CN100543016C - 3-杂芳基-3,5-二氢-4-氧代-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺衍生物的中间体化合物 - Google Patents
3-杂芳基-3,5-二氢-4-氧代-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺衍生物的中间体化合物 Download PDFInfo
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Abstract
本发明提供一种通式(Ⅲ)化合物,见右式,其中X为一个氢原子或卤素原子,R1为一个氢原子或一个(C1~C4)烷基,R’和R”,每个相互独立地为一个(C1~C4)烷基。该化合物作为3-杂芳基-3,5-二氢-4-氧代-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺衍生物的中间体化合物。
Description
本申请是国际申请号为PCT/FR03/01027,中国国家申请号为03812222.7,申请日为2003年4月2日,发明名称为“3-杂芳基-3,5-二氢-4-氧代-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺衍生物,其制备和在治疗中的应用”发明专利申请的分案申请。
技术领域
本发明涉及3-杂芳基-3,5-二氢-4-氧代-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺衍生物的中间体化合物。
背景技术
发明内容
本发明首先提供了具有下列通式(I)的化合物。
本发明还提供了通式(I)化合物的制备方法。
本发明进一步提供可用作合成通式(I)化合物的中间体的化合物。
本发明还提供了具有通式(I)的化合物在医药产品或药物组合物中的用途。
本发明的化合物具有通式(I)的结构:
其中
X代表氢或卤素原子;
R1代表一个氢原子或一个(C1~C4)烷基,R2和R3可互相独立地代表一个氢原子和一个(C1~C4)烷基,或R2和R3与它们所连接的氮原子一起形成一个吡咯烷基,哌啶基,吗啉基或4-(C1~C4)烷基哌嗪基,
Het代表一个杂芳基,其为吡啶基,喹啉基,异喹啉基,嘧啶基,吡嗪基或哒嗪基类型的基团,其上可以带有一个或多个卤素原子和/或一个或多个(C1~C4)烷基和/或(C1~C4)烷氧基。
本发明的化合物以碱或酸加成盐的形式存在。这种加成盐构成了本发明的一部分。
这些盐较好用药学上可接受的酸制得,尽管适用于例如纯化或分离式(I)化合物的其它酸的盐同样构成本发明的一部分。
通式(I)的化合物可以水合物或溶剂化物的形式存在;也就是和一分子和更多分子数的水分子或溶剂分子结合。这些水合物和溶剂化物同样也成为本发明的一部分。
在本发明的文本中,
卤素原子是指氟、氯、溴和碘;
(C1~C4)烷基是指直链和支链的饱和脂族基,含1至4个碳原子。举例而言:可以是甲基、乙基、丙基、异丙基,丁基,异丁基和叔丁基;
(C1~C4)烷氧基指带有1至4个碳原子的氧基团,其被如上所述烷基所取代;
在本发明的通式(I)的化合物中,优选的化合物是:
X代表卤素原子;和/或
R1代表一个(C1~C4)烷基;和/或
R2和R3可互相独立地代表一个(C1~C4)烷基,或R2和R3与它们所连接的氮原子一起形成一个吡咯烷基或4-(C1~C4)烷基哌嗪基;和/或
Het代表一个吡啶基类型的杂芳基,其上可以带有一个或多个卤素原子和/或一个或多个(C1~C4)烷基和/或(C1~C4)烷氧基。
更好的是,X,R1,R2,R3和Het全为如上优选化合物中所定义的化合物。最好的是,X是氯原子,R1是甲基。
在本发明所提供的通式(I)化合物中,举例而言,本发明的化合物为如下所列:
1)7-氟-N,N,5-三甲基-4-氧代-3-(吡啶-2-基)-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺
2)盐酸7-氟-N,N,5-三甲基-4-氧代-3-(吡啶-3-基)-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺(1:1)
3)盐酸7-氟-N,N,5-三甲基-4-氧代-3-(吡啶-4-基)-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺(1:1)
4)7-氯-N,N,5-三甲基-4-氧代-3-(吡啶-2-基)-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺
5)7-氯-N,N,5-三甲基-4-氧代-3-(吡啶-3-基)-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺
6)盐酸7-氯-N,N,5-三甲基-4-氧代-3-(吡啶-3-基)-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺(1:1)
7)盐酸7-氯-N,N,5-三甲基-4-氧代-3-(吡啶-4-基)-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺(1:1)
8)7-氯-N,N,5-三甲基-4-氧代-3-(6-甲基吡啶-3-基)-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺
9)7-氯-N,N-二乙基-5-甲基-4-氧代-3-(吡啶-3-基)-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺
10)盐酸4-甲基-1-[2-(7-氯-5-甲基-3-(吡啶-3-基)-4-氧代-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-基]乙酰-1-基]哌嗪(1:1)
11)1-[2-[7-氯-5-甲基-3-(吡啶-3-基)-4-氧代-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-基]乙酰-1-基]吡咯烷
12)盐酸1-[2-[7-氯-5-甲基-3-(吡啶-4-基)-4-氧代-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-基]乙酰-1-基]吡咯烷(1:1)
具通式(1)的化合物可用下列方法制备。
在本说明书的下列部分中,中间体化合物(II),(III),(IV)和(V)是下列流程中所示的化合物。
反应流程
在室温下,在溶剂(如二氯乙烷)中,在Lewis酸(如四氯化钛)存在的条件下,使通式(II)的化合物(其中X和R1如上所定义,R′代表一个(C1~C4)烷基)经通式为ClCOCH2CO2R"的3-氯-3-氧代丙酸酯处理(其中R"为C1-4烷基),得到如通式(III)的二酯。
在催化剂,如4-(二甲基氨基)吡啶,的存在下,通过通式为HNR2R3作用(其中R2和R3如上定义)将通式(III)的二酯中的酮酯官能团转化为酮酰氨得到通式(IV)化合物。
根据第一条制备路线,在极性溶剂中,在酸存在下,通式(IV)化合物和杂芳基肼反应,得到通式(I)的酰胺。
根据第二条制备路线,在催化剂量的酸存在下,通式(IV)的化合物用肼处理并在溶剂(如甲苯)中加热,生成通式(V)哒嗪并吲哚化合物。最后在通式(V)哒嗪并吲哚化合物上发生N-芳基化反应,反应是在杂芳基卤化物或杂芳基硼酸衍生物和金属盐(如铜盐)的存在下进行的,以生成通式(I)化合物。
上面所用的试剂均可从市场上购得,或在文献中有描述,或用文献所述方法或本领域普通技术人员已知的方法制备。
