CN1166629C - 新型苯磺酰胺化合物、其制备方法和含有其的药物组合物 - Google Patents

新型苯磺酰胺化合物、其制备方法和含有其的药物组合物 Download PDF

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CN1166629C
CN1166629C CNB011016582A CN01101658A CN1166629C CN 1166629 C CN1166629 C CN 1166629C CN B011016582 A CNB011016582 A CN B011016582A CN 01101658 A CN01101658 A CN 01101658A CN 1166629 C CN1166629 C CN 1166629C
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G·拉维勒
B·塞米提勒
T·沃布兰
S·西蒙奈特
J－J·戴司康比斯
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Abstract

化合物；(I)其中：n为1～3的整数，m为0～6的整数，Ra为羟基、烷氧基、芳氧基或芳基烷氧基，R1和R2分别表示氢原子、卤素原子、烷基、烷氧基、羟基或全卤代烷基，R3为氢原子、烷基、芳烷基、环烷基烷基、芳基或环烷基，T1为亚烷基、O-亚烷基、亚烷基、亚烷基-O-或(C1-C3)亚烷基-O-(C1-C3)亚烷基，G为G1-或G1-T2-A，其中：A为芳基；T2为键或亚烷基、-O-亚烷基、亚烷基-O-或(C1-C3)亚烷基-O-(C1-C3)亚烷基；G1为-NR4R5，或G1表示具有结构式见右式(1)的5～7元杂环烷基，其中Y表示氮原子、氧原子或CH，R4、R5和R6如上所述。

Description

新型苯磺酰胺化合物、其制备方法和 含有其的药物组合物
本发明涉及新型苯磺酰胺化合物、其制备方法和含有其的药物组合物。
EP864561已经公开了具苯磺酰胺链化合物的有关NO产生特征及它们的凝血噁烷A2(TXA2)受体拮抗特征，同样在EP648741中仅仅记载了有关它们的TXA2受体拮抗特性。
本发明化合物具有一个新颖的结构，使其具有TXA2受体拮抗和5-HT25-羟色胺能受体拮抗的特征。
血小板聚集和血管痉挛在动脉血栓性心血管障碍的病因学和发展中起重要作用。TXA2是花生四烯酸代谢物，5-羟色胺(5HT)是神经递质，它们都是强大的血管收缩剂，都能引起或加强血小板活化，从而引起聚集。TXA2的血管收缩和前聚合作用通过膜受体TP起效(Medicinal ResearchReview，1991，11，5，P，503)，而5-羟色胺则通过5HT1或5HT2受体起效(T.I.P.S.，1991，121，P.223)。目的在于寻找阻断TXA2生成和/或激活的物质的研究策略已导致选择性TP受体拮抗剂、TXA2合酶抑制剂或同时表现这两种特性物质的开发(Medicinal Research Review，ibid，T.I.P.S.，1991，121，158)。与TXA2一样，5-羟色胺通过激活血小板和动脉收缩起作用，并且发现其活性在动脉血栓性心血管障碍时增加。
有关能够同时对抗引起凝血噁烷活化及5-羟色胺活化两个过程化合物的概念对临床医生非常有用。这样的产品具有在阻碍血小板活化和对抗血管痉挛方面提供更加完全保护的优点。因而这类产品可用于治疗和TXA2和5-HT活性增加有关的病理状态，尤其是动脉血栓性心血管障碍，例如心肌梗塞、心绞痛、脑血管意外、Raynaud氏病、哮喘和支气管痉挛，以及偏头痛和静脉障碍等。
本发明涉及式(I)化合物及其对映异构体和非对映异构体、及其与可药用的酸或碱加成的盐，
其中：
n为1～3的整数，
m为0～6的整数，
Ra为羟基、直链或支链的(C1-C6)烷氧基、芳氧基、芳烷氧基，
R1和R2分别表示氢原子、卤素原子、烷基、直链或支链的(C1-C6)烷氧基、羟基或者直链或支链的(C1-C6)全卤代烷基，
R3为氢原子、烷基、芳烷基、环烷基烷基、芳基或环烷基，
T1为亚烷基、O-亚烷基、亚烷基-O-或(C1-C3)亚烷基-O-(C1-C3)亚烷基，
G为G1-或G1-T2-A，其中：
*A为芳基
*T2为键或亚烷基、-O-亚烷基、亚烷基-O-或(C1-C3)亚烷基-O-(C1-C3)亚烷基
*G1为-NR4R5，其中R4和R5分别表示氢原子、烷基、环烷基、可选取代的芳基、可选取代的芳烷基、环烷基烷基、可选取代的杂芳基或可选取代的杂芳基烷基，
或G1表示具有结构式 的5～7元环杂环烷基，其中Y表示氮原子、氧原子或CH或CH2，R6表示氢原子或烷基、环烷基、环烷基烷基、可选取代的芳基、可选取代的芳烷基、可选取代的芳基羰基、可选取代的芳基羰基烷基、可选取代的二芳基烷基、可选取代的二芳基烯基、可选取代的(芳基)(羟基)烷基、可选取代的杂芳基，可选取代的杂芳基烷基、可选取代的杂环芳羰基或可选取代的杂环芳基羰基烷基；
其中：
-“烷基”表示直链或支链，其碳数为1-6，
-“烯基”表示直链或支链，其碳数为2-6且含有1-3个双键，
-“亚烷基”表示直链或支链的二价基团，除非特别指出外，碳数均为1-6，
-“环烷基”表示饱和的环状基团，碳数3-8，
-“芳基”表示苯基或萘基，
-“杂芳基”表示4～11元的单环或双环基团，不饱和或部分饱和，包含1-5个从氮、氧、硫中选出的杂原子，
