CN1842530A - 吡唑并嘧啶化合物的甲磺酸盐、其结晶及其制备方法 - Google Patents
吡唑并嘧啶化合物的甲磺酸盐、其结晶及其制备方法 Download PDFInfo
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- CN1842530A CN1842530A CNA2004800243652A CN200480024365A CN1842530A CN 1842530 A CN1842530 A CN 1842530A CN A2004800243652 A CNA2004800243652 A CN A2004800243652A CN 200480024365 A CN200480024365 A CN 200480024365A CN 1842530 A CN1842530 A CN 1842530A
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- Prior art keywords
- methyl
- dihydro
- chloro
- methoxy
- phenyl
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Abstract
本发明涉及新的8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐以及该化合物中间产物的制备方法。8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐是具有优异热稳定性的化合物。新的制备方法可以高收率地制备作为中间产物的式(I)化合物,其中Ar是可以被取代基取代的苯环等,R1为C1-8烷基、C2-8烯基、C2-8炔基等。
Description
技术领域
本发明涉及8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐、其结晶、制备其的方法或制备其中间产品的方法。
背景技术
促肾上腺皮质激素释放因子(CRF)是具有41氨基酸残基的肽,并在1981年由羊下丘脑分离。据报道CRF是由下丘脑释放的并控制促肾上腺皮质激素(ACTH)由脑垂体的分泌[Science,
218,377-379(1982)]。
由CRF的刺激而分泌的ACTH,刺激氢化可的松由肾上腺皮质的分泌,并涉及对于生殖、生长、胃肠功能、炎症、免疫系统、神经系统等的全身作用。因此认为CRF作为这些功能的调节剂起到重要的作用。从这些方面看,CRF与中枢神经系统疾病或精神神经病、或者末梢器官之间的关系已经受到关注。
在WO 02/053565的说明书中,描述了作为CRF受体的式(A)化合物
其中XA和YA分别独立地为碳或氮并且不同时为氮;WA是碳或氮;UA和ZA分别独立地为CR2A、NR13A、氮、氧、硫、C=O或C=S;
R2A是(i)氢,(ii)C1-8烷基,(iii)C2-8烯基,(iv)C2-8炔基,(v)卤原子,(vi)CF3,(vii)氰基,(viii)硝基,(ix)NR9AR10A,(x)OR11A,(xi)SH,(xii)S(O)nAR12A,(xiii)COR11A,(xiv)COOR11A,(xv)CONR9AR10A,(xvi)C3-10单环或双环,(xvii)包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环,或者(xviii)取代的C1-4烷基;
为单键或双键;
R1A为(i)未取代的或取代的C1-8烷基,(ii)未取代的或取代的C2-8烯基,(iii)未取代的或取代的C2-8炔基,(iv)NR4AR5A,(v)OR6A,(vi)SH,(vii)S(O)nR7A,(viii)COR6A,(ix)COOR6A,(x)CONR4AR5A,(xi)NR8ACOR6aA,(xii)NR8ACOOR6A,(xiii)NR8ACONR4AR5A,(xiv)未取代的或取代的C3-15单或双碳环,(xv)包含1-4个氮、1-2个氧和/或1-2个硫的未取代的或取代的3-15员单或双杂环;有文献记载R1A具有CRF拮抗作用(参照WO02/0533565号)。
另外,在上述文件中描述了8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶盐酸盐。
另一方面,作为式(A)化合物的中间产物,描述了式(B)化合物
其中R2A-a为(i)氢,(ii)C1-8烷基,(iii)C2-8烯基,(iv)C2-8炔基,(v)卤原子,(vi)三氟甲基,(vii)氰基,(viii)硝基,(ix)NR9AR10A,(x)OR11A,(xi)SH,(xii)S(O)nR12A,(xiii)COR11A,(xiv)COOR11A,(xv)CONR9AR10A,(xvi)C3-10单或双碳环,(xvii)包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环,或者(xviii)取代的C1-4烷基,但条件是R2A-a不是OH、氰基、=N-OR11A或者包含OH、氰基或=N-OR11A的基团;
R3A-a为(i)取代的C5-10单或双碳环,或者(ii)取代的5-10员单或双杂环,该杂环,该杂环包含1-4个氮、1-2个氧和/或1-2个硫,但条件是上述这些基团不是OH、氰基、=N-OR11A或者包含OH、氰基或=N-OR11A的基团。
在式(B)化合物中,描述了1-氰基-1-(2-甲基-4-甲氧基苯基)丙-2-酮(化合物B-1),和1-氰基-1-(2-氯-4-甲氧基苯基)丙-2-酮(化合物B-2)作为参考例,并且显示这些化合物可以通过描述在方案A和B的方法进行制备。
方案A
化合物B-1
方案B
化合物B-2
[工序a]是使1,2-二甲基-4-甲氧基苯与N-溴代琥珀酰亚胺和2,2’-偶氮二异丁腈反应,然后使得到的化合物与氰化钠反应。
[工序b]是在乙酸乙酯中使在[工序A]中制备的化合物和金属钠反应。
[工序c]是在正丁基锂的存在下,使3-氯-4-溴茴香醚和三异丙基硼酸盐在四氢呋喃中反应。
[工序d]是在碳酸钠和四(三苯基膦)钯的存在下,使[工序c]中制备的化合物和4-碘-5-甲基异噁唑在二甲氧基乙烷/水的混合物中反应。
[工序e]是使[工序d]中制备的化合物与甲氧基钠在甲醇中反应。
在WO 02/053565的说明书中,作为基本的化合物,描述了8-(3-戊氨基)-2-甲基-3-(2-氯-4甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶盐酸盐。该化合物的热稳定性不好,并且对于该化合物而言,在高于某一温度时发生盐酸脱离。而且,该化合物的结晶不好,并且结晶收率非常低。
如上所述,很难稳定地提供以热稳定性差并且低结晶率为特征的盐酸化合物。另外,在制备药物产物的过程中,如果需要加热,将会产生问题,因此作为医药品原料该盐酸化合物是不期望的。
另一方面,在制备在上述文献中描述的式(B)的中间产物的过程中,方案A中使用金属钠的反应[工序b]需要特定的装置以在强碱条件下进行,因此不适于工业生产。而且,在两种工序[工序a]和[工序b]中化合物B-1的总收率低,具体为59%。
在方案B的反应中,在[工序d]中使用的4-碘-5-甲基异噁唑不适于工业生产。这是由于,其合成4-碘-5-甲基异噁唑的原料甲基异噁唑很难得到。而且,制备化合物B-2需要三个工序,并且总收率低,具体为27%。
如上所述,在上述文献中描述的制备方法中存在一些问题,例如,工序数目多,目的产物的收率低以及差的工业生产性。
本发明为解决上述问题锐意研究的结果,发现了新型化合物8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐以及新型结晶,而实现该目的。
而且,本发明发现了制备式(I)化合物的方法
其中所有符号如下述的定义;
该式(I)化合物可以在均相催化剂的条件下,使式(II)化合物与式(III)化合物反应而制备,
Ar-X (II)
其中所有符号如下述的定义;
其中所有符号如下述的定义;
式(I)化合物是用于药物的8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐的中间产物,并且该工序为一步骤和高效的,目的化合物可以以高收率得到。
附图说明
图1显示了8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐的差示扫描热量测定图。
图2显示了8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶盐酸盐的差示扫描热量测定图。
图3显示了8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐结晶的X射线粉末衍射图谱。
图4显示了8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐结晶的红外吸收(IR)图谱。
