Novel fluoro substituted benzo[b]pyran with anti-lung cancer activity

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Indian Journal of Chemistry Vol. 44B, eptember 2005, pp. 18871893 ovel fluoro substituted benzo[b]pyran with antilung cancer activity Abou Elotooh G Hammam*, sama I Abd Elalam, Ashraf M Mohamed & agla Abdel Hafez Applied rganic Chemistry Department, ational Research Centre, Dokki, Cairo12622, Egypt Email: Abo_elfotooh@yahoo.com Received 4 January 2005; accepted (revised) 8 June 2005 6luorobenzo[b]pyran4one 1 on condensation with aromatic aldehydes yields 3arylmethylene6fluoro2,3 dihydrobenzo[b]pyran4ones 2 which on treatment with phenylhydrazine and thiourea gives the pyrazole and pyrimidine thione derivatives 3 and 4, respectively. Compound 4 reacts with chloroacetic acid in acetic acidacetic anhydride mixture to afford the thiazolopyrimidines 5 which on condensation with aromatic aldehyde furnish the corresponding arylmethylenethiazolopyrimidine derivatives 6. The product 6 could be prepared directly by the action of chloroacetic acid and the proper aldehyde on 4 in the presence of acetic acidacetic anhydride mixture. Product 2 reacts with malononitrile in the presence of ammonium acetate or piperidine to afford the pyridine and pyran 7 and 8 derivatives, respectively. Also, compound 1 on treatment with arylmethylenecyanoacetamide yields the pyridone derivatives 9. Condensation of 1 with malononitrile affords the yliedinemalononitrile 10, which on reaction with pchlorobenzaldehydeammonium acetate or arylmethylenecyanoacetamide yields the pyridine derivative 11 (isomer of 8) and the dicarbonitrile derivative 12, respectively. The synthesized compounds have been tested against three cell lines of human cancer (lung, breast and C cancer), and these compounds show anticancer activity at low concentration as compared to reference drug 5fluorodeoxyuridine. Keywords: 6luorobenzo[b]pyran4one, pyran4ones, phenylhydrazine, thiourea, pyrimidine thione, thiazolopyrimidines, arylmethylenethiazolopyrimidine derivatives, dicarbonitrile derivative, human cancer, anticancer activity IPC: Int.Cl. 7 C 07 D // A 61 P 35/00 In continuation to our drug research program 18, the present work is aimed towards the construction of novel heterocyclic compounds of anticipated utility as anticancer agents. ince fluorinecontaining compounds are of promising pharmacological activities which are originated from their unique high thermal stabilities and lipophilicity 9, some novel fluorosubstituted benzo[b]pyran compounds are synthesized, which exhibited higher anticancer activities (specially as antilung cancer) when compared with our previous work dealing with the unsubstituted benzo[b]pyran derivatives, which showed moderate anticancer activities 6. Results and Discussion 6luorobenzo[b]pyran4one 1 was condensed with