-“二芳基烷基”和“二芳基烯基”分别表示以上定义的烷基和烯基被二个相同或不同的上述定义的芳基取代的基团。
-和芳基、芳烷基、芳基羰基、芳基羰基烷基、二芳基烷基、二芳基烯基、杂芳基、杂芳基烷基、杂芳基羰基和杂芳基羰基烷基等相关的“取代”概念是指这些基团的芳环部分被一个或多个卤素原子、烷基、直链或支链(C1-C6)烷氧基、羟基、氰基、硝基或氨基(可选被一个或二个烷基取代)取代，其中的杂芳基和杂芳基烷基也可被氧基(＝O)取代。
这里提到的可药用的酸，无任何限制的意思，例如盐酸、氢溴酸、硫酸、膦酸、乙酸、三氟乙酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、酒石酸、马来酸、柠檬酸、抗坏血酸、甲磺酸、樟脑酸等。
这里提到的可药用的碱，无任何限制的意思，例如氢氧化钠、氢氧化钾、三乙胺、叔丁胺等。
本发明中优选化合物的n为2。
本发明中其它优选化合物的m为2。
本发明的优选例是式(I)中R3表示氢原子者。
本发明的另一优选例是式(I)中Ra表示羟基者。
在式(I)中，G1优选表示如式
Figure C0110165800101
所示的杂环烷基；例如哌啶、吡咯、哌嗪等，但并不仅限于此。
优选地，在基团G1中，R6表示选自烷基(如：甲基)、芳基羰基(如：苯甲酰基)、芳基羰基烷基(如：苯甲酰甲基)、二芳基烯基(如：二苯基亚甲基)、(芳基)(羟基)烷基(如：(苯基)(羟基)甲基)、芳基(如：苯基)和杂芳基的基团，所有这些基团的芳环部分，如果存在的话，都可被取代。优选地，取代基为卤素原子或烷氧基。
在优选的杂芳基中，特别优选1，2-苯并异噁唑，1，2-苯并异噻唑等。
本发明特别优选例是式(I)化合物中n和m都为2，Ra表示羟基，R2和R3都表示氢原子，R1表示卤素原子，G1表示式
Figure C0110165800102
所示的杂环烷基，其中Y表示氮原子或-CH或CH2基团，R6选自烷基、芳基羰基、芳基羰基烷基、二芳基烯基、(芳基)(羟基)烷基、芳基和杂芳基。
本发明优选化合物中，更优选3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{2-4-(6-氟-1，2-苯并异噻唑-3-基)-1-哌啶基]乙基}-5，6，7，8-四氢-1-萘基)丙酸和3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{[2-(4-甲基-1-哌嗪基)苯氧基]甲基}-5，6，7，8-四氢-1-萘基)丙酸。
本发明也涉及式(I)化合物的制备方法，其特征在于以式(II)化合物为起始原料，
式(II)中，n、m、R1、R2、R3和T1如式(I)中所定义，Ra’表示直链或支链的(C1-C6)烷氧基，X1表示离去基团(例如卤素原子或甲苯磺酰基)，
-其中，为得到G表示如式(I)中G1所定义基团的式(I)化合物，将其在碱性介质中用式G1H化合物处理得到式(I/a)所示的化合物：
作为式(I)的具体例子，m、n、R’a、R1、R2、R3、T1、G1如式(I)所定义；
-或者，为得到G表示如式(I)所定义基团G1-T2-A的式(I)化合物，将其在碱性介质中用式HO-T2-A-GR所示化合物处理，得到式(IV)化合物，其中T2和A如式(I)中所定义，GR表示可影响底物中离去基团X1亲核取代的反应性基团：
Figure C0110165800112
其中m、n、R’a、R1、R2、R3、T1、A和T2如上所定义，将羟基转化为离去基团或卤素原子后得到如式(V)所示的化合物：
其中m、n、R’a、R1、R2、R3、T1、A和T2如上所定义，X2表示离去基团(如卤素原子或甲苯磺酰基)
将化合物(V)在碱性介质中用式G1H化合物处理，G1如式(I)所定义，得到式(I/b)所示的化合物：
Figure C0110165800121
作为式(I)的具体例子，m、n、R’a、R1、R2、R3、T1、T2、A和G1如上所定义，
可将化合物(I/a)和(I/b)根据分子中的反应性基团而在酸性或碱性介质中将酯水解，得到化合物(I/c)：
作为式(I)的具体例子，m、n、R’a、R1、R2、R3和T1如上所定义，
G如式(I)所定义。
化合物(Ia)、(I/B)和(I/C)组成了所有式(I)化合物，而且：
-可根据需要按照常规纯化技术进行纯化，
-可选采用常规分离技术分离出其立体异构体，
-如有需要可以用可药用的酸或碱转化为加成盐，
其中，在上述过程中的任何合适时候可以将羧酸酯基团-CO-R’a水解为相应的酸，根据合成的需要它也可被再次转化为不同的酯。
本发明也涉及以式(I)化合物作为有效成分，及其与可药用的惰性、无毒赋形剂或载体组成的药物组合物。
根据本发明的药物组合物，具体地说是那些适于经口、胃肠外或经鼻给药的，例如片剂或糖锭、舌下片、明胶胶囊、锭剂、栓剂、霜、软膏、皮肤凝胶等。
用量依患者年龄、体重、疾病的状况和严重程度、给药途径等的不同而异，也因给药途径是经口、经鼻、经直肠或胃肠外的而异。一般每24小时给药1～3次，每单位剂量0.1mg～500mg。
以下实例对本发明进行更详细的说明，但本发明并不仅限于此。制备A：3-(3-(溴甲基)-6-{[(4-氯苯基)磺酰基]氨基}-5，6，7，8-四氢-1-萘基)丙酸甲酯
步骤a：3-(6-{[(4-氯苯基)磺酰基]氨基}-3-甲酰基-5，6，7，8-四氢-1-萘基)丙酸甲酯