图5显示了化合物1的单晶X射线构造解析数据。
图6显示了化合物1的单晶X射线构造解析数据。
发明内容
本发明涉及
1. 8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐,
2. 8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐的结晶,
3.根据上述2的结晶,其具有图3显示的X射线粉末衍射图谱,
4.根据上述2的结晶,其在X射线粉末衍射图谱中具有的衍射角2θ是8.96,12.70,13.69,14.98,15.74,16.38,17.63,18.98,19.71,20.49,21.37,22.26,22.88,23.76,24.70,25.79和26.57,
5.根据上述2的结晶,其具有图4显示的红外吸收光谱,
6.根据上述2的结晶,其在红外吸收光谱中,在1652,1595,1549,1220,1168,1141,1115,1034,790,766,548,533和522cm-1具有吸收。
7.8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐的制备方法,其包含是8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶与甲磺酸进行反应,
8.药物组合物,其包含在上述1中描述的化合物作为活性成分,
9.药物组合物,其包含1%或更多的上述2-6任一项中描述的结晶作为活性成分,
10.根据上述8的药物组合物,其是CRF拮抗剂,
11.根据上述8的药物组合物,其是CRF介导的疾病的预防和/或治疗剂,
12.根据上述11的药物组合物,其中CRF介导的疾病为神经精神病或者消化系统疾病,
13.根据上述12的药物组合物,其中神经精神病是情感障碍、焦虑症、与应激相关的障碍、进食障碍、由于使用精神作用物质的症状或依赖症、器质性精神紊乱、精神分裂症或者注意力缺陷多动症,
14.根据上述12的药物组合物,其中消化系统疾病是过敏性肠综合症或者应激诱导的胃肠道紊乱,
15.根据上述13的药物组合物,其中情感障碍是抑郁、单次发作抑郁、循环发作抑郁、产后精神抑郁、儿童虐待诱导的抑郁、双相情感性障碍或月经前焦虑症,
16.药物,其包含8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐以及一种或多种药物,该药物选自三环抗抑郁药、四环类抗抑郁剂、单胺氧化酶抑制剂、血清素-去甲肾上腺素再吸收抑制剂、选择性血清素再吸收抑制剂、血清素再吸收抑制剂、精神兴奋药、抗焦虑药、抗精神病药物、线粒体苯并二氮类受体配体、NK1拮抗剂、肠胃机能调节剂、5-HT3拮抗剂、5-HT4激动剂、抗胆碱能药物、止泻药、泻药和植物神经调节药,
17.CRF拮抗剂,其包含8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐作为活性成分,
18.注射剂,其包含8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐,
19.根据上述18的注射剂,其包含增溶剂和/或pH值调节剂,
20.拮抗CRF的方法,其包含向哺乳动物给予有效量的8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐,
21.8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐在制备CRF拮抗剂中的用途,
22.式(I)化合物的制备方法
其中所有符号如下述的定义;
该方法包含在均相催化剂的条件下,使式(II)化合物与式(III)化合物反应
Ar-X (II)
其中Ar是可以被取代的苯、萘、吡啶、1,3-二噁茚满或者苯并噻二唑,X是卤原子;
其中R1是(i)C1-8烷基,(ii)C2-8烯基,(iii)C2-8炔基,(iv)三氟甲基,(v)C3-10单或双碳环,(vi)包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环,(vii)由1~2个选自下述取代基取代的C1-4烷基,所述取代基为三氟甲基,NR3R4(其中R3和R4各自独立地是(i)氢,(ii)C1-4烷基,(iii)C3-10单或双碳环,(iv)包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环,或者(v)由C3-10单或双碳环或者包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环所取代的C1-4烷基),OR5(其中R5是(i)氢,(ii)C1-4烷基,(iii)C5-6碳环,(iv)包含1-2个氮、1个氧和/或1个硫的5-或6-员杂环,或者(v)由C5-6碳环或者包含1-2个氮、1个氧和/或1个硫的5-或6-员杂环取代的C1-4烷基),S(O)nR6(其中n是0、1或2,R6是(i)C1-4烷基,(ii)C5-6碳环,(iii)包含1-2个氮、1个氧和/或1个硫的5-或6-员杂环,或者(iv)由C5-6碳环或者包含1-2个氮、1个氧和/或1个硫的5-或6-员杂环所取代的C1-4烷基),COR5,COOR5,CONR3R4,C3-10单或双碳环和包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环;M是金属原子,
以及
23.根据上述22的制备方法,其中均相催化剂是钯系催化剂。
本发明的8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐(此后称为化合物(1))是新型化合物。
更加令人惊讶的是,在由图1所示的DSC图中,化合物(1)在196.1℃具有吸热峰,因此在热稳定性方面是优异的。
另一方面,描述在WO 02/053565中的8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶盐酸盐的DSC图示于图2。在图2中没有显示出如图1所述的稳定的DSC曲线,并且该曲线在40℃附近一度显著地变化,然后在超过50℃后逐渐地变化。
从这些结果,可以确定盐酸盐化合物虽然是对热不稳定的化合物,但是本发明的甲磺酸盐化合物是具有优异的热稳定性的化合物。由于盐的不同对于热稳定性有如此大的影响是令人惊讶的,并且也不是容易想到的。
另外,本发明化合物在溶解性和分散性方面是非常优异的。本发明化合物的结晶收率非常高,在下述说明书的实施例中得到了高达98%的收率,而且本发明化合物适于作为医药品原料用于工业生产。
具有这些优异性能的本发明化合物(1),是可以被稳定地提供的,是适于工业生产的,并且在制剂形成方面是优异的。
毒性
化合物(1)的毒性非常低,因此该化合物在医药用途中被认为是安全的。
工业适应性
在医药品中的应用
化合物(1)可与CRF受体结合并显示CRF受体拮抗活性,在预防和/或治疗与CRF相关的疾病,例如,神经精神病、消化系统疾病、呼吸系统疾病、内分泌系统疾病、代谢系统疾病、循环系统疾病、皮肤疾病、泌尿生殖系统疾病、眼部疾病、肌骨骼系统疾病方面是有用的。
更具体地,作为神经精神病,例如可以列举情感障碍,例如抑郁、单次发作抑郁、循环发作抑郁、产后精神抑郁、儿童虐待诱导的抑郁、双相情感性障碍、月经前焦虑症;焦虑症,例如与焦虑相关的障碍、惊恐性障碍、强制性障碍、恐怖症(例如恐高症、幽居恐怖症、广场恐怖症、社会恐怖);与应激相关的障碍,例如创伤后应激障碍(PTSD)、应激诱导的免疫抑郁、应激诱导的头疼、应激诱导的发热、应激诱导的疼痛、手术诱导的应激,手术诱导的胃肠障碍、过敏性肠综合症;摄食障碍,例如神经性厌食症、暴食症、神经性呕吐症;由于使用精神作用物质的症状或依赖症,例如戒断症状、酒精中毒、药物中毒、药物依赖;器质性精神障碍,例如阿尔茨海默氏痴呆症、多梗塞性痴呆症;精神分裂症;注意力缺陷多动症;神经变性疾病,例如阿尔茨海默氏病、帕金森氏病、亨延顿氏病、肌萎缩性侧索硬化;疼痛;惊厥性病症,例如痉挛、肌肉痉挛;癫痫病症,例如癫痫病、发作、偏头痛;或者睡眠障碍,例如非器质性睡眠障碍、纤维肌痛诱导的睡眠障碍。
消化系统疾病例如可列举,消化性溃疡;炎症性肠疾病,例如溃疡性大肠炎,克隆氏病;过敏性肠综合症;应激诱导的胃肠道紊乱;腹泻和便秘。
呼吸系统疾病例如可列举,哮喘、支气管感染、慢性阻塞性肺疾病和过敏性鼻炎。
内分泌系统疾病例如可列举,甲状腺机能障碍综合症、库兴氏病和抗利尿激素不适合分泌综合症。
代谢系统疾病例如可列举,肥胖和低血糖。
循环系统疾病例如可列举,高血压、缺血性心脏病、心动过速、充血性心力衰竭和脑血管疾病。
皮肤疾病例如可列举,特应性皮炎、过敏性接触性皮炎和牛皮癣。
泌尿生殖系统疾病例如可列举,泌尿障碍、尿频和尿失禁。
眼部疾病例如可列举葡萄膜炎。
肌骨骼系统疾病例如可列举,慢性风湿性关节炎、骨关节炎和骨质疏松。
可以给予将化合物(1)与其它药物联合所得到的联合剂以达到下述目的:
1)为了补充和/或增强本发明化合物的预防和/或治疗效果;
2)为了提高本发明化合物的动力学和/或吸收以及降低剂量;和/或
3)为了消除本发明化合物的副作用。
化合物(1)与其它药物的联合物可以以在一个制剂中包含这些组分的剂型给予,或者以分开的制剂给予。当这些药物通过分开的制剂给予时,可以同时或在不同时间给予它们。在后一种情况中,可以在其它药物之前给予化合物(1)。或者,可以在化合物(1)之前给予其它药物。这些药物的给药方法可以相同或不同。
对于用上述联合制剂能够起到预防和/或治疗效果的疾病没有特别的限制,只要是补充和/或增强化合物(1)治疗效果的疾病即可。
用于补充和/或增强化合物(1)在情感障碍方面的预防和/或治疗效果的其它药物的例子包含,抗抑郁剂,例如三环类抗抑郁剂、四环类抗抑郁剂、单胺氧化酶(MAO)抑制剂、血清素-去甲肾上腺素再吸收抑制剂(SSRI)、血清素再吸收抑制剂;神经兴奋剂;抗焦虑药;安定药;线粒体苯并二氮类受体(MBR)配体;NK1拮抗剂等。
用于补充和/或增强化合物(1)在焦虑症方面的预防和/或治疗效果的其它药物的例子包含,抗焦虑药,例如苯并二氮类抗焦虑药、噻烯杂类抗焦虑药、非苯并二氮类抗焦虑药;MBR配体等。
用于补充和/或增强化合物(1)在过敏性肠综合症方面的预防和/或治疗效果的其它药物的例子包含,肠胃机能调节剂、5-HT3拮抗剂、5-HT4激动剂、抗胆碱药、止泻药、泻药、自律神经调节剂、抗抑郁剂、抗焦虑药等。
抗抑郁剂例如可列举,三环类抗抑郁剂,例如盐酸阿米替林、盐酸丙咪嗪、盐酸氯米帕明、盐酸度硫平、盐酸地昔帕明、盐酸洛非帕明、马来酸曲米帕明、阿莫沙平;四环类抗抑郁剂,例如盐酸麦普替林、盐酸米安舍林、马来酸司普替林;MAO抑制剂,例如盐酸沙夫肼;SNRI,例如盐酸米那普仑、盐酸文拉法辛;SSRI,例如马来酸氟戊肟胺、盐酸帕罗西汀、盐酸氟西汀、盐酸西酞普兰;血清素再吸收抑制剂,例如盐酸曲唑酮。
抗焦虑药例如可列举,苯并二氮类抗焦虑药,例如阿普唑仑、奥沙西泮、奥沙唑仑、氯噁唑仑、二钾氯氮、氯氮、地西泮、托非索泮、三唑仑、普拉西泮、氟地西泮、氟他唑仑、氟托西泮、溴西泮、美沙唑仑、美达西泮、氯氟乙酯、劳拉西泮;噻烯杂类抗焦虑药,例如依替唑仑、氯噻西泮;非-苯并二氮类抗焦虑药,例如坦度螺酮柠檬酸盐和hydroxylzinehydrochloride。
精神兴奋药例如可列举,盐酸哌甲酯和佩默林。
安定药例如可列举,舒必利,盐酸曲唑酮,血清素-多巴胺拮抗剂例如利哌利酮、盐酸哌罗匹隆水合物、富马酸喹硫平和奥氮平。
胃肠调节药例如可列举,马来酸曲美布汀和聚卡波非钙。
5-HT3拮抗剂例如可列举阿洛司琼。
5-HT4激动剂例如可列举,替加色罗、西沙必利和柠檬酸莫沙必利。
对于化合物(1)和其它药物的重量比没有特殊限制。
可以给予两种或更多其它药物的任何联合。
而且,用于补充和/或增强化合物(1)的预防和/或治疗效果的其它药物不仅包含现已发现的那些,还包含基于上述机制将会发现的那些。
制剂例如可列举,用于经口给药的固体制剂、内服用液体制剂,以及用于肠胃外给予的注射剂、外用剂、栓剂。
用于经口给药的固体制剂包含片剂、药丸、胶囊、粉末、颗粒等。胶囊包含硬胶囊和软胶囊。
这些用于内服的固体制剂,按照常法使用未经修饰的活性物质或者活性物质与下述物质的混合制备成为制剂,其中所述物质为赋形剂(乳糖、甘露醇、葡糖糖、微晶纤维素、淀粉等),粘合剂(羟丙纤维素、聚乙烯吡咯烷酮、硅酸镁铝等),崩解剂(羧甲基纤维素钙等),润滑剂(硬脂酸镁等),稳定剂(例如抗氧剂例如亚硫酸盐、焦亚硫酸钠、抗坏血酸),增溶剂(谷氨酸,天冬氨酸,聚山梨酯类例如聚山梨酯20、聚山梨酯60、聚山梨酯65、聚山梨酯80;聚乙二醇类例如聚乙二醇200、聚乙二醇400、聚乙二醇1000、聚乙二醇1500、聚乙二醇4000、聚乙二醇6000、聚乙二醇20000;乙醇,甘油,羧甲基纤维素等)。如果必要,也可以用包衣剂(蔗糖、凝胶、羟丙纤维素、羟丙基甲基纤维素邻苯二甲酸酯等)包衣。也可以用两层或多层进行包衣。而且,在其范围中还包含用可吸收物质例如明胶制得的胶囊。
内服用经口给药的液体制剂包含可药用含水溶液、混悬液、乳液、糖浆、酏剂等。这些液体制剂是通过在常用稀释剂(纯净水、乙醇或其混合物等)中溶解、混悬或乳化活性物质而制备的。这些液体剂型还可以包含一些添加剂例如湿润剂、悬浮剂、乳化剂、甜味剂、香味剂、香料、防腐剂、缓冲液等。
肠胃外给药的注射剂包含溶液、混悬液、乳液和在使用前溶解或悬浮的固体注射剂。这样的注射剂是通过在溶媒中溶解、混悬或乳化活性物质而使用。该溶媒包含例如注射用蒸馏水,生理盐水,植物油,醇例如丙二醇、聚乙二醇和乙醇,及其混合物。注射剂还可以包含稳定剂(例如,抗氧剂例如亚硫酸盐、焦亚硫酸钠、抗坏血酸),增溶剂(例如,谷氨酸,天冬氨酸,聚山梨酯类例如聚山梨酯20、聚山梨酯60、聚山梨酯65、聚山梨酯80;聚乙二醇类例如聚乙二醇200、聚乙二醇400、聚乙二醇1000、聚乙二醇1500、聚乙二醇4000、聚乙二醇6000、聚乙二醇20000;乙醇;甘油;羧甲基纤维素等),pH调节剂(例如,盐酸、柠檬酸、柠檬酸钠、醋酸、酒石酸、琥珀酸、精氨酸、单乙醇胺、二乙醇胺、三乙醇胺、葡甲胺、氢氧化钠、氢氧化钾、碳酸氢钠、碳酸钠),混悬剂,乳化剂,无痛剂(例如,三氯叔丁醇、肌氨酸酐、肌醇),缓冲剂(例如,磷酸、磷酸三钠、磷酸二氢钠、磷酸氢二钾、磷酸二氢钾、磷酸二氢钠),防腐剂(例如,尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、尼泊金丁酯)等。这样的注射剂可以通过在最终步骤进行灭菌或者进行无菌步骤而制备。或者,也可以制备无菌的固体产品例如冻干产品,并在使用前用注射用无菌水或其它溶媒例如生理盐水、5%葡萄糖溶液溶解而使用。
肠胃外的外用制剂包含软膏、凝胶剂、乳剂、热敷剂、贴剂、搽剂、喷雾剂、吸入剂、喷剂、滴眼剂和滴鼻剂等。这样的制剂包含活性物质,并且可以通过已知方法或通常使用的处方进行制备。
肠胃外给药的其它组合物包含栓剂和用于阴道给药的阴道栓剂,其包含一种或多种活性物质,并且按照通常使用的处方进行制备。
本发明的化合物(1)是以具有以下数据为特征的新型结晶。
即,该结晶是以如图3所示由Cu-Kα照射得到的X射线粉末衍射图谱以及以示于表1的衍射角2θ的数据和相对强度为特征的。
表1
衍射角(2θ) | 相对强度 |
8.96 | 44 |
12.70 | 13 |
13.69 | 21 |
14.98 | 10 |
15.74 | 20 |
16.38 | 13 |
17.63 | 44 |
18.98 | 19 |
19.71 | 45 |
20.49 | 32 |
21.37 | 99 |
22.26 | 32 |
22.88 | 31 |
23.76 | 40 |
24.70 | 27 |
25.79 | 100 |
26.57 | 22 |
另外,该结晶是以红外吸收(IR)光谱在1652,1595,1549,1220,1168,1141,1115,1034,790,766,548,533,522cm-1处的吸收为特征的,并且由ATR法测得的该IR光谱示于图4。
而且,该结晶的特征还在于在196.1℃处有吸收峰,该DSC图示于图1。
化合物(1)的结晶的特征在于在本说明书所描述的理化性质,但是由于该性质上多少有变化,所以不应该死板地理解各分析数据。
例如,在从X射线粉末衍射图谱的特征方面鉴定结晶的同一性时,衍射角(2θ)以及全部图像均是重要的,结晶强度可以根据结晶生长方向、粒子大小和测定条件而多少发生变化。在IR光谱中,在确定结晶的同一性时,全部图像是重要的,并且其根据测定条件多少发生变化。在DSC的数据中,在确定结晶的同一性时,全部图像是重要的,并且其根据测定条件多少发生变化。
因此,在X射线衍射图谱、IR光谱和DSC中,具有与化合物(1)结晶相似的数据和图案的结晶,均包含在本发明化合物(1)结晶的范围内。
本发明化合物(1)的结晶,优选的晶型具有如图3所示的X射线粉末衍射图谱和/或图4所示的IR光谱,但是也可以是与在将来发现的不同晶型的混合物,并且可以是与化合物(1)的非结晶物质的混合物。
本发明化合物(1)的结晶除了对于加热稳定外,对于湿度和光均是稳定的。
另一方面,式(I)化合物在制备8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐中是重要的中间产物。
本发明式(I)化合物的制备方法是可以高收率地得到目标化合物,并解决现有技术中的问题。本发明的制备方法示于方案1。
方案1
在方案1中,所有符号如下述的定义。
式(I)化合物可以通过本发明的制备方法,由式(II)化合物通过一个工序而制备。
工序[1]在有机溶剂,例如1,2-二甲氧基乙烷、二乙二醇二甲醚、甲苯、二甲苯、二甲基酰胺、环戊基甲醚、四氢呋喃、二噁烷中;在碱例如叔丁氧基钠、叔丁氧基钾、叔丁氧基锂、氢化钠、碳酸钠、碳酸钾、碳酸锂、磷酸氢二钾、磷酸钠的存在下;使用均相催化剂在70~120℃,在存在或不存在碘化物的条件下进行。