the proper aldehyde in the presence of ethanolic potassium hydroxide to yield 3arylmethylene6 fluoro2,3dihydrobenzo[b]pyran4one derivatives 2 (cheme I). Product 2d showed IR absorption at 1660 cm 1 (C=) and its 1 H MR (CDCl 3 ) showed a singlet at δ 7.8 and a multiplet at δ 7.56.9 for the benzylic proton (1H) and aromatic protons (6H), respectively, two singlets at δ 3.9 for the two methoxy groups (6H) and a singlet at δ 3.7 for the pyran protons (2H). The mass spectrum of 2d showed the molecular ion peak [M + ] at m/z 314 (100%, base peak) and a peak at m/z 177 (36%) for [M + C 6 H 3 (CH 3 ) 2 3,4]. Compounds 2 were reacted with phenylhydrazine in ethanol using triethylamine as a catalyst to yield 3aryl 8fluoro2phenyl2, 3, 3a, 4tetrahydrobenzo[b]pyrano [4,3c]pyrazole derivatives 3ac (cheme I, Table I). The IR spectra of the products 3 showed peaks at 1675 and 1668 cm 1 (C=). The 1 H MR (DMd 6 ) of product 3a showed the following signals at δ 7.706.90 (12 H, m, H), 4.9 (1 H, d, H a ), 4.6 (1 H, m, H b ), 4.5 (1 H, d, H c ), 4.3 (1 H, m, H d ) and 2.33 (3H, s, CH 3 ). The mass spectrum of product 3c showed peaks at m/z 422 (100%, base peak) [M + ], 424 (97.65%) [M + +2] due to the presence of bromine atom and 267 (12%) [M + C 6 H 4 Br4]. Both the IR and 1 H MR spectral data (Table II) showed the absence of H group indicating that the formation of the cyclized product 3A is tentatively favoured over the isomeric structure 3B. Compound 2 was condensed with thiourea in ethanolic potassium hydroxide to yield 4aryl9 fluoro2, 3, 4, 5tetrahydrobenzo[b]thiopyrano[4,3d] pyrimidine2(1h)thione derivatives 4. Compound 4

1888 IDIA J. CHEM., EC B, EPTEMBER 2005 C H 2 CH 3 CH 2 C C C CH=C CH 2 C H 2 11 = C 6 H 4 Clp Ha Hb Hc H d A Ph 3 a, = C 6 H 4 CH 3 p b, = C 6 H 4 p c, = C 6 H 4 Brp B CH Ph H PhHH 2 HC(H 2 ) 2 βalanine 10 1 CH EtH/ HCl or EtH/ KH C CH=C CH 2 12 = C 6 H 4 Clp H C C 9 a, = C 6 H 4 CH 3 p b, = C 6 H 4 p c, = C 6 H 4 Clp d, = C 6 H 3 (CH 3 ) 2 3,4 H =C(H 2 ) 2 H 2 C(C) 2 H 2 4 H a, = C 6 H 4 CH 3 p b, = C 6 H 4 p c, = C 6 H 4 Clp d, = C 6 H 3 (CH 3 ) 2 3,4 e, = C 6 H 4 Brp ClCH 2 CH CH 3 Ca CH ClCH 2 C 2 H Ac 2 2 a, = C 6 H 4 CH 3 p b, = C 6 H 4 p c, = C 6 H 4 Clp d, = C 6 H 3 (CH 3 ) 2 3,4 e, = C 6 H 4 Brp CH Ac 2 CH 3 C 2 H 4 TEA H 2 C(C) 2 piperidine 8 C a, = C 6 H 4 Clp b, = C 6 H 3 (CH 3 ) 2 3,4 H 2 C 7 a, = C 6 H 4 p b, = C6H4Clp c, = C 6 H 3 (CH 3 ) 2 3,4 X A showed IR absorptions at 34343259 cm 1 (H). The 1 H MR (DMd 6 ) of 4a showed two singlets at δ 9.8 and 8.0 (2 H, H, exchanged with D 2 ), a multiplet at δ 7.86.9 (7H, H), a singlet at δ 5 for the pyrimidine proton and two doublets at δ 4.8 and 4.6 for the pyran protons. The mass spectrum of 5 a, = C 6 H 4 Clp b, = C 6 H 3 (CH 3 ) 2 3,4 B cheme I 6 a, = C 6 H 4 p, X= Br b, = C6H4Clp, X= Cl c, = C 6 H 3 (CH 3 ) 2 3,4, X= CH 3 product 4e showed peaks at m/z 392 (100%, base peak) [M + + 2] and 235 (27%) [M + C 6 H 4 Br4]. Pyrimidine thione derivatives 4 were reacted with chloroacetic acid in the presence of fused sodium acetate and acetic acidacetic anhydride mixture to give 4aryl10fluoro2,3,5,6tetrahydrobenzo[b]pyra