在室温下往10g(23mmol)3-(6-{[(4-氯苯基)磺酰基]氨基}-3-乙烯基-5，6，7，8-四氢-1-萘基)丙酸甲酯(EP864561)的100ml二氧六环和50ml水的混合溶液中加入2.5g四氧化锇的2-甲基-2-丙醇溶液(2.5重量％)、然后加入20g高碘酸钠。在室温下搅拌过夜后，将溶液过滤，滤液浓缩。所得残渣用二氯甲烷溶解，用水洗，将有机相浓缩干燥，以硅胶层析进行精制，以环己烷/乙酸乙酯混合物(60/40)作为洗脱剂，得到预期化合物。
步骤b：3-(6-{[(4-氯苯基)磺酰基]氨基}-3-羟甲基-5，6，7，8-四氢-1-萘基)丙酸甲酯
将1g(2.6mmol)硼氢化钠加入4g(9.2mmol)上一步产物的100ml甲醇溶液中。在室温下搅拌反应混合物30分钟。加入饱和碳酸氢钠水溶液并蒸去大部分甲醇后，反应混合物用二氯甲烷萃取。将有机相干燥浓缩。以硅胶层析精制，洗脱剂为乙酸乙酯/环己烷混合物(50/50)，得到预期产物。
步骤c：3-(3-(溴甲基)-6-{[(4-氯苯基)磺酰基]氨基}-5，6，7，8-四氢-1-萘基)丙酸甲酯
于室温下往3.10g(7.1mmol)上步产物的50ml二氯甲烷溶液中加入2.23g(8.5mmol)三苯基膦，再缓慢加入2.83g(8.5mmol)四溴化碳的25ml二氯甲烷溶液。在室温下搅拌1小时后，蒸去溶剂。用硅胶层析进行精制，洗脱剂为环己烷/乙酸乙酯混合物(80/20)，得到预期产物。
制备B：3-(3-(3-溴丙基)-6-{[(4-氯苯基)磺酰基]氨基}-5，6，7，8-四氢-1-萘基)丙酸甲酯
步骤a：3-(7-{[(4-氯苯基)磺酰基]氨基}-4-[2-(甲氧基-羰基)乙基]-5，6，7，8-四氢-1-萘基)-2-丙酸叔丁酯
将1.25g(4mmol)三邻甲苯基膦，8.5ml三乙胺，230mg(1mmol)乙酸钯和9ml丙烯酸叔丁酯加入10g(20.5mmol)3-(3-溴-6-{[(4-氯苯基)磺酰基]氨基}-5，6，7，8-四氢-1-萘基)丙酸甲酯(EP864561)的250ml DMF溶液中。反应混合物在110℃搅拌8小时。蒸去溶剂后，用硅胶层析纯化，用环己烷/乙酸乙酯混合物(80/20)作洗脱剂，得到预期产物。
步骤b：3-([3-(2-叔丁氧基羰基)乙基]-6-{[(4-氯苯基)-磺酰基]氨基}-5，6，7，8-四氢-1-萘基)丙酸甲酯
向上步产物7.5g(14mmol)的100ml甲醇溶液中加入0.87g(3.6mmol)六水合氯化钴，然后逐步加入1.1g(2.9mmol)硼氢化钠。反应混合物在室温下搅拌2小时后过滤。蒸去溶剂，残渣经硅胶层析纯化，用环己烷/乙酸乙酯混合物(80/20)作洗脱剂，得到预期产物。
步骤c：3-(7-{[(4-氯苯基)磺酰基]氨基}-4-[2-(甲氧基羰基)乙基]-5，6，7，8-四氢-2-萘基)丙酸
上步产物6.4g(12mmol)的50ml三氟乙酸溶液在室温下搅拌12小时，蒸去溶剂，残渣溶于乙酸乙酯。有机相用盐水洗，然后干燥并蒸干。用硅胶层析纯化得到产物，用二氯甲烷/甲醇混合物(98/2)作为洗脱剂。
步骤d：3-6-{[(4-氯苯基)-磺酰基]氨基}-3-(3-羟丙基)-5，6，7，8-四氢-1-萘基)丙酸甲酯
将9ml 1M的BH3/THF的THF溶液，在室温下缓缓加入上步产物的2.8g(5.2mmol)的80ml THF溶液中。混合液在室温下搅拌过夜后，加入10ml水。蒸去大部分溶剂后，残渣用乙酸乙酯溶解。有机相用盐水洗后干燥并蒸干，得到预期物质。
步骤e：3-6-{[(4-氯苯基)-磺酰基]氨基}-3-(3-溴丙基)-5，6，7，8-四氢-1-萘基)丙酸甲酯
按照制备方法A的步骤c，将前步骤的产物作为起始化合物，得到产物。
制备C：3-6-{[(4-氯苯基)磺酰基]氨基}-3-({4-[2-(甲苯磺酰基)-乙基]苯氧基}甲基)-5，6，7，8-四氢-1-萘基)丙酸甲酯
步骤a：3-6-{[(4-氯苯基)磺酰基]氨基}-3-({4-(2-羟乙基)-苯氧基甲基]-5，6，7，8-四氢-1-萘基)丙酸甲酯
将165mg(4.2mmol)氢化钠(于矿物油中，60％)、以上制备A得到的产物1.05g(2.1mmol)的50ml THF溶液和1.11g的C18-6冠醚，加入0.58g(4.2mmol)2-(4-羟苯基)乙醇的100ml THF溶液中。反应混合物加热回流1小时。蒸发掉大部分THF，混合物水解，用1N盐酸调节pH为1。用二氯甲烷萃取后，干燥，用硅胶层析纯化，洗脱剂用乙酸乙酯/环己烷混合物(50/50)，得到预期产物。
步骤b：3-6-{[(4-氯苯基)-磺酰基]氨基}-3-({4-(2-(甲苯磺酰基)-乙基]苯氧基}甲基-5，6，7，8-四氢-1-萘基)丙酸甲酯
将1g(5.4mmol)甲苯磺酰氯、0.5ml吡啶，加入0.75g(1.35mmol)上步产物的50ml的二氯甲烷溶液中，室温下搅拌过夜后，用1N盐酸洗，干燥。蒸去溶剂后，经硅胶层析纯化，用环己烷/乙酸乙酯(60/40)混合物作洗脱剂，得到预期产物。
制备D：(2，3-二甲氧基)(4-哌啶基)甲醇
步骤a：1-苄基-4-哌啶基甲酰胺
将20g(156mmol)异哌啶酰胺、32.4g(234mmol)碳酸钾、2g(12mmol)碘化钾和18.6ml(156mmol)苄基溴的400ml乙腈溶液加热回流5小时。蒸去溶剂，残渣用二氯甲烷/水混合液溶解。滗出有机相，用二氯甲烷萃取，用盐水洗、干燥，蒸发除去溶剂，得到预期产物。
步骤b：1-苄基-4-哌啶甲腈