因为各反应试剂均可容易地得到、反应为一步并且可以高收率地得到目标化合物,所以本发明的制备方法在工业生产中是非常优异的方法。
本发明中优选的均相催化剂为钯类均相催化剂。例如可列举四(三苯基膦)钯、醋酸钯、三(二苯亚甲基丙酮)二钯和氯化钯。使用的量为催化剂量,优选相对于原料的量为0.1~20mol%,更优选的量为0.25 to 10mol%,特别优选0.25 to 5mol%。
另外,在本发明中的均相催化剂可以仅是均相催化剂其或者是均相催化剂和配体的组合。配体可列举,三苯基膦、2,2′-二(二苯基膦基)-1,1′-二萘基、9,9′-二甲基-4,5-二(二苯基膦基)呫吨、1,1′-二(二苯基膦基)二茂络铁、1,2-二(二苯基膦基)乙烷、1,3-二(二苯基膦基)丙烷、1,4-二(二苯基膦基)丁烷、三-2-间-三膦、三-对-甲苯基膦、三-邻-甲苯基膦、三(2-甲氧基苯基)膦、三(3-甲氧基苯基)膦、三(4-甲氧基苯基)膦、1,2-二(二苯基膦基)苯、三甲基硅烷基膦、三(4-氟苯基)膦、三(五氟苯基)膦、环己基二苯基膦、二环己基苯基膦、三(3-磺苯基)膦三盐酸化物、二(2-二苯基膦基苯基)醚、顺-1,2-二(二苯基膦基)乙烯、二苯五氟苯基膦、2-(二-叔丁基膦基)联苯、2-(二环己基膦基)联苯、2-二环己基膦基-2′-(N,N-二甲氨基)联苯。优选的配体是1,2-二(二苯基膦基)乙烷、三-2-间-甲苯基膦、三-对-甲苯基膦以及2,2′-二(二苯基膦基)-1,1′-二萘基。
在本发明中,均相催化剂或者均相催化剂和配体的组合,优选四(三苯基膦)钯本身,醋酸钯和1,2-二(二苯基膦基)乙烷,醋酸钯和三-2-间-甲苯基膦,醋酸钯和三-对-甲苯基膦,醋酸钯和2,2′-二(二苯基膦基)-1,1′-二萘基,三(二苯亚甲基丙酮)二钯和1,2-二(二苯基膦基)乙烷,三(二苯亚甲基丙酮)二钯和三-2-间-甲苯基膦,三(二苯亚甲基丙酮)二钯和三-对-甲苯基膦,三(二苯亚甲基丙酮)二钯和2,2′-二(二苯基膦基)-1,1′-二萘基。
在本发明中,碘化物是指可以在反应溶液中产生碘离子的化合物。例如,碘化钠、碘化钾、碘化锂、碘化铷、碘化铯、碘化镁、二碘化锰、碘化铁、碘化钴、碘化镍、碘化亚铜、碘化锌、碘化银、碘化季铵(例如,碘化四-正丁基胺)、碘酒。在反应中碘化物的使用量为相对于式(II)化合物的0.3~2.0当量。优选0.3~1.0当量。
在本发明中,当目标化合物具有羟基、羧基、SH或氨基作为取代基时,该反应可以使用将羟基、羧基、SH或氨基用保护基团保护了的化合物来进行,然后采用适于保护基团的脱保护反应。
可以使用例如甲基、乙基、烯丙基、叔丁基、三氯乙基、苄基(Bn)、苯甲酰甲基、对-甲氧基苄基、三苯甲基、2-氯三苯甲基或者与基团相结合的固相载体,作为羧基的保护基团。
可以使用例如甲基、三苯甲基、甲氧基甲基(MOM)、1-乙氧基乙基(EE)、甲氧基乙氧基甲基(MEM)、2-四氢吡喃基(THP)、三甲基硅烷基(TMS)、三乙基甲硅烷基(TES)、叔丁基二甲基甲硅烷基(TBDMS)、叔丁基二苯基甲硅烷基(TBDPS)、乙酰基(Ac)、新戊酰基、苯甲酰基、苄基(Bn)、对-甲氧基苄基、烯丙氧基羰基(Alloc)和2,2,2-三氯乙氧基羰基(Troc)作为羟基的保护基团。
可以使用例如苄氧基羰基、叔丁氧基羰基、烯丙氧基羰基(Alloc)、1-甲基-1-(4-二苯基)乙氧基羰基(Bpoc)、三氟乙酰基、9-芴基甲氧基羰基、苄基(Bn)、对-甲氧基苄基、苄氧基甲基(BOM)和2-(三甲基硅烷基)乙氧基甲基(SEM)作为氨基和脒基的保护基团。
可以使用苄基、甲氧基苄基、甲氧基甲基(MOM)、2-四氢吡喃基(THP)、二苯基甲基和乙酰基(Ac)作为巯基的保护基团。
用于保护羧基、羟基或氨基的基团,除了上述保护基团之外,其它可以容易地和选择性地被去除的基团也是优选的。例如可以使用描述在T.W.Greene,Protective Groups in Organic Synthesis,Wiley,New York,1999中的基团。
在本发明中,“环可以被取代基取代的苯、萘、吡啶、1,3-二噁茚满或苯并噻二唑”中的“取代基”是指(a)C1-8烷基,(b)C2-8烯基,(c)C2-8炔基,(d)卤原子,(e)三氟甲基,(f)三氟甲氧基,(g)氰基,(h)硝基,(j)NR3R4,(k)OR5,(l)SH,(m)S(O)nR6,(n)COR5,(o)COOR5,(p)CONR3R4,(q)NR7COR5,(r)NR7COOR5,(s)NR3CONR3R4,(t)C3-10单或双碳环,(u)包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环,或者(v)由选自卤原子、三氟甲基、三氟甲氧基、氰基、硝基、NR3R4、OR5、=N-OR5、SH、S(O)nR6、COR5、COOR5、CONR3R4、C3-10单或双碳环、以及包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环中的1-2个取代基所取代的C1-4烷基。
R3、R4、R5、R6和n如下述的定义。
R7是(i)氢,(ii)C1-8烷基,(iii)C2-8烯基,(iv)C2-8炔基,(v)C3-10单或双碳环,(vi)包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环,或者(vii)由选自卤原子、三氟甲基、OCF3、氰基、硝基、NR3R4、OR5、=N-OR5、SH、S(O)nR6、COR5、COOR5、CONR3R4、C3-10单或双碳环,以及包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环中的1-2个取代基所取代的C1-4烷基。
在本发明中,“环可以被取代基取代的苯、萘、吡啶、1,3-二噁茚满或苯并噻二唑”的优选取代基是C1-8烷基;卤原子;三氟甲基;三氟甲氧基;氰基;NR3aR4a,其中R3a和R4a各自独立地是氢或C1-4烷基;OR5a,其中R5a是氢或者C1-4烷基;S(O)nR6a,其中R6a是C1-4烷基;CHO;COOR5a;CONR3aR4a;C3-7环烷基;苯基;萘基;呋喃基;噻吩基;吡咯基;吡啶基;或者由选自卤原子、三氟甲基、三氟甲氧基、氰基、NR3aR4a、OR5a、CHO、COOR5a、CONR3aR4a、C3-7环烷基、苯基、萘基、呋喃基、噻吩基、吡咯基和吡啶基中的1-2个取代基所取代的C1-4烷基。
在本发明中,优选的Ar是可以被上述取代基取代的苯、吡啶或苯并噻二唑。
在本发明中,用X表示的卤原子是氯、溴、氟或碘,其中优选氯和溴。
在本发明中,用M表示的金属原子是钠、钾或锂,其中优选钠。
在本发明中,优选的R1是(i)C1-8烷基,(ii)C2-8烯基,(iii)C2-8炔基,or(iv)由选自三氟甲基、NR3R4、OR5、S(O)nR6、COR5、COOR5、CONR3R4、C3-10单或双碳环、以及包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环中的1-2个取代基所取代的C1-4烷基。
特别地,优选的R1是CH2-R2。优选地R2是(i)C1-7烷基,(ii)C2-7烯基,(iii)C2-7炔基,或者(iv)三氟甲基,NR3aR4a,OR5a,S(O)nR6a,COR5a,COOR5a,CONR3aR4a,C3-10单或双碳环或包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环,或者由它们取代的亚甲基。特别地,优选的R2是(i)C1-7烷基,或者(ii)三氟甲基,OR5a,S(O)nR6a,C3-7环烷基,苯基,呋喃基,噻吩基,吡咯基或吡啶基,或者由它们取代的亚甲基,其中R3a、R4a、R5a和R6a如上述的定义。
在本说明书中,C1-4烷基包含甲基、乙基、丙基、丁基及其同分异构体。
在本说明书中,C1-8烷基包含甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基及其同分异构体。
在本说明书中,C2-8烯基包含具有1-3个双键的乙基、丙基、丁基、戊基、己基、庚基、辛基及其同分异构体。例如,乙烯基,丙烯基,丁烯基,戊烯基,己烯基,己二烯基,庚烯基,庚二烯基,辛烯基和辛二烯基。
在本说明书中,C2-8炔基包含具有1-3个三键的乙基、丙基、丁基、戊基、己基、庚基、辛基及其同分异构体。例如,乙炔基,丙炔基,丁炔基,戊炔基,己炔基,己二炔基,庚炔基,庚二炔基,辛炔基和辛二炔基。
在本说明书中,卤原子包含氟、氯、溴和碘。
在本说明书中,C5-6碳环是C5-6碳环芳基或其部分饱和或全部饱和物。例如可列举环戊烷、环己烷、环戊烯、环己烯、环戊二烯、环己二烯和苯。
在本说明书中,C3-7环烷基是环丙烷、环丁烷、环戊烷、环己烷或者环庚烷。
在本说明书中,C3-10单或双碳环是C3-10单或双碳环芳基或其部分饱和或全部饱和物。例如可列举环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环戊烯、环己烯、环戊二烯、环己二烯、苯、并环戊二烯、茚、萘、薁、全氢化并环戊二烯、茚满、全氢化茚、四氢化萘、全氢化萘以及全氢化薁。