HAMMAM et al.: LUR UBTITUTED BEZ[B]PYRA WITH ATILUG CACER ACTIVITY 1889 Table I Physical data of prepared compounds Compd m.p. (olvent) 2a 4CH 3.C 6 H 4 16567 (EtH) 2b 4.C 6 H 4 14951 (EtH) 2c 4Cl.C 6 H 4 20911 (EtH) 2d 3,4(CH 3 ) 2. C 6 H 3 199201 (EtH) 2e 4Br.C 6 H 4 20608 3a 4CH 3.C 6 H 4 11921 3b 4.C 6 H 4 12426 (EtH) 3c 4Br.C 6 H 4 15052 4a 4CH 3.C 6 H 4 20305 (EtH) 4b 4.C 6 H 4 27476 4c 4Cl.C 6 H 4 24547 4d 3,4(CH 3 ) 2. C 6 H 3 14244 (EtH) 4e 4Br.C 6 H 4 25961 5a 4Cl.C 6 H 4 12325 (EtH) 5b 3,4(CH 3 ) 2. C 6 H 3 11416 (EtH) 6a 4.C 6 H 4, X= Br 6b 4Cl.C 6 H 4, X= Cl 6c 3,4(CH 3 ) 2. C 6 H 3, X= CH 3 4 189191 14042 (EtH) 13032 (EtH) 7a 4.C 6 H 4 30911 7b 4Cl.C 6 H 4 30305 7c 3,4(CH 3 ) 2. C 6 H 3 17981 (EtH) 8a 4Cl.C 6 H 4 13537 (EtH) 8b 3,4(CH 3 ) 2. C 6 H 3 21820 9a 4CH 3.C 6 H 4 31012 Mol. formula Calcd % (ound) (Mol. Wt) C H C 17 H 12 2 (267.27) C 16 H 10 2 2 (272.25) C 16 H 10 Cl 2 (288.7) C 18 H 15 4 (314.31) C 16 H 10 Br 2 (333.15) C 23 H 19 2 (358.41) C 22 H 16 2 2 (362.37) C 22 H 16 Br 2 (423.28) C 18 H 15 2 (326.39) C 17 H 12 2 2 (330.35) C 17 H 12 Cl 2 (346.81) C 19 H 17 2 3 (372.41) C 17 H 12 Br 2 (391.26) C 19 H 12 Cl 2 2 (386.83) C 21 H 17 2 4 (412.43) C 26 H 15 Br 2 2 2 (537.38) C 26 H 15 Cl 2 2 2 (509.38) C 29 H 23 2 5 (530.57) C 19 H 12 2 2 2 (338.31) C 19 H 12 Cl 2 2 (354.76) C 21 H 17 2 4 (380.37) C 19 H 11 Cl 3 (351.76) C 21 H 16 3 3 (377.37) C 20 H 13 2 2 (332.33) 76.11 (76.06 70.59 (70.56 66.56 (66.52 68.78 (68.72 57.68 (57.59 77.08 (77.00 72.92 (72.86 62.43 (62.34 66.24 (66.18 61.81 (61.76 58.87 (58.82 61.28 (61.18 52.19 (52.12 58.99 (58.88 61.16 (61.10 58.11 (57.99 61.31 (61.24 65.65 (65.52 67.45 (67.36 64.33 (64.28 66.31 (66.22 64.87 (64.82 66.84 (66.76 72.28 (72.22 4.88 4.82 3.70 3.68 3.49 3.47 4.81 4.76 3.03 2.95 5.34 5.26 4.45 4.38 3.81 3.76 4.63 4.58 3.66 3.64 3.49 3.43 4.60 4.56 3.09 3.10 3.13 3.10 4.15 4.10 2.81 2.74 2.97 2.93 3.58 3.54 3.58 3.54 3.41 3.38 4.50 4.48 3.15 3.11 4.27 4.23 3.94 3.89 ) ) ) ) ) 7.82 7.88) 7.73 7.68) 6.62 6.70) 8.58 8.52) 8.48 8.44) 8.08 7.98) 7.52 7.48) 7.16 7.12) 7.24 7.30) 6.79 6.81) 5.21 5.18) 5.50 5.45) 5.28 5.23) 8.28 8.22) 7.90 7.95) 7.36 7.32) 11.95 11.96) 11.14 11.15) 8.43 8.45) Contd