将26g(119mmol)上步产物逐步加入83ml(890mmol)三氯氧磷和17g(290mmol)氯化钠混合物中，加热回流1小时。冷却后，将反应液注入75ml氨水溶液中。用二氯甲烷萃取后，有机相用水洗、干燥，蒸去溶剂，得到预期产物。
步骤c：1-苄基-4-哌啶甲醛
在0℃下往22g(110mmol)上步产物的500ml THF溶液中加入120ml 1M氢化二异丁基铝的己烷溶液。将混合物在室温下搅拌2小时。用10％盐酸水解后，混合物用浓氢氧化钠水溶液中和。用***萃取后，干燥，蒸去溶剂，以硅胶层析纯化，洗脱剂为环己烷/乙酸乙酯混合物(50/50)，得到预期产物。
步骤d：(1-苄基-4-哌啶基)(2，3-二甲氧基苯基)甲醇
在0℃下往7.07g(51mmol)黎芦醚的150ml THF溶液中加入32.5ml1.6M正丁基锂的己烷溶液。在0℃下搅拌2小时后，反应混合物冷却至-78℃，加入8.6g(42mmol)上步产物的200mlTHF溶液。继续在-78℃下搅拌1小时。恢复至室温后，混合物用水水解，用乙酸乙酯萃取，干燥浓缩。用硅胶层析纯化，以乙酸乙酯作为洗脱剂，得到预期产物。
步骤e：(2，3-二甲氧基苯基)(4-哌啶基)甲醇
将7.5g(22mmol)上步产物、1.5g钯碳(10％)、5.5g(87mmol)甲酸铵的150ml甲醇溶液和30ml水加热回流1小时。恢复至室温后，过滤，蒸去溶剂。残渣用二氯甲烷回收，用2N氢氧化钠溶液处理至pH10。用二氯甲烷萃取后，干燥，蒸去溶剂，得到预期产物。
制备E：2-(4-甲基-1-哌嗪基)苯酚
步骤a：4-(2-羟基苯基)-1-哌嗪基羧酸乙酯
将15ml(156mmol)氯甲酸乙酯加入18g(100mmol)2-(1-哌嗪基)苯酚的250ml二氯甲烷溶液中。在室温下搅拌1小时后，将混合物水解，以二氯甲烷萃取。有机相用1N盐酸洗，干燥。浓缩，残渣用***重结晶，得到预期产物。
步骤b：4-〔2-(甲苯磺酰氧基)苯基〕-1-哌嗪基羧酸乙酯
在室温下往23g(91mmol)上步产物的100ml二氯甲烷溶液中加入25g(130mmol)对甲苯磺酰氯和20ml三乙胺。在室温下搅拌72小时后，蒸去溶剂。用硅胶层析精制，洗脱剂为乙酸乙酯/环己烷混合物(30/70)，得到预期产物。
步骤c：〔2-(4-甲基-哌嗪基)苯酚〕4-甲苯磺酸酯
在0℃下往23.2g(57mmol)上步产物的100ml THF溶液中加入3g(79mmol)氢化锂铝。将混合物在室温下搅拌2小时后水解。浓缩后用二氯甲烷萃取，有机相干燥浓缩得到预期化合物。
步骤d：2-(4-甲基-哌嗪基)苯酚
将18g(52mmol)上步产物和44g(785mmol)氢氧化钾的400ml乙醇溶液加热回流2小时。恢复至室温后，用1N盐酸调节pH至7。浓缩后，混合物用二氯甲烷萃取，将有机相干燥浓缩，得到预期产物。
制备F：4-(4-甲基-1-哌嗪基)苯酚
如制备E的方法，将步骤a中的2-(1-哌嗪基)苯酚用4-(1-哌嗪基)苯酚代替，可以得到产物。
实施例1：3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{2-[4-(4-氟苯甲酰基)-1-哌啶基]乙基}-5，6，7，8-四氢-1-萘基)丙酸
步骤a：3-(6-{[(4-氯苯基)磺酰基]氨基}3-{2-[4-(4-氟苯甲酰基)-1-哌啶基]乙基}-5，6，7，8-四氢-1-萘基)丙酸甲酯
将6.5g(17.3mmol)4-(4-氟苯甲酰基)哌啶甲苯磺酸盐和2.4g(17.3mmol)碳酸钾加入3.5g(5.7mmol)3-(6-{[(4-氯苯基)磺酰基]氨基}-3-(2-{[(4-甲基苯基)磺酰基]氧}乙基)-5，6，7，8-四氢-1-萘基)丙酸甲酯(EP 864561)的100ml DMF溶液中。将反应混合物加热回流1小时，然后浓缩。用二氯甲烷溶解残渣，用水清洗。将有机相干燥浓缩，用硅胶层析纯化，以二氯甲烷/甲醇/氨水混合物(98/2/0.2)为洗脱剂，得到预期化合物。
步骤b：3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{2-[4-(4-氟苯甲酰基)-1-哌啶基]乙基}-5，6，7，8-四氢-1-萘基)丙酸甲酯
在3.5m 12N氢氧化钠溶液的存在下将2.2g(3.5mmol)上步产物的溶液加热回流2小时。将反应混合物过滤，滤液浓缩。加入100ml水，用乙酸调节pH至5。滤取形成的沉淀，用二氯甲烷重结晶，得到标题化合物。
熔点：210℃
元素分析：
       C％    H％   N％   S％
计算值：63.20    5.79    4.47    5.11
实测值：62.89    5.87    4.46    4.82
实施例2：3-[6-{[(4-氯苯基)磺酰基]氨基}-3-(2-{4-[(2，3-二甲氧基苯基)(羟基)甲基]-1-哌啶基}乙基)-5，6，7，8-四氢-1-萘基]丙酸
如实施例1的步骤，将步骤a的4-(4-氟苯甲酰基)哌啶甲苯磺酸盐用制备D的化合物代替，得到预期化合物。
元素分析：
       C％    H％   N％   S％
计算值：62.63    6.46    4.17    4.78
实测值：62.13    7.00    4.17    4.64
实施例3：3-[6-{[(4-氯苯基)磺酰基]氨基}-3-{2-[4-(6-氟-1，2-苯并异噁唑-3-基)-1-哌啶基]乙基}-5，6，7，8-四氢-1-萘基]丙酸