在本说明书中,包含1-2个氮、1个氧和/或1个硫的5-或6-员杂环是包含1-2个氮、1个氧和/或1个硫的5-或6-员杂环芳基或者其部分饱和或全部饱和物。例如可列举吡咯、咪唑、吡唑、吡啶、吡嗪、嘧啶、哒嗪、呋喃、吡喃、噻吩、thiain(噻喃)、噁唑、异噁唑、噻唑、异噻唑、吡咯啉、吡咯烷、哌啶、咪唑啉、四氢咪唑、吡唑啉、吡唑烷、哌嗪、全氢化嘧啶、全氢化哒嗪、二氢呋喃、四氢化呋喃、四氢化吡喃、二氢噻吩、四氢化噻吩、tetrahydrothiain、吗啉和硫吗啉。
在本说明书中,包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环是包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员单或双杂环芳基或其部分饱和或全部饱和物。
上述包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员单或双杂环芳基是例如吡咯、咪唑、吡唑、三唑、四唑、吡啶、吡嗪、嘧啶、哒嗪、氮杂、二氮杂、呋喃、吡喃、oxepine、噻吩、thiain(噻喃)、thiepine、噁唑、异噁唑、噁二唑、噁嗪、噁二嗪、噁氮杂(oxazepine)、噁二氮杂(oxadiazepine)、噻唑、异噻唑、噻二唑、噻嗪、噻二嗪、噻氮杂(thiazepine)、噻二氮杂(thiadiazepine)、吲哚、异吲哚、吲嗪、苯并呋喃、异苯并呋喃、苯并噻吩、异苯并噻吩、吲唑、喹啉、异喹啉、喹嗪、酞嗪、萘啶、喹噁啉、喹唑啉、噌啉、苯并噁唑、苯并噁二唑、苯并噻唑、苯并咪唑、苯并呋咱、苯并噻二唑或苯并三唑。
上述部分或全部饱和的包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员单或双杂环芳基是例如氮丙啶、氮杂环丁烯、氮杂环丁烷、吡咯啉、吡咯烷、咪唑啉、四氢咪唑、吡唑啉、吡唑烷、三唑啉、三唑烷、四唑啉、四唑烷、哌啶、哌嗪、二氢吡啶、四氢化吡啶、二氢吡嗪、四氢化吡嗪、二氢嘧啶、四氢化嘧啶、全氢化嘧啶、二氢哒嗪、四氢化哒嗪、全氢化哒嗪、二氢氮杂、四氢化氮杂、全氢化氮杂、二氢二氮杂、四氢化二氮杂、全氢化二氮杂、环氧乙烷、环氧丙烷、二氢呋喃、四氢化呋喃、二氢吡喃、四氢化吡喃、digydrooxepine、tetrahydrooxepine、pergydrooxepine、硫杂丙环、thietane、二氢噻吩、四氢化噻吩、dihydrothiain(二氢噻喃)、tetrahydrothiain(四氢化噻喃)、dihydrothiepine、tetrahydrothiepine、perhydrothiepine、噁唑啉(二氢噁唑)、噁唑烷(四氢化噁唑)、二氢异噁唑、四氢化异噁唑、噁二唑啉(oxadiazoline)(二氢噁二唑)、噁二唑烷(oxadiazolidine)(四氢化噁二唑)、噻唑啉(二氢噻唑)、噻唑烷(四氢化噻唑)、二氢异噻唑、四氢化异噻唑、吗啉、硫吗啉、二氢吲哚、异二氢吲哚、二氢苯并呋喃、全氢化苯并呋喃、二氢异苯并呋喃、全氢化异苯并呋喃、二氢苯并噻吩、全氢化苯并噻吩、二氢异苯并噻吩、全氢化异苯并噻吩、二氢吲唑、全氢化吲唑、二氢喹啉、四氢化喹啉、全氢化喹啉、二氢异喹啉、四氢化异喹啉、全氢化异喹啉、二氢酞嗪、四氢化酞嗪、全氢化酞嗪、二氢萘啶、四氢化萘啶、全氢化萘啶、二氢喹噁啉、四氢化喹噁啉、全氢化喹噁啉、二氢喹唑啉、四氢化喹唑啉、全氢化喹唑啉、二氢噌啉、四氢化噌啉、全氢化噌啉、二氢苯并噁唑、全氢化苯并噁唑、二氢苯并噻唑、全氢化苯并噻唑、二氢苯并咪唑、全氢化苯并咪唑、二氧戊烷、二噁烷、二噁嗪、二噁茚满、色满或异色满。
在本发明中,除了甲磺酸盐之外,使8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶具有优异热稳定性的盐是甲苯磺酸盐、苯磺酸盐和樟脑磺酸盐(D、L或DL)。
本发明化合物的制备:
本发明化合物(1)可以通过使8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶与甲磺酸反应制备。
详细地,将8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶溶解在有机溶剂(例如乙酸乙酯、甲醇、四氢化呋喃、1,2-二甲氧基乙烷、异丙醇、乙腈)中,然后在20-60℃将甲磺酸加入到混合物中。过滤收集沉淀的结晶并干燥,得到目标化合物。
另一方面,可以按照在方案2中描述的方法,制备作为原料的8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶。
方案2
工序[2]是在有机溶剂(例如甲苯、甲醇、异丙醇、乙酸乙酯、醋酸异丙酯、四氢化呋喃、乙腈、二甲基甲酰胺、二甲基亚砜)中,在酸(例如醋酸、丙酸、对甲苯磺酸、甲磺酸)的存在下,使用肼、肼一水合物、或者肼或肼一水合物的60~80wt%水溶液,在10~60℃或者加热回流的条件下进行。
工序[3]是使用酸(例如醋酸、硫酸、甲磺酸)作为溶剂,在50~100℃或者加热回流的条件下;或者在有机溶剂(例如甲醇、乙醇、甲苯、二甲基甲酰胺、1-丙醇、2-丙醇、乙腈)中,在酸(例如醋酸、硫酸、甲磺酸、对甲苯磺酸)的存在下,在50~100℃或加热回流的条件下进行。
在上述使用有机溶剂的反应中酸的使用量比以酸作为溶剂时的使用量少。因此可以容易地移除并且可以安全地进行该反应。
工序[4]是在有机溶剂(例如甲苯、1,2-二甲氧基乙烷、乙腈、四氢化呋喃)中,在碱(例如吡啶、三乙基胺、二甲基苯胺、二甲基氨基吡啶、二异丙基乙基胺、2,6-二甲基吡啶、2-甲基吡啶、N-甲基吗啉、N-乙基吗啉、三-正丙基胺、三-正丁基胺)的存在下,使用磷酰氯,在70~120℃的条件下进行。
工序[5]是在有机溶剂(例如甲苯、二甲苯、1,2-二甲氧基乙烷、二甲基甲酰胺、二甲基胺、二甲基亚砜、2-丙醇、乙腈)中或无溶剂的条件下,在存在或不存在碱(例如三乙基胺、三甲基胺、二异丙基乙基胺、N-甲基吗啉、N-乙基吗啉、三-正丙基胺、三-正丁基胺)的条件下,在80~150℃进行。
在本发明使用甲磺酸的情况下,可以仅使用原料其本身,也可以为了确保安全将其溶解在有机溶剂(例如乙酸乙酯、甲醇、四氢化呋喃、1,2-二甲氧基乙烷、异丙醇、乙腈,正庚烷)滴入。甲磺酸使强腐蚀性的,操作时要注意。
甲磺酸的使用量,相对于8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶,为0.5~2.2当量,优选0.95~1.2当量。
另外,在加入甲磺酸之后,可以进一步加入有机溶剂(例如乙酸乙酯、正庚烷),搅拌得到上述结晶。
本发明化合物(1)可以使用选自可以包含水的低级醇、酯类溶剂中至少一种的溶剂;或者使用上述溶剂的一种或多种以及选自可以包含水的直链烷基类、酯类溶剂、链状的醚类溶剂以及酮类溶剂中至少一种的混合物,进行再结晶而精制。
在本说明书中,低级醇溶剂是指在结构中具有羟基的C1-4烷基溶剂。具体可列举甲醇、乙醇和2-丙醇。
在本说明书中,酯类溶剂是指在结构中具有酯键的溶剂。具体可列举乙酸乙酯。
在本说明书中,直链烷基类溶剂是指在结构中具有直链烷基的溶剂。具体可列举正戊烷、正己烷和正庚烷。
在本说明书中,链状的醚类溶剂是指在结构中具有醚键并且结构是链状的溶剂。醚键的碳取代基可以是链状或者环状。具体可列举1,2-二甲氧基乙烷、环戊基甲基醚、二乙基醚、异丙基醚和甲基叔丁基醚。
在本发明中,酮类溶剂是指在结构中具有酮基的溶剂。具体可列举丙酮等。
在再结晶中溶剂的优选使用量,相对于化合物(1)1g是约1~100mL,更优选约2~50mL,特别优选约5~20mL。
用于再结晶的溶剂可以包含水。水的含量取决于各个溶剂,例如可以0到各个溶剂的饱和量。具体地,在乙酸乙酯的情况下,水的含量为0~3.3%。
该结晶可以在正常温度、加温或者加热的条件下,必要时在减压或正常压力的条件下,进行干燥。
在本说明书的各个反应中,按照本领域普通技术人员所熟知的,伴随加热的反应可以在水浴、油浴、沙浴或者微波炉中进行。
在本说明书的各个反应中,反应生成物可以使用通常的精制方法,例如,通过在常压或减压下蒸馏、使用硅胶或硅酸镁的高效液相色谱、薄层色谱、离子交换树脂、净化树脂(scavenger resin)、柱色谱清洗或再结晶等方法进行精制。精制可以在各个反应进行后或者在几个反应进行后进行。
实施本发明的最佳形式
以下的实施例用于详述本发明,而不是限定本发明。
实施例1
1-氰基-1-(2-氯-4-甲氧基苯基)丙-2-酮:
在氩气氛下,向1-溴-2-氯-4-甲氧基苯(54g)、钠代氰基丙酮(sodium cyanoacetone)(28.2g)以及叔丁氧基钠(51.5g)的1,2-二甲氧基乙烷(243mL)混悬液中,加入四(三苯基膦)钯(7.04g)。将混合物加热回流10.5小时。将反应混合物冷却至25℃,加入甲苯(21.6mL)。在内部温度20~30℃将混合物搅拌1小时。过滤反应混合物,并将得到的固体用甲苯清洗。将得到的固体在2mol/L盐酸/甲苯的混合溶剂中溶解,分离混合物。在有机层中的标题化合物(300.7g)通过使用HPLC内部标准法进行定量。