1890 IDIA J. CHEM., EC B, EPTEMBER 2005 Table I Physical data of prepared compounds Contd Compd m.p. (olvent) 9b 4.C 6 H 4 30507 9c 4Cl.C 6 H 4 299301 9d 3,4(CH 3 ) 2. C 6 H 3 15860 (EtH) 10 29698 11 4Cl.C 6 H 4 15355 12 4Cl.C 6 H 4 25456 Mol. formula Calcd % (ound) (Mol. Wt) C H C 19 H 10 2 2 2 67.86 3.00 8.33 (336.29) (67.75 2.98 8.28) C 19 H 10 Cl 2 2 (352.75) C 21 H 15 2 4 (378.35) C 12 H 7 2 (214.20) C 19 H 11 Cl 3 (351.76) C 21 H 11 Cl 3 (375.78) 64.69 (64.63 66.66 (66.60 67.29 (67.25 64.87 (64.82 67.12 (67.10 2.86 2.81 4.00 3.98 3.29 3.24 3.15 3.10 2.95 2.92 7.94 7.97) 7.40 7.42) 13.08 13.10) 11.95 11.97) 11.18 11.16) Table II pectral data of compounds having anticancer activity Compd 1 H MR (δ, ppm) 3b 7.76.9 (m, 12H, H), 4.9 (d, 1H, H a ), 4.6 (m, 1H, H b ), 4.5 (d, 1H, H c ), 4.3 (m, 1H, H d ). 3c 7.716.91 (m, 12H, H), 4.92 (d, 1H, H a ), 4.7 (m, 1H, H b ), 4.6 (d, 1H, H c ), 4.4 (m, 1H, H d ). 4c 9.8 (s, 1H, H, D 2 exchangeable), 8.0 (s, 1H, H, D 2 exchangeable), 7.86.9 (m, 7H, H), 5.2 (s, 1H, pyrimidineh), 4.8 (d, 1H, pyranh), 4.6 (d, 1H, 4d 9.9 (s, 1H, H, D 2 exchangeable), 8.1 (s, 1H, H, D 2 exchangeable), 7.76.9 (m, 6H, H), 4.9 (s, 1H, pyrimidineh), 4.8 (d, 1H, pyranh), 4.7 (d, 1H, pyranh), 3.9 (s, 6H, 2 x CH 3 ). 5a 7.46.9 (m, 7H, H), 5.5 (s, 1H, pyrimidineh), 4.8 (d, 1H, pyranh), 4.6 (d, 1H, pyranh), 3.7 (s, 2H, thiazoleh). 6c 7.86.9 (m, 11H, H+benzylicH), 5.5 (s, 1H, pyrimidineh), 4.6 (d, 1H, pyranh), 4.1 (d, 1H, pyranh), 4.0 (s, 2H, thiazoleh), 3.9 (s, 3H, CH 3 ), 3.7 (s, 6H, 2 x CH 3 ). 7c 7.86.8 (m, 6H, H), 4.7 (s, 2H, H 2, D 2 exchangeable), 4.5 (d, 1H, pyranh), 4.3 (m, 1H, pyranh), 4.1 (s, 1H, pyranh), 3.9 (s, 6H, 2 x CH 3 ). 8a 7.516.8 (m, 7H, H), 4.8 (s, 2H, H 2, D 2 exchangeable), 4.6 (s, 2H, 8b 7.516.8 (m, 6H, H), 4.8 (s, 2H, H 2, D 2 exchangeable), 4.5 (s, 2H, pyranh), 3.8 (s, 6H, 2 x CH 3 ). 9a 12.8 (br s, 1H, H, D 2 exchangeable), 7.66.9 (m, 7H, H), 4.5 (s, 2H, pyranh), 3.5 (s, 3H, CH 3 ). 9b 12.8 (br s, 1H, H, D 2 exchangeable), 7.76.8 (m, 7H, H), 4.4 (s, 2H, 9c 12.5 (br s, 1H, H, D 2 exchangeable), 7.66.8 (m, 7H, H), 4.5 (s, 2H, olvent* M m/z (%) C 362 (M +, base peak, 100%), 267 (M + C 6 H 4, 45%). D 422 (M +, base peak, 100%), 424 (M + +2, 97.65%), 267 (M + C 6 H 4 Br, 0.3%). D 394 (M +, base peak, 100%), 235 (M + C 6 H 4 Cl, 35%). C 372 (M +, base peak, 100%), 238 (M + C 6 H 3 (CH 3 ) 2, 40%). C 388 (M + +2, 42%), 386 (M +, base peak, 100%), 275 (M + C 6 H 4 Cl, 41%). C 530 (M +, base peak, 100%), 392 (M + C 6 H 3 (CH 3 ) 2, 30%). C 380 (M +, base peak, 100%), 242 (M + C 6 H 3 (CH 3 ) 2, 40%). C 353 (M + +2, 46%), 351 (M +, base peak, 100%), 240 (M + C 6 H 4 Cl, 17%). D 377 (M +, base peak, 100%), 239 (M + C 6 H 3 (CH 3 ) 2, 55%). D 332 (M +, base peak, 100%), 240 (M + C 6 H 4 CH 3, 55%). D 336 (M +, base peak, 100%), 241 (M + C 6 H 4 Cl, 25%). D 354 [(M + +2), base peak, 100%], 352 (M +, 35%), 241 (M + C 6 H 4 Cl, 9%). Contd