如实施例1的步骤，将步骤a的4-(4-氟苯甲酰基)哌啶甲苯磺酸盐用6-氟-3-哌啶-4-基苯并[d]异噁唑盐酸盐代替，得到预期化合物。
熔点：125℃
元素分析：
       C％    H％   N％   S％
计算值：61.92    5.51    6.56    5.01
实测值：61.33    5.45    6.36    4.91
实施例4：3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{2-[4-(6-氟-1，2-苯并异噻唑-3-基)-1-哌啶基]乙基}-5，6，7，8-四氢-1-萘基)丙酸
如实施例1的步骤，将步骤a的4-(4-氟苯甲酰基)哌啶甲苯磺酸盐用6-氟-3-哌啶-4-基苯并[d]异噻唑盐酸盐代替，得到预期化合物。
熔点：232℃
元素分析：
       C％    H％   N％   S％
计算值：60.40    5.38    6.40    9.77
实测值：60.17    5.36    6.39    9.50
实施例5：3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{2-[4-(1，2-苯并异噻唑-3-基)-1-哌啶基]乙基}-5，6，7，8-四氢-1-萘基)丙酸
如实施例1的步骤，将步骤a的4-(4-氟苯甲酰基)哌啶甲苯磺酸盐用3-哌啶-1-基苯并[d]异噻唑盐酸盐代替，得到预期化合物。
实施例6：3-(3-(2-{4-[双(4-氟苯基)亚甲基]-1-哌啶基}乙基)-6-{[(4-氯苯基)磺酰基]氨基}-5，6，7，8-四氢-1-萘基)丙酸
如实施例1的步骤，将步骤a的4-(4-氟苯甲酰基)哌啶甲苯磺酸盐用双(4-氟苯基)-亚甲基哌啶代替，得到预期化合物。
熔点：242℃
元素分析：
       C％    H％   N％   S％
计算值：66.42    5.57    3.97    4.55
实测值：66.27    5.52    4.05    4.32
实施例7：3-[6-{[(4-氯苯基)磺酰基]氨基}-3-(2-{3-[2-(4-氟苯基)-2-氧乙基]-1-吡咯烷基}乙基)-5，6，7，8-四氢-1-萘基)丙酸
如实施例1的步骤，将步骤a的4-(4-氟苯甲酰基)哌啶甲苯磺酸盐用1-(4-氟苯基)-2-吡咯烷-3-基乙酮盐酸盐代替，得到预期化合物。
熔点：143℃
元素分析：
       C％    H％   N％   S％
计算值：63.20    5.79    4.47    5.11
实测值：63.79    5.79    4.52    4.99
实施例8：3-(6-{[(4-氯苯基)磺酰基]氨基}-2-{2-[4-(4-氟苯甲酰基)-1-哌啶基]乙基}-5，6，7，8-四氢-1-萘基)丙酸
如实施例1的步骤，将3-[6-{[(4-氯苯基)磺酰基]氨基}-3-(2-{[(4-甲基苯基)磺酰基]氧}乙基)-5，6，7，8-四氢-1-萘基]丙酸甲酯用EP 864 561中的3-[6-{[(4-氯苯基)磺酰基]氨基}-2-(2-{{(4-甲基苯基)磺酰基]氧}乙基)-5，6，7，8-四氢-1-萘基]丙酸甲酯代替，得到预期化合物。
熔点：223℃
元素分析：
       C％    H％   N％   S％
计算值：63.20    5.79    4.47    5.11
实测值：63.14    5.80    4.56    5.17
实施例9：3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{[4-(4-氟苯甲酰基)-1-哌啶基]甲基}-5，6，7，8-四氢-1-萘基)丙酸
如实施例1的步骤，将3-[6-{[(4-氯苯基)磺酰基]氨基}-3-(2-{[(4-甲基苯基)磺酰基]氧}乙基)-5，6，7，8-四氢-1-萘基]丙酸甲酯用制备A的产物代替，得到预期化合物。
熔点：147℃
元素分析：
       C％    H％   N％   S％
计算值：62.69    5.59    4.59    5.23
实测值：62.99    5.49    4.48    5.17
实施例10：3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{3-[4-(4-氟苯甲酰基)-1-哌啶基]丙基}-5，6，7，8-四氢-1-萘基)丙酸
如实施例1的步骤，将3-[6-{[(4-氯苯基)磺酰基]氨基}-3-(2-{[(4-甲基苯基)磺酰基]氧}乙基)-5，6，7，8-四氢-1-萘基]丙酸甲酯用制备B的产物代替，得到预期化合物。
熔点：118℃
元素分析：
       C％    H％   N％   S％
计算值：63.69    5.97    4.37    5.00
实测值：63.55    6.02    4.37    4.98
实施例11：3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{3-[4-(4-氟苯甲酰基)-1-哌嗪基]丙基}-5，6，7，8-四氢-1-萘基)丙酸
如实施例1的步骤，将3-[6-{[(4-氯苯基)磺酰基]氨基}-3-(2-{[(4-甲基苯基)磺酰基]氧}乙基)-5，6，7，8-四氢-1-萘基]丙酸甲酯用制备B的产物代替，4-(4-氟苯甲酰基)哌啶甲苯磺酸盐用(4-氟苯基)哌嗪代替，得到预期化合物。
元素分析：
       C％    H％   N％