定量值:71%;
收率:38.7g;
TLC:Rf 0.29(正己烷∶乙酸乙酯=3∶1);
NMR(300MHz,CDCl3):δ7.38(d,J=8.4Hz,1H),7.01(d,J=2.7Hz,1H),6.90(dd,J=8.4,2.7Hz,1H),5.12(s,1H),3.83(s,3H),2.29(s,3H)。
实施例2
1-氰基-1-(2-氯-4-甲氧基苯基)丙-2-酮:
在氩气氛下,向1-溴-2-氯-4-甲氧基苯(120g)在二乙二醇二甲醚(230mL)和1,2-二甲氧基乙烷(90mL)的混合溶液中,于室温在搅拌下加入钠代氰基丙酮(62.6g)、叔丁氧基钠(114.6g)和碘化钠(81.2g),得到混悬液。通过另一工序,在氩气氛下,将二乙二醇二甲醚(40mL)、醋酸钯(426mg)和三苯基膦(1.99
g)的混合物在110℃搅拌约30分钟使之溶解。将该溶液滴入上述混悬液中。将混合物加热到内部温度为110~115℃并搅拌7小时。冷却反应混合物,用乙酸乙酯(480mL)稀释,并用硫酸水溶液(浓硫酸101g/水660mL)清洗。将有机层用10%氯化钠饱和水溶液(360mL)洗两次。向有机层中加入活性炭(3.6g)。将该混合物搅拌1小时后过滤。将滤液用乙酸乙酯(240mL)清洗,以得到1-氰基-1-(2-氯-4-甲氧基苯基)丙-2-酮的溶液(971.7g)。
按照在实施例1中所述的用HPLC的内部标准法进行定量,标题化合物的收率为101.7g。
实施例3
5-氨基-3-甲基-4-(2-氯-4-甲氧基苯基)吡唑:
在氩气氛下,向在实施例1中制备的化合物(38.7g)在甲苯的溶液中,在内部温度10~30℃,按顺序加入醋酸(14.5mL)和水合肼的60%水溶液(17.7mL)。将该混合物在45~55℃的内部温度搅拌7小时。向内部温度冷却为10~30℃的反应溶液中,加入2mol/L盐酸,然后分离混合物。通过加入25wt%氢氧化钠将水层的pH值调整为6.5~7.5。将醋酸异丙酯(216mL)加入到调整了pH值的水层中。在减压下浓缩分离的有机层。加热残渣,加入正庚烷。将溶液的内部温度冷却为10~30℃。析出结晶后,搅拌30分钟。并且,向溶液中加入正庚烷,搅拌混合物1小时。析出的结晶通过过滤进行收集,在减压下在约50℃干燥14小时或者更多,以得到具有下述物理数据的标题化合物(35.5g(94.8area%);取得率:61%(2工序))。
TLC:Rf 0.34(氯仿∶甲醇=10∶1);
NMR(300MHz,CDCl3):δ7.19(d,J=8.1Hz,1H),7.04(d,J=2.7Hz,1H),6.86(dd,J=8.1,2.7Hz,1H),3.83(s,3H),2.14(s,3H)。
实施例4
8-羟基-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶:
在氩气氛下,向在实施例3中制备的化合物(26.0g)在乙醇(109mL)中的溶液中,在10~30℃的内部温度,加入2-氧代环戊烷羧酸乙酯(17.3mL),加入醋酸(18.7mL)。混合物在80~90℃的内部温度加入回流7小时。在将反应混合物冷却至55~65℃的内部温度后,加入甲苯(109ml)。在40~65℃的内部温度,将稀释的溶液搅拌30分钟或更多,然后将该溶液冷却至10~30℃。通过过滤收集析出的结晶,在约50℃减压干燥14小时或更多,以得到具有下述物理数据的标题化合物(33.3g(98.6area%);取得率:92.8%)。
TLC:Rf 0.59(氯仿∶甲醇∶醋酸∶水=50∶10∶1∶1);
NMR(300MHz,DMSO-d6):δ12.04(s,1H),7.31(d,J=8.4Hz,1H),7.18(d,J=2.4Hz,1H),7.00(dd,J=8.4,2.4Hz,1H),3.81(s,3H),2.82(t,J=7.5Hz,2H),2.66(t,J=6.9Hz,2H),2.11(s,3H),2.03(m,2H)。
实施例5
8-氯-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶:
在氩气氛下,向在实施例4中制备的化合物(300g)在甲苯(910mL)中的混悬液中,加入N,N-二异丙基乙基胺(141g),然后滴加磷酰氯(419g)。在80~95℃的内部温度,将混合物搅拌9小时。将内部温度冷却至20~30℃的反应溶液,倒入乙酸乙酯和水的混合溶剂中,搅拌混合物15分钟。将有机层使用碳酸氢钠的饱和溶液和氯化钠的饱和溶液清洗,然后加入活性炭(30g),搅拌1小时后过滤混合物。向滤液中加入N,N-二甲基乙酰胺(600mL)。将该混合物减压浓缩。将具有下述物理数据的标题化合物(316.9g;100%换算)在N,N-二甲基乙酰胺中的溶液,不进行精制用于下一工序。
TLC:Rf 0.42(正己烷∶乙酸乙酯=2∶1);
NMR(300MHz,CDCl3):δ7.28(d,J=8.7Hz,1H),7.07(d,J=2.4Hz,1H),6.90(dd,J=8.7,2.4Hz,1H),3.84(s,3H),3.06(m,4H),2.43(s,3H),2.23(m,2H)。
实施例6
8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶:
在氩气氛下,将在实施例5中制备的化合物(177.6g)在N,N-二甲基乙酰胺(355mL)中的溶液、与三乙基胺(103.2g)和3-氨基戊烷(88.9g)在异丙醇(178mL)中的溶液的混合物,在95~105℃的内部温度搅拌4小时。向内部温度冷却为70~80℃的反应溶液中倒入水。将稀释溶液冷却到50~60℃的内部温度,然后在析出结晶后,搅拌该溶液30分钟。此外,向该溶液中倒入水,并在20~30的内部温度搅拌该稀释溶液1小时。通过过滤收集析出的结晶,在约50℃将得到的结晶减压干燥14小时或更多,以得到标题化合物的粗结晶(174g,(97.4area%),取得率:85%(2工序))。
将得到的结晶(1.0g)在乙醇/水(3/1;2mL)中的溶液在油浴中加热回流。而且,加入乙醇/水(3/1;5mL)。移去油浴,将该溶液放置过夜。通过过滤收集析出的结晶,用乙醇/水(3/1)清洗,在50℃减压干燥14小时或更多,以得到具有以下物理数据的标题化合物(920mg)。
TLC:Rf 0.45(正己烷∶乙酸乙酯=2∶1);
NMR(300MHz,CDCl3):δ7.31(d,J=8.4Hz,1H),7.05(d,J=2.7Hz,1H),6.88(dd,J=8.4,2.7Hz,1H),6.22(brd,J=10.5Hz,1H),3.82(s,3H),3.80(m,1H),3.08(t,J=7.2Hz,2H),2.90(t,J=7.5Hz,2H),2.34(s,3H),2.14(m,2H),1.52-1.82(m,4H),1.01(t,J=7.5Hz,3H)。
实施例7
8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐:
将在实施例6中制备的粗结晶(71.6g)在加热中溶解在乙酸乙酯(250mL)中。在溶液冷却至50℃的内部温度后,向溶液中滴加99.3%甲磺酸(17.3g)。向内部温度冷却为30℃的混合溶液中加入正庚烷,然后将混合物在25℃搅拌30分钟。通过过滤收集得到的结晶,在约50℃减压干燥14小时或更多,以得到作为粉末的标题混合物(87.1g(97.4area%);取得率:98%)。
TLC:Rf 0.17(正己烷∶乙酸乙酯=2∶1);
熔点:196-197℃(未校正,加热金属模式(heated metal block));
NMR(300MHz,CDCl3):δ7.36(d,J=8.4Hz,1H),7.23(d,J=10.5Hz,1H),7.08(d,J=2.4Hz,1H),6.97(dd,J=8.4,2.4Hz,1H),4.03-3.90(m,1H),3.85(s,3H),3.63-3.35(m,2H),3.13(t,J=7.2Hz,2H),2.42(s,3H),2.35-2.25(m)和2.34(s)总共5H,1.90-1.50(m,4H),1.06(t,J=7.5Hz)和1.05(t,J=7.5Hz)总共6H。
结晶的物性数据
实施例7中制备的化合物,以下述条件测定的X射线粉末衍射图谱示于图3中,IR光谱示于图4中,以及DSC图示于图1中。
(1)X射线粉末衍射图谱
装置:由BRUKER制的具有GADD(C2)的BRUKER DISCOVER,
靶:Cu,
过滤器:无,
电压:40kV,
电流:40mA,
曝光时间:5分钟。
(2)红外线吸收(IR)光谱
装置:日本分光制FTIR-660Plus/SENSIR制DURASCOPE,
测定方法:以ATR方法测定结晶,
