CN1289334A - 苯并噻二唑及其衍生物 - Google Patents

苯并噻二唑及其衍生物 Download PDF

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CN1289334A
CN1289334A CN99802662A CN99802662A CN1289334A CN 1289334 A CN1289334 A CN 1289334A CN 99802662 A CN99802662 A CN 99802662A CN 99802662 A CN99802662 A CN 99802662A CN 1289334 A CN1289334 A CN 1289334A
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B·P·纽曼
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Abstract

本发明提供了式(Ⅰ)的化合物,其中X,R1,R2和Het如说明书所定义,还提供了一种制备它们的方法。式(Ⅰ)化合物可以用作药物。

Description

苯并噻二唑及其衍生物
本发明涉及新型苯并噻二唑及其衍生物，其制备方法，其作为药物的用途和包含它们的药物组合物。
更具体而言，本发明提供了一种游离碱或酸加成盐形式的式I化合物
Figure 998026620005129
其中X为O，S，N-CH3，CH=CH或CAlk=CAlk，其中Alk独立地为(C1-4)烷基，R1和R2独立地为氢，卤素，(C1-4)烷基，(C1-4)烷氧基或三氟甲基，以及Het为具有下式(a)-(p)之一的基团：
Figure 998026620006131
其中R3和R8独立地为氢或(C1-4)烷基，R4为氢，卤素，(C1-4)烷基，氰基，硝基，甲酰基或(C1-4)烷基羰基，R5和R6独立地为氢，(C1-7)烷基，(C3-7)链烯基，(C3-7)环烷基，(C3-7)环烷基(C1-4)烷基，(C1-4)烷氧基(C2-5)烷基或苄基，R7为氢，羟基，(C1-4)烷基或(C1-4)烷氧基，W为N，C-CN，C-NO2，C-COH或C-CO-Alk，其中Alk如上所定义，以及X如上所定义。
卤素为氟、氯、溴或碘，优选氟或氯。
基团Het优选位于与式I中的杂环部分相邻的碳原子上。优选Het具有式(a)-(k)，特别是式(a)。
另一方面，本发明提供了一种制备式I化合物及其盐的方法，其中使式II化合物
Figure 998026620006132
其中X，R1和R2如上所定义，Y为具有下式(a’)-(p’)之一的基团：
Figure 998026620007133
其中R3-R8，W和X如上所定义，Hal为卤素，与式III化合物反应其中R5和R6如上所定义，以及以游离碱或酸加成盐形式回收如此得到的式I化合物。
该反应可以已知方式进行，如实施例1所述。Hal优选为氯、溴或碘，特别是氯。
根据上述方法得到的反应混合物的处理以及由此得到的化合物的提纯可以按照已知的程序进行。
酸加成盐可以已知的方式由游离碱生产，反之亦然。适用于本发明的可药用酸加成盐包括例如盐酸盐，马来酸氢盐，富马酸氢盐和丙二酸氢盐。
式II的原料可以按照如下得到：
其中Y为具有式(a’)和(d’)之一的基团的式II化合物可以通过使式IV化合物
Figure 998026620008135
其中X，R1和R2如上所定义，与式Va或Vd的化合物反应得到
Figure 998026620008136
其中R3和R4如上所定义，且Hal独立地为卤素。
其中Y为具有式(b’)，(c’)和(e’)-(l’)之一的基团的式II化合物可以通过使POCl3与式VI化合物反应得到
Figure 998026620008137
其中Y’为具有下式(b”)，(c”)和(e”)-(l”)之一的基团，
Figure 998026620009139
其中R3，R4，R7，R8和W如上所定义。
所有上述反应都是常规的。
式III，IV，Va，Vd和VI的化合物是已知的或可以使用常规程序由已知的化合物得到。
式I化合物及其可药用酸加成盐(下文称为本发明的试剂)在使用促肾上腺皮质素释放因子(CRF)受体表达细胞培养物进行体外实验和在动物中进行实验中时显示有价值的药理性能，因此可以用作药物。
具体而言，本发明的试剂与CRF受体结合。更具体地说，它们对CRF1受体显示拮抗活性，由下列分析在体外测定：
将表达人重组CRF1的中国仓鼠卵巢(CHO)细胞(Chen等，美国国家科学院院报(Proc Natl Acad Sci USA)90，8967-8971，1993)在补充有10％胎牛血清，非必需氨基酸，100U／ml青霉素，100mg／l链霉素和1g／l geneticin(G418)的Dulbecco改性Eagle培养基中繁殖。对于环化AMP测定，将细胞生长至在24-多孔板中融合。在完整细胞中测量CRF(人／小鼠形式)对环化AMP累积的刺激，如先前所述(Schoeffer等，神经药理学(Neuropharmacology)36，429-437，1997)使用[3H]腺嘌呤标记技术。CRF的浓度-响应曲线在推定拮抗剂(10μM)或载体(二甲亚砜，1％vol)存在下进行构建。由对照曲线的向右移动计算KB值，使用如下等式：KB=[拮抗剂，M]／浓度-比率-1)，其中浓度-比率表示存在拮抗剂时CRF EC50值／不存在拮抗剂时CRFEC50值的比率[Furchgott，In：儿茶酚胺(Blaschko H和Muscholl E编)pp．283-335，Springer，Berlin，1972]。
在该实验中，本发明试剂显示出CRF1拮抗活性，Kb CRF1值约为1-500nM。
