Synthesis and anti-inflammatory study of novel fluoro-benzothiazole derivatives

N-{6-fluoro-7-[(substituted)-amino] 1, 3-benzothiazole-2-yl}-2-nitrobenzamides; N-{6-fluoro-7-[(substituted)-amino] 1, 3-benzothiazole-2-yl}-3-nitrobenzamides and N-{6-fluoro-7-[(substituted)-amino] 1, 3-benzothiazole-2-yl}-4-nitrobenzamides derivatives were synthesized. Sythesised compounds were tested for anti-inflammatory activity bycarrageenin induced rat hind paw edema method compared to standard Diclofenac.Cyclisation Mechanismof BenzothiazoleSince, in 3-chloro -4fluoro aniline, the 2nd and 6th position is the most positive center but 2nd position behave as a more electrophilic centre. As the attack however was on the 2nd position, which is the electrophilic center and it is probable that bromine being as pseudohalogen, behaves as an electrophile by attacking this electrophilic center followed by replacement of hydrogen of 2nd position as one hydrogen bromide while one bromine atom remain attached. Replacement of bromine takes place by attack of thiocyanogen,behaves as a pseudo halogen (electrophile) followed by elimination of potassium bromide. Finally ring closure occur when pH adjusted at pH6 with ammonia and further rearrangement produce 2-amino-6-fluoro-7-chloro-(1, 3)-benzothiazole. Thus the reaction sequence can be as follows.RESULTS AND DISCUSSIONIn the present work, fluorochloroaniline was treated with KSCN in presence of bromine in glacial acetic acid and ammonia to get 2-amino-6-fluro-7-chloro (1, 3)-benzothiazolewith yield around 51%, which was condensed with 2 (3 or 4)- nitrobenzoyl chloride in presence of dry pyridine and acetone to get N-(7-chloro-6-fluoro-1, 3-benzothiazole-2-yl)-2 (3 or 4)-nitrobenzamides with yield around 45-55% . To the above product 2-chloroaniline, 3-chloroaniline, 4-chloroaniline, o-toludine, m-toludine, p-toludine, 2-nitroaniline, 3-nitroaniline, 4-nitroaniline, 2-aminophenol, 3-aminophenol, 4-aminophenol, 2-anisidine, 3-anisidine and 4-anisidine in presence of DMF were treated toget newly synthesized N-{6-fluoro-7-[(substituted)-amino] 1, 3-benzothiazole-2-yl}-4-nitrobenzamides derivatives through replacing at 7th position chlorine with yield around58-78%. Reaction progress was monitored by thin layer chromatography. All the synthesized compounds of were characterized by melting point, solubility, TLC, IR,1HNMR spectra studies.All the newly synthesized compounds were evaluated for anti-inflammatory activity. Anti-inflammatory activity of synthesized compounds were perform by carrageenininduced rat hind paw edema method on healthy wistar albino rats of either sex weighing between 100-200gm using dose 20 mg/kg body weight (b.w.) for all the synthesizedcompounds as well as for diclofenac as standard.The response to injected carrageenin provides a convenient experimental model of inflammation which has been widely used for evaluating anti-inflammatory drugs.However, from the obtained results by anti-inflammatory activity it found that compound S-7, S-8, S-9, S-202, S-21, S-22 and S-35 exhibited excellent percentage of inhibition as compared to diclofenac.

N-{6-氟-7-[(取代)氨基]-1,3-苯并噻唑-2-基}-2-硝基苯甲酰胺、N-{6-氟-7-[(取代)氨基]-1,3-苯并噻唑-2-基}-3-硝基苯甲酰胺以及N-{6-氟-7-[(取代)氨基]-1,3-苯并噻唑-2-基}-4-硝基苯甲酰胺衍生物已成功合成。合成所得化合物采用角叉菜胶（carrageenin）诱导大鼠足肿胀法开展抗炎活性测试，并以双氯芬酸（Diclofenac）作为阳性对照药物。
苯并噻唑环化机制（Cyclisation Mechanism of Benzothiazole）：在3-氯-4-氟苯胺中，2位与6位为最具正电性的位点，其中2位表现出更强的亲电中心特性。尽管亲电进攻发生于2位这一亲电位点，而溴作为拟卤素（pseudohalogen）可作为亲电试剂进攻该位点，随后2位的氢以溴化氢的形式脱去，同时保留一个溴原子。随后硫氰基（thiocyanogen）作为拟卤素（亲电试剂）发起进攻，实现溴原子的取代，同时伴随溴化钾的消除。当用氨水将反应体系pH调节至6时发生环合反应，进一步重排即可得到2-氨基-6-氟-7-氯-(1,3)-苯并噻唑。因此该反应序列可表述如下。
结果与讨论（RESULTS AND DISCUSSION）：本研究中将氟氯苯胺与硫氰酸钾（KSCN）在溴、冰乙酸（glacial acetic acid）及氨水的共存体系中反应，得到2-氨基-6-氟-7-氯-(1,3)-苯并噻唑，产率约为51%。将该产物与2(3或4)-硝基苯甲酰氯在无水吡啶（dry pyridine）与丙酮的存在下进行缩合反应，得到N-(7-氯-6-氟-1,3-苯并噻唑-2-基)-2(3或4)-硝基苯甲酰胺，产率约为45%~55%。将上述产物与2-氯苯胺、3-氯苯胺、4-氯苯胺、邻甲苯胺、间甲苯胺、对甲苯胺、2-硝基苯胺、3-硝基苯胺、4-硝基苯胺、2-氨基苯酚、3-氨基苯酚、4-氨基苯酚、2-茴香胺、3-茴香胺及4-茴香胺在N,N-二甲基甲酰胺（DMF）中反应，通过取代7位的氯原子，得到新型N-{6-氟-7-[(取代)氨基]-1,3-苯并噻唑-2-基}-4-硝基苯甲酰胺衍生物，产率约为58%~78%。
反应进程通过薄层色谱（TLC）进行监测。所有合成化合物均通过熔点、溶解度、薄层色谱、红外光谱（IR）及氢核磁共振（1HNMR）光谱进行了结构表征。
所有新合成的化合物均进行了抗炎活性评价。抗炎活性测试采用角叉菜胶诱导大鼠足肿胀法，实验对象为体质量100~200g的健康Wistar白化大鼠（wistar albino rats，不分性别），所有合成化合物及标准品双氯芬酸的给药剂量均为20mg/kg体质量（b.w.）。
角叉菜胶注射诱导的炎症模型是一种便捷的炎症实验模型，已被广泛应用于抗炎药物的活性评价。
然而，从抗炎活性测试结果来看，化合物S-7、S-8、S-9、S-202、S-21、S-22及S-35相较于双氯芬酸表现出更为优异的炎症抑制率。