HAMMAM et al.: LUR UBTITUTED BEZ[B]PYRA WITH ATILUG CACER ACTIVITY 1891 Table II pectral data of compounds having anticancer activity Contd Compd 1 H MR (δ, ppm) 9d 12.5 (br s, 1H, H, D 2 exchangeable), 7.66.8 (m, 6H, H), 4.6 (s, 2H, pyranh), 3.8 (s, 6H, 2 x CH 3 ). olvent* M m/z (%) C 378 (M +, base peak, 100%), 352 (M + C, 10%). 10 7.6 (m, 3H, H), 3.4 (t, 2H, CH 2 ), 2.9 (s, 2H, =CCH 2 ). D 214 (M +, base peak, 100%), 188 (M + C, 21%). 11 7.86.9 (m, 7H, H), 5.5 (s, 2H, H 2, D 2 exchangeable), 4.9 (s, 2H, 12 7.57.1 (m, 7H, H), 6.25 (s, 2H, H 2, D 2 exchangeable), 4.7 (s, 2H, *olvent: C= CDCl 3, D= DMd 6 D D 353 (M + +2, 31%), 351 (M +, base peak, 100%), 240 (M + C 6 H 4 Cl, 7%). 375 (M +, 10%), 340 (M + Cl, base peak, 100%), 264 (M + C 6 H 4 Cl, 30%). no[4,3d]thiazolo[3,2a]pyrimidin3ones 5. The IR spectra of 5 showed peaks at 1722 cm 1 (C=). The 1 H MR (DMd 6 ) of 5b showed a multiplet at δ 7.86.9 (6H, H), a singlet at δ 5.6 for the pyrimidine proton, a singlet at δ 4.0 (2H) for the thiazole ring protons, two doublets at δ 4.8 and 4.6 for the pyran protons and a singlet at δ 3.9 for the two methoxy groups (6H). The mass spectrum of 5b showed the molecular ion peak [M + ] at m/z 412 (100, base peak), and a peak at m/z 275 (24%) for [M + C 6 H 3 (CH 3 ) 2 3,4]. The formation of the linear cyclized products 5A is tentatively favoured over the angular structure 5B due to the chemical shift of the pyrimidine proton which was deshielded by about δ 0.6 relative to the pyrimidine proton of compounds 4. Product 5 was condensed with the proper aromatic aldehydes in refluxing acetic anhydride to afford 4 aryl2arylmethylene10fluoro2,3,5,6tetrahydrobenzo[b]pyrano[4,3d]thiazolo[3,2a]pyrimidin3one derivatives 6 (Method A). Compounds 6 were prepared directly by the action of chloroacetic acid and the proper aromatic aldehydes on 4 in the presence of fused sodium acetate and acetic acidacetic anhydride mixture (Method B). The IR spectra of compounds 6 showed absorption peaks at 1700 1710 cm 1 (C=). The 1 H MR (DMd 6 ) of 6b showed signals at δ 7.806.90 (m, 11H, H + benzylich), 5.5 (s, 1H, pyrimidineh, 4.6 (d, 1H, pyranh) and 4.1 (d, 1H, The mass spectrum of 6a showed the molecular ion peak [M + ] at m/z 537 (100%, base peak) and other peaks at m/z 539 (11%) for [M + +2], 443 (20%) for [M + C 6 H 4 4] and 415 (41%) for [443(C=)]. Compounds 2 reacted with malononitrile in ethanol in the presence of piperidine at room temperature to yield 2amino4aryl9fluoro4,5dihydrobenzo [b]pyrano[4,3b]pyran3carbonitrile derivatives 7. The IR spectra of product 7 showed peaks at 3401 3345 (H 2 ) and 22232219 cm 1. The 1 H MR (CDCl 3 ) of 7a showed signals at δ 7.706.75 (m, 7 H, H), 4.7 (s, 2 H, H 2, exchangeable with D 2 ), 4.5 (d, 1 H, H a ), 4.3 (1 H, m, H b ) and 4.1 (1 H, d, H c ). Also, compounds 2 were condensed with malononitrile and ammonium acetate in the presence of triethyl amine to afford 2amino4aryl9fluoro5Hbenzo[b]pyrano[4,3b]pyridine3carbonitrile derivatives 8. Its spectral data are given in Table II. Compound 1 was reacted with the proper arylmethylenecyanoacetamide derivatives to yield 4 aryl9fluoro1,2dihydro2oxobenzo[b]pyrano[4,3 b]pyridine3carbonitrile derivatives 