The green precipitate was collected and crystallized from ethanol to give the title compound 4 (1.85 g, 80%), m.p. 230-232 "C (decomp.); R,,,/nm (pH 1) 332 (&/dm3 mol-I cm-' 8300) and 236 (18 400); (methanol) 336 (8700) and 236 (21 000); (pH 13) 330 (9000) and 233 (20 300); GH[(CD,),SO] 4.60 (s, 2 H, CH,), * For details of the deposition scheme, see 'Instructions for Authors', J.Chem. Soc., Perkin Trans. I, 1994, Issue 1. 5.69(s,2 H,3-NH2),5.85(s,2 H,6-NH2),7.34(s, 5 H,ArH)and 7.68 (br s, 1 H, NH); G,[(CD,),SO] 43.99 (CH,), 125.07 (C- 6), 127.27,127.78,128.59,138.78(ArCs), 150.50(C-5)and 156.44 (C-3); m/z 232 (M+, 4.573, 216 (10.8), 215 (25.3) and 91 (100) (Found: C, 51.4; H, 5.2; N, 36.1. CloH12N60 requires C, 51.71; H, 5.21; N, 36.19%). 6-Amino-5-benzylamino-3-methoxy-1,2,4-triazine 1-Oxide 5.-A mixture of compound 2 (295 mg, 1.0 mmol) and methanolic ammonia (30 cm3, previously saturated at 5 "C) was heated in a steel bomb at 80 "C for 24 h. The reaction mixture was concentrated to 10 cm3, and the white precipitate was collected and crystallized from methanol to give the title compound 5 (155 mg, 63%), m.p.208-210 "C; A,,,/nm (pH 1) 328 (&/dm3 mol-I cm-' 13 400) and 225 (21 000); (methanol) 327 (14 100) and 226 (23600); (pH 13) 326 (9700); BH-[(CD,),SO] 3.73 (s, 3 H, OCH3),4.62 (d,J5, 2 H, CH,), 6.15 (s, 2 H,NH,), 7.28-7.35 (m, 5 H,ArH)and8.14(t, J5,l H,NH); G,[(CD,),SO] 44.38 (CH,), 54.43 (OCH,), 127.40, 127.81, 128.62, 138.25 (Arcs), 127.50 (C-6), 150.60 (C-5) and 158.06 (C-3); m/z 247 (M', 6.8%), 231 (5.1), 230 (33.6) and 91 (100) (Found: C. 53.4; H, 5.15; N, 28.5. C,,H,,N,O, requires C, 53.43; H, 5.30; N, 28.33%). 3-Amino-5-benzyl-5H-imidazo[4,5-e]-1,2,4-triazine 1-Oxide 6.-To a well stirred suspension of compound 4 (232 mg, 1.0 mmol) in triethyl orthoformate (15 cm3) and dimethyl-formamide (3 cm3) was added concentrated hydrochloric acid (0.3 cm3).The mixture was then heated at reflux (oil bath) for 2 h. The hot filtrate was evaporated under reduced pressure to give a brown syrup to which was added methanolic ammonia (25 cm3) and then the mixture was stirred at room temperature for 16 h. The excess solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel with chloroform-methanol (20 :1) as eluent. The homogeneous fractions were pooled and evaporated. The residue was crystallized from ethanol to afford the title compound 6 (1 35 mg, 45%), m.p. 262-264 "C;i,,,/nm (pH 1) 362 (&/dm3 mo1-I cm-' 7100), 258 (8900) and 233 (24 000); (methanol) 363 (7600), 258 (9600) and 234 (25 200); (PH 13) 347 (5400) and 233 (17900); dH[(CD3),S0] 5.30 (s, 2 H, CH,), 7.1 1 (s, 2 H, 3-NH2), 7.31-7.37 (m, 5 H, ArH) and 8.34 (s, 1 H, 6-H); Gc[(CD,),SO] 46.74 (CH,), 127.43, 128.08, 128.94, 136.09 (Arcs), 131.40 (C-7a), 143.36 (C-6), 150.42 (C-4a) and 161.63 (C-2); m/z 242 (M', 26.8%), 225 (9.0) and 91 (100) (Found: C, 54.4; H, 4.2; N, 34.4.C1 1H10N60 requires C, 54.54; H, 4.16; N, 34.69%). 5-Benzyl-3-methoxy-5H-imidazo[4,5-e]-1,2,4-triuzine 1-Ox-ide 7.