本发明试剂因此可用于治疗任何CRF的内源性水平增加或其中HPA(下丘脑垂体轴)失调的状态或由CRF诱发或促进的各种疾病，包括炎症疾病，如关节炎，哮喘和过敏反应；焦虑，包括一般性焦虑；恐怖和恐慌发作；抑郁；疲劳综合征；头痛；疼痛，如炎性或神经病性疼痛；癌症；过敏性肠综合征，包括局限性回肠炎，结肠痉挛或结肠过敏；免疫机能障碍；人免疫缺陷病毒(HIV)感染；神经变性疾病，如老年性痴呆，阿尔茨海默氏病和帕金森氏病；中风和头外伤；癫痫；胃肠疾病；饮食和体重紊乱，如肥胖和神经性厌食；出血性应激反应；毒品和酒精戒除症状；药瘾；睡眠疾病；激素失调；皮肤疾病；应激反应诱发的精神病发作；生育问题；性机能障碍和早产。
本发明试剂在上述疾病中的有用性可以通过许多标准实验来证实：
例如，本发明试剂的抗焦虑活性可以在小鼠突起迷宫实验(mouseelevated plus-maze)中证实[参见例如Rodgers R．J．，行为药理学(Behavioural Pharmacology)8：477-496(1997)，其中有关突起迷宫实验在第486页上讨论；对于该方法，参见Rodgers R．J．等人，Ethology and Psychopharmacology(SJ Cooper和CA Hendrie编)，pp9-44(1994)，J．Wiley，Chichester]。在该实验中，本发明试剂在给药0．1-30mg／kg p．o．时显示出类似抗焦虑的活性。
对于上述适应症，合适的剂量当然可以随例如所用化合物，宿主，给药模式以及待治疗病症的性质和严重程度而改变。然而，通常而言，以约0．1-约100，优选约0．5-约100mg／kg动物体重的日剂量在动物中得到令人满意的结果。在更大的哺乳动物例如人中，所示日剂量为约1-约500，优选约1-约300mg本发明试剂，例如每日至多四次以分开剂量或以缓释形式方便地给药。
本发明试剂可以通过任何常规途径给药，特别是经肠，优选口服，例如以片剂或胶囊形式，或经胃肠外，例如以可注射溶液或悬浮液形式。
对于上述适应症，优选的化合物是下面实施例1的化合物。在上述结合实验中，所述化合物显示出CRF1拮抗活性，Kb CRF1为36nM。在上述突起迷宫实验中，0．1-10mg／kg p．o．(在3mg／kg时具有最大值)的剂量显著影响与焦虑相关的行为参数。与标准的利眠宁相反，与运动刺激相关的参数不受影响，这表明观察到的抗焦虑作用并不归因于普通运动刺激。
根据前面所述，本发明还提供了一种本发明试剂，用作药物，例如用于治疗由CRF诱发或促进的疾病，如上面所示那些。
本发明还提供了一种药物组合物，包含本发明的试剂和至少一种药物载体或稀释剂。该类组合物可以常规方式制备。单位剂型含有例如约0．25-约150，优选0．25-约25mg本发明化合物。
此外，本发明提供了本发明试剂在制备用于治疗任何上述症状的药物中的用途。
本发明再一方面提供了一种在需要该治疗的主体中治疗任何上述症状的方法，包括对该主体给药治疗有效量的本发明试剂。
下列实施例说明本发明。温度以摄氏度给出且未经校正。实施例1：5，7-二甲基-4-[2，5-二甲基-6-(二正丙基)氨基-嘧啶-4-基]氨基-2，1，3-苯并噻二唑
将4-(4-氯-2，5-二甲基嘧啶-6-基)氨基-5，7-二甲基-2，1，3-苯并噻二唑(3．5g)和二正丙基胺(5．35ml)在无水N-甲基吡咯烷酮(35ml)中的溶液于157℃下在密封容器中搅拌96小时。使用薄层色谱法监测反应。冷却反应混合物，加入50ml水并用甲基叔丁基醚(2×200ml)萃取水相两次。干燥有机相，蒸发并在硅胶上使用环己烷／甲基叔丁基醚(5∶1)进行色谱分离。蒸发合适的级分并将残余物用甲醇重结晶得到标题产物。Mp=117-119℃。
原料4-(4-氯-2，5-二甲基嘧啶-6-基)氨基-5，7-二甲基-2，1，3-苯并噻二唑按如下制备：
将4，6-二甲基-2，1，3-苯并噻二唑(7．7g)溶于浓硫酸(20ml)中，在搅拌下冷却到0-5℃并滴加硝酸(2．5ml；d=1．52)。将透明溶液倾倒在冰上，滤出如此得到的沉淀物并用水洗涤。所得5，7-二甲基-4-硝基-2，1，3-苯并噻二唑用环己烷重结晶。Mp=105-106℃。
将5，7-二甲基-4-硝基-2，1，3-苯并噻二唑(20g)温热至在水(2．21)和乙醇(2．21)中沸腾并分批加入连二硫酸钠(强烈的放热反应)。立即在冰浴中冷却反应混合物并用乙酸乙酯萃取。蒸发浓缩有机相并将残余物在水中重结晶得到4-氨基-5，7-二甲基-2，1，3-苯并噻二唑。Mp=113-114℃。
将4-氨基-5，7-二甲基-2，1，3-苯并噻二唑(4g)在氩气氛下分批加入氢化钠(2．72g)在无水四氢呋喃(50ml)中的55％分散液中。在25-30℃下将反应混合物搅拌3小时，然后在5℃下经30分钟滴加4，5-二氯-2，5-二甲基嘧啶(4g)在无水四氢呋喃(20ml)中的溶液。将反应混合物在室温下再搅拌16小时，然后小心加入冰水。所得沉淀物用水和少量甲醇洗涤。用甲醇或环己烷重结晶后，得到4-(4-氯-2，5-二甲基嘧啶-6-基)氨基-5，7-二甲基-2，1，3-苯并噻二唑。Mp=174-177℃。
类似于实施例1制备下列式I化合物：
Figure 998026620014143
Me=甲基；Et=乙基；*：富马酸盐b)下式化合物
Figure 998026620014144
Me=甲基；Et=乙基c)下式化合物
Figure 998026620014146
Figure 998026620014147
Figure 998026620015148
Me=甲基；Et=乙基d)下式化合物
Figure 998026620015149
Figure 998026620015150
Me=甲基；Et=乙基e)下式化合物
Figure 998026620016151
Me=甲基；Et=乙基f)下式化合物
Figure 998026620016153
Figure 998026620016154
Me=甲基；*：富马酸盐