9 (cheme I). Its spectral data are given in Table II. n the other hand, condensation of 1 with malononitrile gave 2(6fluorobenzo[b]pyran4yildine) malononitrile 10. Product 10 on reaction with p chlorobenzaldehyde and ammonium acetate in acetic acid gave 2amino4(4chlorophenyl)9fluoro5Hbenzo[b]pyrano[3,4c]pyridine1carbonitrile 5,6 11. Compounds 10 were condensed with arylmethylenecyanoacetamide in ethanol in the presence of triethyl amine to yield 2amino4aryl9fluoro5Hdibenzo[b,d]pyrano1,3dicarbonitrile 12 [see original reference] 10 The spectral data of compounds 1012 are given in Table II. Biological activity ome of the synthesized heterocyclic compounds were screened for their anticancer activity. Each compound was tested at five different concentrations against 3 cell lines of human cancer which are Lung,

1892 IDIA J. CHEM., EC B, EPTEMBER 2005 Table III In vitro tumor cell growth inhibition data against different tumor/cell lines Compd Lung cancer CIH460 Panel/cell line Breast cancer MC7 C cancer 268 Activity 3b 1 56 85 active 4c 16 81 83 active 4d 5 21 43 active 5b 49 36 92 active 6c 25 37 77 active 7c 22 37 63 active 8a 17 60 72 active 8b 0 24 54 active 9a 13 53 79 active 9b 79 83 104 inactive 9c 18 77 88 active 9d 90 57 108 inactive 10 23 59 70 active 11 17 60 72 active 12 20 98 89 active Breast and C cancer. The results expressed as log 10 GI 50, which the drug concentration (M) is causing a 50% reduction in the net protein increase in control cells during the drug incubation, are collected in Table III. An inspection of these data shows that the majority of the compounds tested exhibit lung anticancer activity at low concentration comparable with that of 5fluorodeoxyuridine (log 10 GI 50 = 4.7) used as the reference compound 11. Experimental ection Melting points are uncorrected and are taken on Electrothermal IA 9000 eries digital melting point apparatus. Microanalyses were performed by the Central ervices Laboratory, RC. IR spectra were recorded on a CarlZeiss spectrophotometer model UR 10 using KBr; 1 H MR spectra on a Varian Gemini 200 MHz using TM as an internal standard; and mass spectra on a innigan Q7000 mass spectrometer. Purity of the products was checked by TLC on silica gel aluminum sheets 60 254 (E. Merck). 3ylmethylene6fluoro2,3dihydrobenzo[b] pyran4ones 2. A solution of KH [5.6 g (100 mmoles) in 5 ml H 2 ] was added to a mixture of 6 fluorobenzo[b]pyran4one 1 (16.6 g, 100 mmoles) and the aromatic aldehydes (100 mmoles) in ethanol (50 ml), and the reaction mixture was stirred at room temperature for halfanhour. The formed yellow precipitate was filtered off, washed thoroughly with water, dried and crystallized from ethanol to give 2 (Table I). 