分解能:4cm-1,
扫描次数:16次。
(3)差示扫描热计(DSC)
装置:SEIKO INSTRUMENT DSC6200,
样品质量:6.35mg,
样品池:铝开放池,
氮气流:20mL/分,
升温速度:5℃/分。
实施例7(1)
将在实施例7中制备的化合物(500mg)置入螺旋管(直径18mm,高40mm)中,然后加入甲醇(0.5mL)和乙酸乙酯(0.5mL)。加上盖后,在油浴中加热该螺旋管。固体溶解后,在避光和室温将混合物冷却,得到单晶的8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐。
化合物(1)的单晶X射线结构分析数据示于图5和图6。
测定条件
装置:Rigaku Co.制R-AXIS RAPID型单晶X射线结构分析装置,
分析软件:Crystal Structure produced by Rigaku Co.,
测定温度:室温,
靶:CuKα(λ=1.54187),
R=0.059。
结晶学数据如下所述。
晶格常数:a=8.165(2),b=38.140(8),c=7.947(2),
β=94.32(2)°,
空间群:P21/c
实施例8
8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲苯磺酸盐:
将在实施例6中制备的粗结晶(100mg)在加热下溶解于四氢化呋喃(0.5mL)中。将混合物冷却至60℃,并将对甲苯磺酸(47.7mg)加入该混合物。将混合物冷却至25℃,加入甲基叔丁基醚(2.5mL)。通过过滤收集析出的结晶。在50℃减压干燥得到的结晶14小时或更多,以得到具有下述物理数据的作为粉末的标题化合物(105mg,(97.6area%);取得率:71.1%)。
TLC:Rf 0.38(正己烷∶乙酸乙酯=2∶1);
NMR(200MHz,CDCl3):δ7.51(d,J=8.4Hz,2H),7.31(d,J=8.6Hz,1H),7.30-7.20(m,1H),7.09(d,J=8.4Hz,2H),6.93(d,J=2.6Hz,1H),6.69(dd,J=8.6,2.6Hz,1H),4.10-3.90(m,1H),3.80-3.35(m)和3.72(s)总共5H,3.14(t,J=7.2Hz,2H),2.40-2.20(m,2H),2.35(s,3H),2.33(s,3H),1.90-1.60(m,4H),1.06(t,J=7.5Hz)和1.05(t,J=7.5Hz)总共6H。
药理活性
通过下述实验例,确认化合物(1)具有CRF受体拮抗活性。
实验例1
结合测定:
制备细胞膜
在将表达人CRF1受体的细胞系(亲株:CHO-K1细胞)培养达到汇合后,使用刮器收集细胞。用PBS清洗收集的细胞两次,然后混悬在用冰冷却的结合测定缓冲液(Tris-HCl(50mM,pH 7.0)、EDTA(2mM,pH 8.0)和MgCl2(10mM))中。将悬浮的细胞用Downs型均化器均化后,在10,000g进行离心以收集膜级分。收集的细胞膜级分使用少量结合测定缓冲液再次悬浮,并用所述缓冲液稀释为1mg/mL。将因此得到的膜级分用于结合测定。
结合测定
将50μL用结合测定缓冲液配制为0.5nM的[125I]h/r CRF加入1.5mL的硅化处理的管中。将各为1μL的稀释为适当倍数的化合物、DMSO(用于总结合的用途)和100μM的h/r CRF溶液(用于非特异结合的用途)加入管中。向管中加入50μL膜级分,以开始反应([125I]h/r CRF的终浓度:0.25nM),然后在室温培养2小时。反应结束后,将管以20,000g离心,收集膜级分。除去上清,使用冷却的包含0.01% Triton X-100的PBS(-)清洗沉淀物两次。用γ-计数器测定各个管的放射性值。
特异性结合由从每个结合值中减去非特异性结合而得到。
结果显示化合物(1)对于CRF1受体显示了强的结合活性(IC50:<1μM)。
实验例2
受体拮抗活性(环磷腺苷测定):
使用10%胎牛血清和含有抗生素和抗真菌剂的1%F-12培养基,在37℃、5%二氧化碳、95%空气的条件下,培养表达人CRF1受体的细胞系。在测定环磷腺苷的前一天,以1×104细胞/孔将细胞接种在96孔板中。在测定当天,使用F-12培养基清洗两次,向各孔中添加F-12培养基/1mM 3-异丁基-1-甲基黄嘌呤(测定培养基)(178μL)。将其在37℃培养10分钟后,添加不同浓度的测试化合物溶液(2μL),将DMSO(2μL)添加到CRF组和空白组中。将其在37℃培养15分钟后,将10nM的包含人/大鼠CRF的测定培养基(20μL)加入到测试化合物组和CRF组。向空白组中,加入包含0.00001%醋酸的测定培养基(20μL)。然后,在37℃培养15分钟。除去上清,用冰冷却以停止反应。并且,全部反应在3个孔中进行。在细胞内环磷腺苷的累积量通过Biotrak酶免疫测定法(Amersham Biosciences)进行测定。环磷腺苷的累积量是从3孔的平均值中减去空白组的3孔平均值算出的。IC50值是通过以化合物的对数浓度作为自主变量,以环磷腺苷的累积量作为因变量,进行非线性回归分析得到的。
结果显示化合物(1)对于CRF受体具有强的抑制活性(IC50:<1μM)。
制剂例1
按照常法混合下述组分并压片,以得到每片包含10mg活性成分的100万个片剂。
8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7- 10kg
二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐
羧甲基纤维素钙(崩解剂) 2kg
硬脂酸镁(润滑剂) 1kg
微晶纤维素 87kg
制备例2
按照常法混合下述组分。按照常法进行灭菌,向每个安瓿中充填5ml并冻干,以得到每个包含20mg活性成分的100万个安瓿。
8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7- 20kg
二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐
甘露醇 200kg
蒸馏水 5kl
1N盐酸 20~30ml
Claims (23)
1. 8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐。
2. 8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐的结晶。
3.根据权利要求2的结晶,其具有示于图3的X射线粉末衍射图谱。
4.根据权利要求2的结晶,其在X射线粉末衍射图谱中的衍射角2θ为8.96,12.70,13.69,14.98,15.74,16.38,17.63,18.98,19.71,20.49,21.37,22.26,22.88,23.76,24.70,25.79和26.57。
5.根据权利要求2的结晶,其具有示于图4的红外吸收光谱。
6.根据权利要求2的结晶,其在红外吸收光谱中在1652,1595,1549,1220,1168,1141,1115,1034,790,766,548,533和522cm-1处有吸收。
7. 8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐的制备方法,其包含使8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶与甲磺酸反应。
8.药物组合物,其包含在权利要求1所述的化合物作为活性成分。
9.药物组合物,其包含1%或更多的在权利要求2-6任一项中所述的结晶作为活性成分。
10.根据权利要求8的药物组合物,其是CRF拮抗剂。
11.根据权利要求8的药物组合物,其是CRF介导的疾病的预防和/或治疗剂。
12.根据权利要求11的药物组合物,其中CRF介导的疾病是神经精神病或消化系统疾病。
13.根据权利要求12的药物组合物,其中神经精神病是情感障碍、焦虑症、与应激相关的障碍、进食障碍、由于使用精神作用物质的症状或依赖症、器质性精神紊乱、精神分裂症或者注意力缺陷多动症。
14.根据权利要求12的药物组合物,其中消化系统疾病是过敏性肠综合症或者应激诱导的胃肠道紊乱。
15.根据权利要求13所述的药物组合物,其中情感障碍是抑郁、单次发作抑郁、循环发作抑郁、产后精神抑郁、儿童虐待诱导的抑郁、双相情感性障碍或者月经前焦虑症。
16.药品,其包含8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐以及一种或多种选自三环抗抑郁药、四环类抗抑郁剂、单胺氧化酶抑制剂、血清素-去甲肾上腺素再吸收抑制剂、选择性血清素再吸收抑制剂、血清素再吸收抑制剂、精神兴奋药、抗焦虑药、抗精神病药物、线粒体苯并二氮受体配体、NK1拮抗剂、肠胃机能调节剂、5-HT3拮抗剂、5-HT4激动剂、抗胆碱能药物、止泻药、泻药和植物神经调节药中的药物。
