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Synthesis and antitumor evaluation of fluoroquinolone C3 fused heterocycles(Ⅱ):From triazolothiadiazines to pyrazolotriazoles 被引量：1

Synthesis and antitumor evaluation of fluoroquinolone C3 fused heterocycles(Ⅱ):From triazolothiadiazines to pyrazolotriazoles
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摘要 To further expand an effective modified route for the shift from an antibacterial fluoroquinolone （FQ） to an antitumor FQ, two series of title compounds based on an isostere of the FQ C3 carboxylic group with two fused heterocyclic rings, [ 1,2,4]triazolo[3,4- b][1,3,4]thiadiazine and pyrazolo[5,1-c][1,2,4]triazole, respectively, were designed and synthesized starting from the current antibacterial FQs, and their in vitro antitumor activity against L1210, CHO cell lines were evaluated via their respective IC50 values. To further expand an effective modified route for the shift from an antibacterial fluoroquinolone （FQ） to an antitumor FQ, two series of title compounds based on an isostere of the FQ C3 carboxylic group with two fused heterocyclic rings, [ 1,2,4]triazolo[3,4- b][1,3,4]thiadiazine and pyrazolo[5,1-c][1,2,4]triazole, respectively, were designed and synthesized starting from the current antibacterial FQs, and their in vitro antitumor activity against L1210, CHO cell lines were evaluated via their respective IC50 values.
作者 Guo Qiang Hu Li Li Hou Yong Yang Lei Yi Song Qiang Xie Guo Qiang Wang Nan Nan Duan Tie Yao Chao Xiao Yi Wen Wen Long Huang
机构地区 Institute of Chemistry & Biology China Pharmaceutical University
出处 《Chinese Chemical Letters》 SCIE CAS CSCD 2011年第7期804-806,共3页 中国化学快报（英文版）
基金 supported by National Natural Science Foundation of China(Nos.20872028,21072045)
关键词 FLUOROQUINOLONE Triazolothiadiazine Pyrazolotriazole Antitumor evaluation Fluoroquinolone Triazolothiadiazine Pyrazolotriazole Antitumor evaluation
分类号 O626 [理学—有机化学] S859.796 [农业科学—临床兽医学]
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参考文献16

  • 1G.Q. Hu, Y. Yang, L. Yi, et al, Acta Pharm. Sin. 45 (2010) 1012 (in Chinese).
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  • 8(a) A general procedure for synthesis of 3-(6-catechol-4-yl-3-FQ-3-yl-7H-[1,2,4]triazolo[3,4-b][1,3,411thiadiazines 3a-3e:To a mixture of each of the starting materials la-le (10 mmol) and 4-(chloroacetyl)catechol (2.0 g, 10 mmol) in ethanol (50 mL) was added 30% sodium hydroxide (1.5 g, 11 mmol), and stirred at room temperature for 12 h. Then, a concentrated hydrochloric acid (5 mL) was added to the above reaction solution, the resultant mixture was refluxed for 6 h. The resultant solid was collected, and recrystallized from ethanol to give the title compounds 3a-3e as respective hydrochloride. (b) A general procedure for synthesis of 6-catechol-4-yl-3-FQ-3-yl-1H-pyrazolo[5, l-c] [1,2,4]triazole 5a-Se: Each of compounds 3a-3e hydrochloride (5 mmol) in refluxing acetic anhydride (10 mL) was stirred for 1 h, a concentrated hydrochloric acid (5 mL) was then added to the above reaction solution. Refluxing was continued for 3 h. After removal of the solvents on a rotary evaporator, the residue was recrystallized from ethanol to give the title compounds 5a-Se as respective hydrochloride. 3-(6-Catechol-4-yl-1H-pyrazolo[5, l- c] [ 1,2,4]triazol-3-yl)- I-ethyl-6-fluoro-7-piperazin- 1 -yl-quinolin-4( 1H)-one HC1 5a: yield 52%, mp >260 ℃. IR (KBr, v): 3458, 3158, 1626, 1574, 1457, 1248 cm-1; 1H NMR (DMSO-d6) & 13.16 (s, 1 H, NH), 1 1.45 (brs, IH, HC1), 9.66, 9.53 (2 s, 2H, 2 x OH), 9.07 (s, 1 H, H-2), 7.84 (d, 1 H, J = 5.4 Hz, H-8), 7.75 (s, 1 H, Ph-H), 7.62 (d, 1 H, J = 13.2 Hz, H-5), 7.52 (dd, J = 7.2 Hz, Ph-H), 7.44 (dd, J = 7.2 Hz, Ph-H), 6.76 (s, 1 H, 7'- H), 3.48-3.22 (m, 8H, pipemzine-H), 2.67 (q, 2H, J= 7.2 Hz, N~H2), 1.38(t, J = 7.2 Hz, 3H, CH3); MS m/z: Found 490 (M+ + H), Calcd. 489.51 (M+) for C25H24FNTO3. Anal. Calcd. for C25H24FN703 HCI: C 57.09, H 4.79, N 18.64; Found C 57.32, H 4.6 I, N 18.83.3-(6-Catechol-4- yl-lH-pyrazolo[5,l-c][1,2, 4]triazol-3-yl)-l-cyclopropyl-6-fluoro-7-piperazin-l-yl-quinolin-4-(IH)-one.HC1 5b: yield 52%, mp >260 ℃. IR (KBr, v): 3528, 3356, 2894, 1632, 1568, 1455, 1268 cm-l; I H NMR (DMSO-d6 & 12.67 (s, 1 H, NH), I 1.36 (br s, 1 H, HCI), 9.58, 9.50 (2 s, 2H, 2 x OH), 8.97 (s, IH, H-2), 8.04 (d, 1H, J = 5.5 Hz, H-8), 7.86 (d, 1 H, J = 13.2 Hz, H-5), 7.68-7.47 (m, 3H, Ph-H), 6.54 (s, 1 H, 7'-H), 3.74-3.68 (m, 1H, CH-cyclopropyl), 3.36-2.58 (m, 8H, piperazine-H), 1.36-1.21 (m, 4H, CH2CH2-cyclopropyl)57.09, H 4.79, N 17.26; Found C 57.28, H 4.84, N 17.48.
  • 9MS m/z: Found 490 (M+ + H), Calcd.489.51 (M+) for C25H24FN703. Anal. Calcd. for C25H24FN703 HCI: C 57.09, H 4.79, N 18.64; Found C 57.32, H 4.61, N 18.83.3-(6-Catechol-4-yl-lH-pYrazolo[5,-l-c][1,2, 4]iriazol-3-yl)-l-cyclopropyl-6-1~uoro-7-piperazin-l-yl-quinolin-4-(IH)-one.HCl 5b: yield 52%, mp >260 ℃. IR(KBr, v): 3528, 3356, 2894, 1632, 1568, 1455, 1268 cm-l.
  • 10IH NMR (DMSO-d~,) ~: 12.67 (s, 1H, NH), I 1.36 (br s, 1 H, HCI), 9.58, 9.50 (2 s, 2H,2 ~ OH), 8.97 (s, IH, H-2), 8.04 (d, 1H, J = 5.5 Hz, H-8), 7.86 (d, 1 H, J = 13.2 Hz, H-5), 7.68-7.47 (m, 3H, Ph-H), 6.54 (s, 1 H, 7'-H), 3.74-3.68(m, 1H, CH-cyclopropyl), 3.36-2.58 (m, 8H, piperazine-H), 1.36-1.21 (m, 4H, CH2CH2-cyclopropyl).

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Chinese Chemical Letters
2011年 第7期

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