3yl8fluoro2phenyl2,3,3a,4tetrahydrobenzo[b]pyrano[4,3c]pyrazoles 3. A suspension of 2 (2 mmoles) in gl. acetic acid (10 ml) was treated with phenylhydrazine (0.2 ml 0.22 g, 2 mmoles). The reaction mixture was refluxed for 2hr, poured onto water and the solid formed was separated by filtration and crystallized from ethanol to yield 3 (Table I). 4yl9fluoro2,3,4,5tetrahydrobenzo[b]thiopyrano[4,3d]pyrimidine2(1H)thiones 4. To a mixture of 2 (10 mmoles) and thiourea (1 g, 13 mmoles) in ethanol (50 ml), was added a solution of KH [(1 g, 18 mmoles in H 2 (1 ml)]. The mixture was refluxed for 4 hr, poured onto water and the solid formed was filtered off, dried and crystallized from dioxane to get 4 (Table I). 4yl10flouro2,3,5,6tetrahydrobenzo[b]pyrano[4,3d]thiazolo[3,2a]pyrimidin3ones 5. A mixture of 4 (10 mmoles), chloroacetic acid (1 g, 11 mmoles), fused sodium acetate (4 g, 49 mmoles), acetic acid (40 ml) and acetic anhydride (20 ml) was refluxed for 4 hr, cooled and poured onto water. The solid formed was collected by filtration, washed with water, dried and crystallized from ethanol to get 5 (the product didn t dissolve in a sodium hydroxide solution) (Table I). 4yl2arylmethylene10fluoro2,3,5,6tetrahydrobenzo[b]pyrano[4,3d]thiazolo[3,2a]pyrimidin9ones 6. Method A Equimolar amount (10 mmoles) of compound 5 and the appropriate aromatic aldehyde, gl. acetic acid (30 ml), acetic anhydride (10 ml) and fused sodium acetate (3 g, 37 mmoles) were refluxed for 1hr, cooled and poured onto cold water. The solid formed was collected by filtration and crystallized from proper solvent to get 6b,c (Table I). Method B A mixture of 4 (10 mmoles), chloroacetic acid (1.39 g, 10 mmoles), fused sodium acetate (2 g, 24 mmoles), acetic acid (30 ml), acetic anhydride (10 ml) and the proper aromatic aldehyde (10 mmoles) was refluxed for 3 hr. The reaction mixture was cooled and poured onto cold water. The solid formed was collected by filtration, dried and crystallized from the proper solvent to get 6 (Table I). 2amino4aryl9fluoro4,5dihydrobenzo[b]pyrano[4,3b]pyrane3carbonitriles 7. A mixture of 2 (10 mmoles) and malononitrile (0.66 g, 10 mmoles), and piperidine (2 ml) in ethanol (100 ml) was stirred

HAMMAM et al.: LUR UBTITUTED BEZ[B]PYRA WITH ATILUG CACER ACTIVITY 1893 at room temperature for 1 hr. Excess solvent was distilled off under reduced pressure and the residue obtained was dissolved in acetic acid and poured onto icewater. The separated solid was collected by filtration, dried and crystallized from the proper solvent to afford 7 (Table I). 2Amino4aryl9fluoro5Hbenzo[b]pyrano[4,3 b]pyridine3carbonitriles 8. A few drops of TEA were added to a mixture of 2 (3 g, 10 mmoles), malononitrile (0.66 g, 10 mmoles) and ammonium acetate (0.62 g, 80 mmoles) in absolute ethanol (50 ml). The reaction mixture was refluxed for 8 hr, allowed to cool and poured gradually while stirring onto cold water. The solid formed was collected by filtration, dried and crystallized from the proper solvent to get 8 (Table I). 