更具体地说,带有杂芳基基团的硼酸衍生物可以用与文献(Synth.Commun.1996,26,3543和WO 9803484中公开的方法相似的方法进行制备。
当X为氯原子时,通式(II)原料化合物的制备在文件WO-A-0044751中有阐述。在X为氟原子的情况中,通式(II)化合物用相似的方法从6-氟吲哚-2-羧酸甲酯起始制备,其在文献(J.Med.Chem.2000,43,4701)中有描述。
本发明还提供了通式(III)化合物,
其中
X为一个氢或卤素原子,
R1为一个氢原子或一个(C1~C4)烷基,
R′和R”,每个可独立地为一个(C1~C4)烷基,
该式(II)化合物可用作制备通式(I)化合物的合成中间体。
本发明还提供了通式(IV)化合物,
其中
X为一个氢或卤素原子,
R1为一个氢原子或一个(C1~C4)烷基,
R′为一个(C1~C4)烷基,
R2和R3,每个可独立地为一个氢原子或一个(C1~C4)烷基,或R2和R3与带有这些基团的氮原子一起形成一个吡咯烷基,哌啶基,吗啉基或4-(C1~C4)烷基哌嗪基;
该式(IV)化合物可用作制备通式(I)化合物的合成中间体。
本发明还提供了通式(V)化合物,
其中
X为一个氢或卤素原子,
R1为一个氢原子或一个(C1~C4)烷基,
R2和R3,每个可独立地为一个氢原子或一个(C1~C4)烷基,或R2和R3与带有这些基团的氮原子一起以形成一个吡咯烷基,哌啶基,吗啉基或4-(C1~C4)烷基哌嗪基;
该式(V)化合物可用作制备通式(I)化合物的合成中间体。
下面的实施例阐述了本发明化合物的制备。这些实施例不是限制性的,只是阐述本发明。举例的化合物的编号和随后的列表中的化合物相对应,该表中列明了本发明化合物的化学结构和物理特性。元素分析,红外光谱,核磁共振谱确认获得的化合物的结构。
具体实施方式
实施例1(化合物1)
7-氟-N,N,5-三甲基-4-氧代-3-(吡啶-2-基)-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺
1.1. 6-氟-1-甲基-1H-吲哚-2-羧酸甲酯
在环境温度下将7.9g(197mmol)NaH(预先用石油醚冲洗)和36.1g(176mmol)6-氟-1H-吲哚-2-羧酸甲酯(含10%至20% 6-氟-1H-吲哚-2-羧酸乙酯)在250ml N,N-二甲基甲酰胺中的60%悬浮液在室温下搅拌2小时。然后加入在50ml N,N-二甲基甲酰胺中的12ml(193mmol)碘代甲烷,在环境温度下搅拌12小时。
将内容物倒入冰/水混合物中。加入二氯甲烷,并用盐酸(1N)中和水相。分离有机相,用水洗涤,用硫酸钠干燥,减压过滤并浓缩。残渣用硅胶柱色谱纯化,溶剂混合物为环己烷/二氯甲烷:50/50至0/100,然后用二氯甲烷/乙酸乙酯100/0至70/30。分离得到32.7g(170mmol)6-氟-1-甲基-1H-吲哚-2-羧酸甲酯白色化合物,含10%至20% 6-氟-1-甲基-1H-吲哚-2-羧酸乙酯。
1.2 3-[6-氟-2-(甲氧基羰基)-1-甲基-1H-吲哚-3-基]-3-氧代丙酸甲酯
分批地,将6.5ml(60mmol)3-氯-3-氧代-丙酸甲酯加入6.6ml(60mmol)四氯化钛的80ml1,2-二氯乙烷中。此混合物在环境温度下搅拌30分钟。加入含5g(24.1mmol)由步骤1.1中获得的6-氟-1-甲基-1H-吲哚-2-羧酸甲酯的溶液(含10%至20% 6-氟-1-甲基-1H-吲哚-2-羧酸乙酯)并在40摄氏度下搅拌20小时。将混合物倒入冰水中,用二氯甲烷萃取。分离有机相,用水洗涤,用硫酸钠干燥,减压过滤并浓缩。残渣用硅胶柱色谱纯化,洗脱液为环己烷/二氯甲烷:90/10至0/100,然后用二氯甲烷/乙酸乙酯100/0至50/50。得到13g糊状固体,主要含所述化合物。在后续合成中它未经进一步处理即投入使用。