计算值：59.07    5.89    6.46
实测值：59.10    5.83    6.34
实施例12：3-{6-{[(4-氯苯基)磺酰基]氨基}-3-[(4-{2-[4-(4-氟苯甲酰基)-1-哌啶基]乙基}苯氧基)甲基]-5，6，7，8-四氢-1-萘基}丙酸
如实施例1的步骤，将3-[6-{[(4-氯苯基)磺酰基]氨基}-3-(2-{[(4-甲基苯基)磺酰基]氧}乙基)-5，6，7，8-四氢-1-萘基]丙酸甲酯用制备C的产物代替，得到预期化合物。
熔点：196℃
元素分析：
       C％    H％   N％   S％
计算值：62.52    5.77    3.82    4.37
实测值：64.89    6.29    3.84    4.34
实施例13：3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{[2-(4-甲基-1-哌嗪基)苯氧基]甲基}-5，6，7，8-四氢-1-萘基)丙酸
步骤a：3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{[2-(4-甲基-1-哌嗪基)苯氧基]甲基}-5，6，7，8-四氢-1-萘基)丙酸甲酯
将1.30g(2.6mmol)制备A的产物、0.5g(2.6mmol)制备E的产物、200mg(5.2mmol)氢化钠(60％，油)和670mg C18-6冠醚加热回流2小时。冷却混合物后，加入2ml乙酸，浓缩反应混合物。残渣用二氯甲烷回收，用水洗。将有机相干燥，浓缩，以硅胶层析精制，以二氯甲烷/甲醇/氨水(95/5/0.5)为洗脱剂，得到预期产物。
步骤b：3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{[2-(4-甲基-1-哌嗪基)苯氧基]甲基}-5，6，7，8-四氢-1-萘基)丙酸
如实施例1的步骤b，以上步化合物作为起始原料，得到预期产物。
熔点：122℃
元素分析：
       C％    H％   N％   S％
计算值：62.25    6.07    7.02    5.36
实测值：61.52    6.09    6.84    5.22
实施例14：3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{[4-(4-甲基-1-哌嗪基)苯氧基]甲基}-5，6，7，8-四氢-1-萘基)丙酸
如实施例13，将步骤a中制备E的产物用制备F的产物代替，得到预期产物。
熔点：148℃
元素分析：
       C％    H％   N％   S％
计算值：62.25    6.07    7.02    5.36
实测值：61.94    6.36    6.66    5.11
实施例15：3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{2-[4-(6-氟-1，2-苯并[b]噻吩-3-基)-1-哌啶基]乙基}-5，6，7，8-四氢-1-萘基)丙酸
如实施例1，将步骤a中4-(4-氟苯甲酰基)哌啶甲苯磺酸盐用4-(6-氟苯并[b]噻吩-3-基)哌啶盐酸盐代替，得到预期产物。
熔点：140℃
元素分析：
       C％    H％   N％   S％
计算值：62.32    5.54    4.28    9.79
实测值：62.01    5.36    4.28    9.80
实施例16：3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{2-[4-(6-氟-1H-吲唑-3-基)-1-哌啶基]乙基}-5，6，7，8-四氢-1-萘基)丙酸
如实施例1，将步骤a中4-(4-氟苯甲酰基)哌啶甲苯磺酸盐用6-氟-3-哌啶-4-基-1H-吲唑二盐酸盐代替，得到预期产物。
熔点：142℃
元素分析：
       C％    H％   N％   S％
计算值：62.01    5.68    8.77    5.02
实测值：61.98    5.74    8.70    4.83
药理学研究
实施例A：人血小板聚集试验
从实验前至少14天没有服用阿司匹林的人类志愿者采取静脉血。取血时使用柠檬酸钠(0.109M)(1体积柠檬酸盐对9体积血液)。以200g离心(20℃)10分钟得到富血小板血浆(PRP)。血小板数目平均250000PL/mm3。PRP贮存在室温下直至实验，并在抽取后2小时内使用。TXA2激动剂U46619所用浓度为1μM，5-羟色胺所用浓度为10μM，后者在0.3μM二磷酸腺苷和1μM肾上腺素存在下使用。
本发明化合物同时抑制TXA2诱导和5-羟色胺所致的血小板聚集。以实施例的方法，实施例4的化合物对两个靶点的IC50分别为170nM和230nM。此数据表明本发明化合物是强大的抗血小板聚集剂，通过TXA2和5-羟色胺两条激活通路平衡地起作用。
实施例B：制剂组成
制备1000片每片含有5mg活性成分的制剂：
实施例4化合物------------  ----5g
羟丙基甲基纤维素---------------2g
小麦淀粉----------------------10g
乳糖-------------------------100g
硬脂酸镁-----------------------3g

Claims (11)