-Compound 7 was prepared from compund 5 in 88% yield by using a procedure similar to that which afforded compound 3. An analytical sample was prepared by crystallization from methanol-chloroform (1 :lo), m.p.198- 200 "C; A,,,/nm (pH 1) 328 (&/dm3 mol-' cm-' 13 500) and 225 (21 000); (methanol) 327 (14 100) and 226 (23 600); (pH 13) 326 (9700); ~H[(CD~),SO] 3.97 (S, 3 H, OCH,), 5.40 (S, 2 H, CH,), 7.33-7.41 (m, 5 H, ArH) and 8.64 (s, 1 H, 6-H); Gc[(CD3)2S0] 47.30 (CH,), 56.04 (OCH,), 128.03, 128.30, 128.94, 135.61 (Arcs), 134.0 (C-7a), 145.76 (C-6), 150.1 (C-4a) and 162.91 (C-3); m/z 257 (M+, 7%), 241 (26), 240 (1 1) and 91 (100) (Found: C, 55.8; H, 4.4; N, 26.9. Cl,H,,N50, requires C, 56.02; H, 4.31; N, 27.23%). 6-Amino-5-benzylamino-3-hydrazino-1,2,4-triazine 1-Oxide 8.-Hydrazine (4 cm3, 95% solution) was added to a solution of compound 2 (1.18 g, 4.0 mmol) in absolute ethanol (30 cm'). The resulting solution was refluxed (oil bath) for 3 h.After this period, the clear solution was evaporated under reduced pressure to 15 cm3 and was allowed to cool to room temperature. The precipitate was collected and crystallized from ethanol to give the title compound 8 (740 mg, 75%) as colourless needles, m.p. 218-220 "C; AmaX/nm (pH 1) 338 (&/dm3 mol-' cm-' 8500) and 240 (20 200); (methanol) 326 (9700) and 225 (17 200); (pH 13) 336 (7400) and 239 (16 800); 6,[(CD3)2S0] 3.87 (br s, 2 H, hydrazino NH,), 4.61 (d, 2 H, CH,), 5.77 (s, 2 H, NH,), 7.27-7.35 (m, 5 H, ArH) and 7.82 (t, 1 H, NH); Gc[(CD3)2SO] 44.08 (CHJ, 127.32, 127.94, 128.58, 138.71 (Arcs), 125.45 (C-6), 150.12 (C-5) and 158.06 (C-3); m/z 247 (M ,7.4%), 23 1 (5.7), 230 (1 7) and 9 1 (100) (Found: C, 48.2; + H, 5.4; N, 39.2.CloH13N,0 requires C, 48.58; H, 5.30; N, 3 9.59%). 6-Amino-5-benzylamino- 1,2,4-triazine 1-Oxide !).-To a sus- pension of compound 8 (741 mg, 3.0 mmol) in absolute ethanol (80 cm3) was added yellow mercury(rr) oxide (3 g). The resulting mixture was stirred and refluxed (oil bath) for 24 h. The hot filtrate was concentrated to 25 cm3 and allowed to cool to 4 "C overnight. The yellow precipitate was collected and crystallized from ethanol to give the title compound 9 (358 mg, 5573, m.p. 263-266 "C; ,l,,,/nm (pH 1) 319 (&/dm3 mol-' cm-' 9400) and 222 (14 900); (methanol) 322 (10 500) and 223 (20 100); (pH 13) 317 (7700); G,[(CD,),SO] 4.64 (d, J 5, 2 H, CH,), 6.63 (s, 2 H, NH,), 7.27-7.35 (m, 5 H, ArH), 7.90 (s, 1 H, 3-H) and 7.96 (t, J 5, 1 H, NH); Gc[(CD3)2SO] 44.38 (CH,), 127.40, 127.76, 128.67, 138.41 (Arcs), 131.81 (C-6), 146.55 (C-3) and 148.83 (C-5); m/z 217 (Mf, 4.573, 201 (5.2), 200 (33) and 91 (100) (Found: C, 55.2; H, 4.8; N, 32.5.CloHl 'N,O requires C, 55.30; H, 5.07; N, 32.26%). 5- Benzy l-5H -imidazo [4,5-e] -1,2,4- tr iazine 1-Oxide 10.