Claims (9)

1．一种游离碱或酸加成盐形式的式I化合物
Figure 998026620002123
其中X为O，S，N-CH3，CH=CH或CAlk=CAlk，其中Alk独立地为(C1-4)烷基，R1和R2独立地为氢，卤素，(C1-4)烷基，(C1-4)烷氧基或三氟甲基，以及Het为具有下式(a)-(p)之一的基团：
Figure 998026620002124
其中R3和R8独立地为氢或(C1-4)烷基，R4为氢，(C1-4)烷基，氰基，硝基，甲酰基或(C1-4)烷基羰基，R5和R6独立地为氢，(C1-7)烷基，(C3-7)链烯基，(C3-7)环烷基，(C3-7)环烷基(C1-4)烷基，(C1-4)烷氧基(C2-5)烷基或苄基，R7为氢，羟基，(C1-4)烷基或(C1-4)烷氧基，W为N，C-CN，C-NO2，C-COH或C-CO-Alk，其中Alk如上所定义，以及X如上所定义。
2．游离碱或酸加成盐形式的5，7-二甲基-4-[2，5-二甲基-6-(二正丙基)氨基嘧啶-4-基]氨基-2，1，3-苯并噻唑。
3．一种制备如权利要求1所定义的式I化合物或其盐的方法，包括使式II化合物其中X，R1和R2如权利要求1所定义，Y为具有下式(a’)-(p’)之一的基团： 其中R3-R8，W和X如权利要求1所定义，Hal为卤素，与式III化合物反应
Figure 998026620004128
其中R5和R6如权利要求1所定义，以及以游离碱或酸加成盐形式回收如此得到的式I化合物的步骤。
4．根据权利要求1或2的游离碱或可药用酸加成盐形式的化合物，用作药物。
5．根据权利要求1或2的游离碱或可药用酸加成盐形式的化合物，用于治疗任何CRF的内源性水平增加或其中HPA失调的状态或由CRF诱发或促进的疾病。
6．一种药物组合物，包含权利要求1或2的游离碱或可药用酸加成盐形式的化合物以及药物载体或稀释剂。
7．根据权利要求1或2的游离碱或可药用酸加成盐形式的化合物作为治疗任何CRF的内源性水平增加或其中HPA失调的状态或由CRF诱发或促进的疾病的药物的用途。
8．根据权利要求1或2的游离碱或可药用酸加成盐形式的化合物在制备用于治疗任何CRF的内源性水平增加或其中HPA失调的状态或由CRF诱发或促进的疾病的药物中的用途。
9．一种在需要该治疗的主体中治疗任何CRF的内源性水平增加或其中HPA失调的状态或由CRF诱发或促进的疾病的方法，包括对该主体给药治疗有效量的权利要求1或2的游离碱或可药用酸加成盐形式的化合物。
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