1.式(I)化合物，其对映异构体和非对映异构体、及其与可药用的酸或碱加成的盐：
Figure C011016580002C1
其中：
n为1～3的整数，
m为0～6的整数，
Ra为羟基或直链或支链的C1-C6烷氧基，
R1和R2独立地表示氢原子或卤素原子，
R3为氢原子，
T1为亚烷基、O-亚烷基，
G为G1-或G1-T2-A，其中：
*A为芳基，
*T2为键或亚烷基，
G1表示具有结构式 的5～7元杂环烷基，其中Y表示氮原子、CH或CH2，R6表示烷基、取代或未取代的芳基、取代或未取代的芳基羰基、取代或未取代的芳基羰基烷基、取代或未取代的二芳基烯基、取代或未取代的芳基羟基烷基、取代或未取代的杂芳基；
其中：
-“烷基”表示直链或支链，其碳数为1-6，
-“烯基”表示直链或支链，其碳数为2-6且含有1-3个双键，
-“亚烷基”表示直链或支链的二价基团，除非特别指出，碳数均为1-6，
-“芳基”表示苯基或萘基，
-“杂芳基”表示4～11元的单环或双环基团，其是不饱和或部分饱和的，包含1-5个从氮、氧、硫中选出的杂原子，
-“二芳基烯基”表示被二个相同或不同的上述定义的芳基取代的以上定义的烯基基团，
-和芳基、芳基羰基、芳基羰基烷基、二芳基烯基、杂芳基等相关的“取代”概念是指这些基团的芳环部分被一个或多个卤素原子、直链或支链C1-C6烷氧基取代。
2.根据权利要求1的化合物及其对映异构体和非对映异构体、及其与可药用的酸或碱加成的盐，其中n为2。
3.根据权利要求1的化合物及其对映异构体和非对映异构体、及其与可药用的酸或碱加成的盐，其中m为2。
4.根据权利要求1的化合物及其对映异构体和非对映异构体、及其与可药用的酸或碱加成的盐，其中Ra为羟基。
5.根据权利要求1的化合物及其对映异构体和非对映异构体、及其与可药用的酸或碱加成的盐，其中n和m都为2，Ra为羟基，R2和R3分别为氢原子，R1为卤素原子，G1为式 所示的杂环烷基，其中Y为氮原子、-CH或CH2，R6选自烷基、芳基羰基、芳基羰基烷基、二芳基烯基、芳基羟基烷基、芳基和杂芳基。
6.根据权利要求1的化合物，为3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{2-[4-(6-氟-1，2-苯并异噻唑-3-基)-1-哌啶基]乙基}-5，6，7，8-四氢-1-萘基)丙酸。
7.根据权利要求1的化合物，为3-(6-{[(4-氯苯基)磺酰基]氨基}-3-{[2-(4-甲基-1-哌嗪基)苯氧基]甲基}-5，6，7，8-四氢-1-萘基)丙酸。
8.根据权利要求1的式(I)化合物的制备方法，其特征在于以式(II)化合物为起始原料，
其中，n、m、R1、R2、R3和T1如式(I)中所定义，R’a表示直链或支链C1-C6烷氧基，X1表示离去基团，
-其中，为得到G表示如式(I)中所定义的G1基团的式(I)化合物，将其在碱性介质中用式G1H化合物处理得到式(I/a)所示的化合物：
Figure C011016580004C2
作为式(I)化合物的具体例子，其中m、n、R’a、R1、R2、R3、T1和G1如式(I)所定义，
-或者，为得到G表示如式(I)所定义的基团G1-T2-A的式(I)化合物，将其在碱性介质中用式HO-T2-A-GR所示化合物处理，得到式(IV)化合物，其中T2和A如式(I)中所定义，GR表示可影响底物中离去基团X1亲核取代的反应性基团：
Figure C011016580004C3
其中m、n、R’a、R1、R2、R3、T1、A和T2如上所定义，将羟基转化为离去基团或卤素原子后得到如式(V)所示的化合物：
其中m、n、R’a、R1、R2、R3、T1、A和T2如上所示，X2表示离去基团，
将式(V)化合物在碱性介质中用式G1H化合物处理，G1如式(I)所定义，得到式(I/b)所示的化合物：
作为式(I)化合物的具体例子，其中m、n、R’a、R1、R2、R3、T1、T2、A和G1如上所定义，
可将化合物(I/a)和(I/b)根据分子中的反应性基团而在酸性或碱性介质中进行酯水解，得到化合物(I/c)：
Figure C011016580005C3
作为式(I)化合物的具体例子，其中m、n、R1、R2、R3和T1如上所定义，G如式(I)所定义；
化合物(Ia)、(I/b)和(I/c)组成了所有式(I)化合物，而且：
-可根据需要按照常规纯化技术进行纯化，
-可选根据常规分离技术分离其立体异构体，
-如有需要可以用可药用的酸或碱转化为加成盐，
其中，在上述过程中的任何合适时候，可以将羧酸酯基团-CO-R’a水解为相应的酸，根据合成的需要它也可被再次转化为不同的酯。
9.药物组合物，以根据权利要求1～7中任一项的化合物作为有效成分，与可药用的惰性、无毒赋形剂或载体组成。
10.根据权利要求9的药物组合物，以权利要求1～7中的任一项作为有效成分，用于生产作为TXA2受体拮抗剂和5-HT2受体拮抗剂有用的药物。
11.根据权利要求9的药物组合物，以权利要求1～7中的任一项作为有效成分，用于生产作为治疗血栓性心血管障碍，如心肌梗塞、心绞痛、脑血管意外、雷诺病、哮喘、支气管痉挛、偏头痛和静脉障碍有用的药物。
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AU2006249577A1 (en) 2005-05-20 2006-11-30 Janssen Pharmaceutica N.V. Process for preparation of sulfamide derivatives