-To a well stirred suspension of compound 9 (21 7 mg, 1.O mmol) in tri- ethyl orthoformate (25 cm3) was added concentrated hydro- chloric acid (0.3 cm3). The mixture was heated at reflux (oil bath) for 2 h. After this period, the hot filtrate was evaporated under reduced pressure to give an orange syrup which was purified by column chromatography on silica gel with chloro- form-methanol (30: I) as eluent.The homogeneous fractions were pooled and evaporated to obtain an oil which was cooled to 4 "C for 16 h to give the title compound 10 (148 mg, 65%), m.p. 110-1 12 "C; A,,,/nm (pH 1) 308 (&/dm3 mol-' ern--' 13 400) and 225 (16 700); (methanol) 308 (12 300) and 227 (1 5 000); (pH 13) 329 (8200) and 228sh (23 100);G,[(CD,),SO] 5.48 (s, 2 H, CH,), 7.38 (s, 5 H, ArH), 8.23 (s, 1 H, 3-H) and 8.74 (s, 1 H, 6-H); Gc[(CD,)2SO] 48.51 (CH,), 128.16, 129.08, 129.27, 133.57 (Arcs), 137.28 (C-7a), 144.69 (C-6), 148.43 J. CHEM. SOC. PERKIN TRANS. 1 1994 (C-4a) and 152.76 (C-3); m/z 227 (M', 9.6%), 210 (2) and 91 (100) (Found: C, 57.9; H, 4.0; N, 30.6. CllH,N,O requires C, 58.15; H, 3.99; N, 30.82%). Acknowledgements We gratefully acknowledge the financial support from the National Science Council of the Republic of China (NSC 82- 0208-M-037-013).References 1 J. L. Kelly, C. A. Miller, J. W. T. Selway and H. J. Shaeffer, Eur. J. Med. Chem., 1988,23, 3 19. 2 J. L. Kelly, J. A. Linn, M. P. Krochmal, J. W. T. Selway and H. J. Shaeffer, J. Med. Chem., 1988,31,2001. 3 J. L. Kelly, J. A. LinnandJ. W. T. Selway, J. Med. Chem., 1991,34,157. 4 J. L. Kelly, J. A. Linn, M. P. Krochmal and J. W. T. Selway, J. Med. Chem., 1989,32, 1757. 5 J.L.Kelly,J.A.LinnandJ.W.T.Selway,J.Med.Chem.,1989,32,218. 6 J. L. Kelly, J. A. Linn and J. W. T. Selway, Eur. J. Med. Chem., 1990, 25, 131. 7 J. L. Kelly, J. A. Linn, R. G. Davis and J. W. T. Selway, Eur. J. Med. Chem., 1990,25,623.8 R. A. Sharma, M. Bobek, F. E. Coleand A. Bloch, J. Med. Chem., 1973, 16,643. 9 G. L. Szekeres, R. K. Robins, P. Dea, M. P. Schweizer and R. A. Long, J. Org. Chem., 1973,38,3277. 10 M. Bobek, A. Bloch, P. Berkowitz and T. J. Bardos, J. Med. Chem., 1977,20,485. 11 A.R.BanijamaliandW.O.Foye,J. Heterocycl. Chem., 1986,23,1613. 12 C. C. Tzeng, N. C. Motola and R. P. Panzica, J. Org. Chem., 1983,48, 1271. 13 C. M. Atkinson, D. A. Ibbitson, F. J. Rice and J. P. B. Sandall, J. Chem. Soc., 1964,4209. 14 T. Sasaki and K. Minamoto, J. Org. Chem., 1966,31, 3914. 15 W. W. Paudler and T. K. Chen, J. Org. Chem., 1971,36,787. 16 R. J. Radel, B. T. Keen, C. Wang and W. W. Paudler, J. Org. Chem., 1977,42, 546. 17 J. Riand, M. T. Chenon, C. C. Tzeng and R. P. Panzica, J. Chem. Soc., Perkin Trans. 2, 1986,931. 18 D. C. Wei, L. C. Hwang, C. H. Han, K. H. Lee and C. C. Tzeng, Hererocycles, 1993, 36,2733. 19 L. C. Hwang, D. C. Wei, C. H. Han, K. H. Lee and C. C. Tzeng, J. Chem. Rex, 1994, (S),121. 20 J. Lee and W. W. Paudler, J. Heterocycl. Chem., 1972,9,995. 21 E. J. Gabe, Y. Le Page, J.-P. Charland, F. L. Lee and P. S. White, J. Appl. Cryst., 1989, 22, 384. Paper 4/0 1696C Received 22nd March 1994 Accepted 10th May 1994
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