17.CRF拮抗剂,其包含8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐作为活性成分。
18.注射剂,其包含8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐。
19.根据权利要求18的注射剂,其包含增溶剂和/或pH值调节剂。
20.拮抗CRF的方法,其包含向哺乳动物给予有效量的8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐。
21. 8-(3-戊氨基)-2-甲基-3-(2-氯-4-甲氧基苯基)-6,7-二氢-5H-环戊二烯并[d]吡唑并[1,5-a]嘧啶甲磺酸盐在制备CRF拮抗剂中的用途。
22.式(I)化合物的制备方法
其中所有符号如下述的定义;
该方法包含在均相催化剂的条件下,使式(II)化合物与式(III)化合物反应
Ar-X (II)
其中Ar是可以被取代基取代的苯、萘、吡啶、1,3-二噁茚满或者苯并噻二唑,X是卤原子;
其中R1是(i)C1-8烷基,(ii)C2-8烯基,(iii)C2-8炔基,(iv)三氟甲基,(v)C3-10单或双碳环,(vi)包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环,(vii)由1~2个选自下述取代基取代的C1-4烷基,所述取代基为三氟甲基,NR3R4(其中R3和R4各自独立地是(i)氢,(ii)C1-4烷基,(iii)C3-10单或双碳环,(iv)包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环,或者(v)由C3-10单或双碳环或者包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环所取代的C1-4烷基),OR5(其中R5是(i)氢,(ii)C1-4烷基,(iii)C5-6碳环,(iv)包含1-2个氮、1个氧和/或1个硫的5-或6-员杂环,或者(v)由C5-6碳环或者包含1-2个氮、1个氧和/或1个硫的5-或6-员杂环取代的C 1-4烷基),S(O)nR6(其中n是0、1或2,R6是(i)C1-4烷基,(ii)C5-6碳环,(iii)包含1-2个氮、1个氧和/或1个硫的5-或6-员杂环,或者(iv)由C5-6碳环或者包含1-2个氮、1个氧和/或1个硫的5-或6-员杂环所取代的C1-4烷基),COR5,COOR5,CONR3R4,C3-10单或双碳环和包含1-4个氮、1-2个氧和/或1-2个硫的3-到10-员的单或双杂环;M是金属原子。
23.根据权利要求22的制备方法,其中均相催化剂是钯系催化剂。
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JPWO2005061508A1 (ja) * | 2003-12-22 | 2007-07-12 | 小野薬品工業株式会社 | 三環式複素環化合物およびその化合物を有効成分とする医薬 |
WO2005087775A1 (ja) * | 2004-03-15 | 2005-09-22 | Ono Pharmaceutical Co., Ltd. | 三環式複素環化合物およびその化合物を有効成分として含有する医薬組成物 |
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CN1030768C (zh) * | 1990-10-09 | 1996-01-24 | 大塚制药株式会社 | 嘧啶衍生物或其药用盐的制备方法 |
US5420128A (en) | 1990-10-09 | 1995-05-30 | Otsuka Pharmaceutical Co., Ltd. | Pyrimidine derivatives, method of manufacturing the same, and androgen inhibitor |
JPH05112571A (ja) | 1990-10-19 | 1993-05-07 | Otsuka Pharmaceut Co Ltd | ピリミジン誘導体 |
EP0795555A4 (en) | 1995-09-28 | 1998-01-07 | Otsuka Pharma Co Ltd | ANALGETICS |
WO1999064422A1 (en) | 1998-06-09 | 1999-12-16 | Neurogen Corporation | Pyrido[2,3-b]indolizine derivatives and aza analogues thereof; crf1 specific ligands |
US6531475B1 (en) | 1998-11-12 | 2003-03-11 | Neurocrine Biosciences, Inc. | CRF receptor antagonists and methods relating thereto |
WO2000027850A2 (en) | 1998-11-12 | 2000-05-18 | Neurocrine Biosciences, Inc. | Crf receptor antagonists and methods relating thereto |
PT1129091E (pt) | 1998-11-12 | 2003-02-28 | Neurocrine Biosciences Inc | Antagonistas de receptor de crf e metodos relacionados |
CA2432148C (en) | 2000-12-28 | 2011-01-18 | Ono Pharmaceutical Co., Ltd. | Tri-heterocyclic compounds and a pharmaceutical comprising them as an active ingredient |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN112225732A (zh) * | 2019-07-15 | 2021-01-15 | 四川科瑞德制药股份有限公司 | 一种新的盐酸哌罗匹隆水合物晶型及其制备方法 |
CN112225732B (zh) * | 2019-07-15 | 2024-01-09 | 四川科瑞德制药股份有限公司 | 一种盐酸哌罗匹隆水合物晶型及其制备方法 |
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NZ544301A (en) | 2008-08-29 |
TWI356058B (en) | 2012-01-11 |
KR20060026060A (ko) | 2006-03-22 |
KR101082227B1 (ko) | 2011-11-09 |
RU2006101986A (ru) | 2006-07-27 |
ATE478873T1 (de) | 2010-09-15 |
NO20056093L (no) | 2006-03-24 |
CA2529561A1 (en) | 2004-12-29 |
MXPA05013917A (es) | 2006-03-09 |
ES2349393T3 (es) | 2010-12-30 |
IL172697A (en) | 2013-05-30 |
WO2004113344A1 (ja) | 2004-12-29 |
US7947697B1 (en) | 2011-05-24 |
CN100422186C (zh) | 2008-10-01 |
NO332186B1 (no) | 2012-07-23 |
EP1637531A1 (en) | 2006-03-22 |
JPWO2004113344A1 (ja) | 2006-07-27 |
ZA200510450B (en) | 2006-12-27 |
CA2529561C (en) | 2012-05-29 |
AU2004249629B2 (en) | 2009-07-30 |
EP1637531A4 (en) | 2008-09-03 |
RU2345995C2 (ru) | 2009-02-10 |
EP1637531B1 (en) | 2010-08-25 |
TW200504064A (en) | 2005-02-01 |
IL172697A0 (en) | 2006-04-10 |
JP4655276B2 (ja) | 2011-03-23 |
AU2004249629A1 (en) | 2004-12-29 |
BRPI0411923A (pt) | 2006-08-15 |
DE602004028820D1 (de) | 2010-10-07 |
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