US8492431B2 (en) 2005-12-19 2013-07-23 Janssen Pharmaceutica, N.V. Use of benzo-fused heterocycle sulfamide derivatives for the treatment of obesity
US8937096B2 (en) 2005-12-19 2015-01-20 Janssen Pharmaceutica Nv Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder
US8716231B2 (en) 2005-12-19 2014-05-06 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for the treatment of pain
US8691867B2 (en) 2005-12-19 2014-04-08 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction
US8497298B2 (en) 2005-12-19 2013-07-30 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels
US20070191461A1 (en) * 2006-02-15 2007-08-16 Smith-Swintosky Virginia L Use of benzo-heteroaryl sulfamide derivatives for the treatment of migraine
JP2009537635A (ja) 2006-05-19 2009-10-29 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 癲癇の処置のための共同−療法
CA2729056A1 (en) 2008-06-23 2010-01-21 Janssen Pharmaceutica Nv Crystalline form of (2s)-(-)-n-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide
US8815939B2 (en) 2008-07-22 2014-08-26 Janssen Pharmaceutica Nv Substituted sulfamide derivatives
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AU1636201A (en) 2001-07-26
DE60100015T2 (de) 2003-05-08
CA2332461A1 (fr) 2001-07-19
ES2180524T3 (es) 2003-02-16
HU225747B1 (en) 2007-08-28
EP1118610B1 (fr) 2002-08-21
EA200100059A2 (ru) 2001-08-27
PL345236A1 (en) 2001-07-30
KR20010076389A (ko) 2001-08-11
NZ509455A (en) 2001-06-29
US20020137742A1 (en) 2002-09-26
HU0100274D0 (en) 2001-03-28
NO317891B1 (no) 2004-12-27
CN1305989A (zh) 2001-08-01
CA2332461C (fr) 2005-10-25
DK1118610T3 (da) 2002-12-16
FR2803848A1 (fr) 2001-07-20
EA003426B1 (ru) 2003-04-24
US6545037B2 (en) 2003-04-08
ZA200100565B (en) 2001-07-30
BR0100107A (pt) 2001-08-28
NO20010305D0 (no) 2001-01-18
AU772978B2 (en) 2004-05-13
US6469011B2 (en) 2002-10-22
FR2803848B1 (fr) 2002-02-15
EP1118610A1 (fr) 2001-07-25
DE60100015D1 (de) 2002-09-26
HUP0100274A2 (hu) 2002-03-28
MXPA01000363A (es) 2002-06-04
PT1118610E (pt) 2002-11-29
US20010009915A1 (en) 2001-07-26
SI1118610T1 (en) 2002-12-31
KR100517387B1 (ko) 2005-09-28
HK1038912A1 (en) 2002-04-04
JP2001226353A (ja) 2001-08-21
AR027239A1 (es) 2003-03-19
ATE222586T1 (de) 2002-09-15
NO20010305L (no) 2001-07-20
JP3462858B2 (ja) 2003-11-05
EA200100059A3 (ru) 2001-10-22

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