4yl9fluoro1,2dihydro2oxobenzo[b]pyrano[4,3b]pyridine3carbonitriles 9. To a mixture of 1 (1.66 g, 10 mmoles) and the proper arymethylenecyanoacetamide derivatives (10 mmoles) in ethanol (50 ml), a few drops of TEA were added and the reaction mixture was refluxed for 8hr, allowed to cool, then poured onto icewater. The solid formed was filtered off, washed with water, dried and crystallized from the proper solvent to give 9, respectively (Table I). 2(6luorobenzo[b]pyran4yildine)malononitrile 10. A mixture of 1 (1.66 g, 10 mmoles), malononitrile (0.66 g, 10 mmoles) and β alanine (50 mg) in ethanol (25 ml) was refluxed for 3hr. The reaction mixture was cooled and poured onto cold water. The solid formed was filtered off, washed with water, dried and crystallized from the proper solvent to get 10 (Table I). 2Amino4(4 chlorophenyl)9fluoro5hbenzo [b]pyrano[3,4c]pyridine1carbonitrile 11. A mixture of 10 (1.07 g, 5 mmoles), 4chlorobenzaldehyde (0.7 g, 5 mmoles) and ammonium acetate (1.4 g, 20 mmoles) in ethanol (50 ml) was refluxed for 5hr. The reaction mixture was cooled and poured onto icewater. The solid formed was filtered off, washed thoroughly with water, dried and crystallized from the proper solvent to afford 11 (Table I). 2Amino4(4 chlorophenyl)9fluoro5hdibenzo[b,d]pyrano1,3dicarbonitrile 12. To a mixture of 10 (1.66 g, 10 mmoles), arylmethylenecyanoacetamide derivative (2.06 g, 10 mmoles) in ethanol (50 ml), a few drops of TEA were added. The reaction mixture was refluxed for 8hr, cooled and poured onto icewater. The solid formed was filtered off, washed with water, dried and crystallized from the proper solvent to yield 12 (Table I). Acknowledgement Authors thank the United tates ational Institute of Health (IH)/ational Cancer Institute (CI) and specially Dr V L arayanan and his team, for the inhibition of tumor growth measurements reported in this paper. References 1 Ali M I, Hammam A G & Mohamed, Phosphorus and ulfur, 39, 1988, 211. 2 Hammam A G, Hussain M & Kotob I R, Phosphorus ulfur and ilicon, 47, 1990, 47. 3 Hammam A G, Zahran M A, Elhag A & Helmy K M, Egypt J Pharm ci, 37, 1996, 565. 4 Hammam A G, Zaki M E A & ElAssasy M, Egypt J Pharm ci, 38, 1997, 291. 5 Hammam A G, Mohie A & Abdel Hafez A, Indian J Chem, 40B, 2001, 213. 6 Hammam A G, ahmy A M, Amr A E & Mohamed A M, Indian J Chem, 42B, 2003,1985. 7 Ali M I, ElKashif A, Hammam A G & Khallef A, J Chem Eng Data, 24, 1979, 377. 8 Hammam A G, Abdel Hafez A, Midura W H & Mikolajcik M, Z aturforsch, 55B, 2000, 417. 9 Haga T, ujikawa K, Koyanag T, akajima T & Hayashi K, Heterocycles, 22, 1984, 117. 10 ElGemeie G E H, ElZanate A M & Mansour A, J Chem oc Perkin Trans I, 1992, 1073. 11 Bhatt J J, hah B R, hah H B, Trivedi P B, Undavia K & Desai C, Indian J Chem, 33B, 1994, 189.

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