1.3 N.N-二甲基-3-[6-氟-2-(甲氧基羰基)-1-甲基-1H-吲哚-3-基]-3-氧代丙酰胺
将一股气态二甲基胺通入13g(44.4mmol)步骤1.2中获得的3-[6-氟-2-(甲氧基羰基)-1-甲基-1H-吲哚-3-基]-3-氧代丙酸甲酯和在80ml甲苯中的0.2g(1.63mmol)4-(N,N-二甲基)氨基吡啶的混合物中。马上装上顶部带有球形烧瓶的冷凝器,并将溶液在100摄氏度下搅拌20小时。混合物冷却至环境温度并减压浓缩。加入200ml二氯乙烷,水和盐酸(1N),分离有机相,用水洗涤,用硫酸钠干燥,减压过滤并浓缩。残渣用硅胶柱色谱纯化(洗脱液:环己烷/二氯甲烷:50/50,然后用二氯甲烷/乙酸乙酯100/0至0/100)。分离得到4.6g(14mmol)黄色固体,在后续合成中它未经进一步处理即投入使用。
1.4 7-氟-N,N,5-三甲基-4-氧代-3-(吡啶-2-基)-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺
将1.4g(4.1mmol)步骤1.3获得的N,N-二甲基-3-[6-氟-2-(甲氧基羰基)-1-甲基-1H-吲哚-3-基]-3-氧代丙酰胺在40ml无水乙醇中的溶液与几滴冰醋酸和1.4g(12.8mmol)2-吡啶肼一起加热回流22小时。
将混合物冷却并减压浓缩。加入水和200ml二氯甲烷。加入NaOH溶液使pH>10。分离有机相,用水洗涤,用硫酸钠干燥,减压过滤并浓缩。残渣用硅胶柱色谱纯化,溶剂混合物为二氯甲烷/乙酸乙酯100/0至0/100,然后用乙酸乙酯/甲醇:100/0至90/10。再用装有中性氧化铝的色谱纯化,溶剂混合物为二氯甲烷/乙酸乙酯100/0至0/100,然后用乙酸乙酯/甲醇:100/0至90/10,得到固体,用二乙基醚洗涤。得到0.25g(0.66mmol)白色固体的化合物。
熔点:222-223摄氏度,M+H+:380
实施例2(化合物6)
盐酸7-氯-N,N,5-三甲基-4-氧代-3-(吡啶-3-基)-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺
2.1 3-[6-氯-2-(甲氧基羰基)-1-甲基-1H-吲哚-3-基]-3-氧代丙酸乙酯
将溶于70ml 1,2-二氯乙烷中的6.2ml(48.4mmol)3-氯-3-氧代丙酸乙酯的溶液冷却至0摄氏度,分成小批量地加入5.3ml(48.3mmol)四氯化钛,混合物在0摄氏度下搅拌30分钟。加入4.3g(19.2mmol)6-氯-1-甲基-1H-吲哚-2-羧酸甲酯在35ml 1,2-二氯乙烷中的溶液,混合物在环境温度下搅拌12小时。将它倒入冰水中并用二氯甲烷萃取,分离有机相,用水洗涤,用硫酸钠干燥,减压过滤并浓缩。残渣用硅胶柱色谱纯化(洗脱液:环己烷/乙酸乙酯:90/10至80/20),得到黄色固体,其在庚烷然后在二异丙醚中研制。获得2.84g(8.4mmol)化合物,其为奶油色固体。
2.2 3-[6-氯-2-(甲氧基羰基)-1-甲基-1H-吲哚-3-基]-N,N-二甲基-3-氧代丙酰胺
将一股气态二甲基胺通入15g(44.4mmol)步骤2.1中获得的3-[6-氯-2-(甲氧基羰基)-1-甲基-1H-吲哚-3-基]-3-氧代丙酸乙酯和0.2g(1.63mmol)4-(N,N-二甲基)氨基吡啶在100ml甲苯中的混合物,马上装上顶部有球形烧瓶的冷凝器,并将混合物在100摄氏度下减压搅拌20小时。混合物冷却至环境温度并减压浓缩。残渣用硅胶柱色谱纯化(洗脱液:环己烷/二氯甲烷:50/50,然后用二氯甲烷/乙酸乙酯100/0至0/100)。得到3.8g黄色固体,将其在二氯甲烷/乙酸乙酯混合物中重结晶。
得到1.8g(5.3mmol)黄白色固体。
2.3 7-氯-N,N,5-三甲基-4-氧代-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺
在1.8ml(36.8mmol)单水合肼及催化剂量的p-甲苯磺酸存在下将步骤2.2中获得的1.7g(5.2mmol)3-[6-氯-2-(甲氧基羰基)-1-甲基-1H-吲哚-3-基]-N,N-二甲基-3-氧代丙酰胺在150ml甲苯中的溶液在90摄氏度下保温24小时。此混合物经冷却,经过滤收集不溶物并用水洗涤,再用二异丙醚洗涤,再进行减压干燥。分离得到1.70g(5.2mmol)化合物,为白色固体。
熔点>300摄氏度。
2.4 盐酸7-氯-N,N,5-三甲基-4-氧代-3-(吡啶-3-基)-3,5-二氢-4-氢-哒嗪并[4,5-b]吲哚-1-乙酰胺
将0.2g(0.63mmol)步骤2.3中获得的7-氯-N,N,5-三甲基-4-氧代-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺溶于15mlN-甲基吡咯烷酮中。在环境温度下,氩气氛中加入0.11ml(1.4mmol)吡啶,0.19ml(1.4mmol)三乙胺,1g分子筛,0.24g(1.3mmol)醋酸铜和0.22g(1.4mmol)2-(吡啶-3-基)-1,3,2-二氧杂硼烷。反应24小时后滤除不溶物,溶液与0.11ml(1.4mmol)吡啶,0.19ml(1.4mmol)三乙胺,1g分子筛,0.24g(1.3mmol)醋酸铜和0.22g(1.4mmol)2-(吡啶-3-基)-1,3,2-二氧杂硼烷混和。将反应物再搅拌24小时。过滤去除不溶物,滤液经减压除去溶剂而浓缩。加入二氯甲烷和水。水相用二氯甲烷萃取,合并有机相并用水洗涤。其用硫酸钠干燥,减压过滤并浓缩。残渣用硅胶色谱柱纯化(洗脱液:二氯甲烷,然后用乙酸乙酯/甲醇:100/0至80/20)。所得的固体溶于二氯甲烷/甲醇混合物中,加入乙酸乙酯,并部分浓缩该混合物。过滤分离固体并用乙醇和二氯甲烷混合物进行重结晶。得到110mg 7-氯-N,N,5-三甲基-4-氧代-3-(吡啶-3-基)-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺(化合物5),为白色固体。
熔点:255-256摄氏度。
如下得到盐酸盐溶液:将上述所得到的固体溶解在甲醇和二氯甲烷混合物中,加入盐酸在2-丙醇中的5N溶液,在乙醇中重结晶后,分离得到0.09g(0.20mmol),为白色固体混合物。
熔点:250-252摄氏度,M+H+:396。
实施例3(化合物10)
盐酸4-甲基-1-[2-(7-氯-5-甲基-4-氧代-3-(吡啶-3-基)-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-基]乙酰-1-基]哌嗪(1:1)
3.1 [3-(6-氯-2甲氧基羰基)-1-甲基-1H-吲哚-3-基]-3-氧代-1-丙基(propion-1-y1)]-4-甲基哌嗪
在3.7ml(34mmol)N-甲基哌嗪和110mg(0.9mmOl)4-(N,N-二甲基氨基)吡啶存在下,将2.84g(8.4mmol)实施例2、步骤2.1中得到的3-[6-氯-2-(甲氧基羰基)-1-甲基-1H-吲哚-3-基]-3-氧代丙酸乙酯在160ml甲苯中的溶液加热回流12小时。混合物冷却至环境温度,加入100ml二氯甲烷,80ml水和10ml 20%氨水。分离有机相,水相用二氯甲烷萃取(100ml 2次),合并有机相。用水洗涤,硫酸钠干燥,减压过滤浓缩。残渣经硅胶柱色谱纯化(洗脱液:二氯甲烷/甲醇:100/0至90/10)这样得到1.68g(4.3mmol)黄色的油。
3.2 4-甲基-1-[2-(7-氯-5-甲基-4-氧代-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-基]乙酰-1-基]哌嗪
在1.7ml(35mmol)单水合肼及催化剂量的对甲苯磺酸存在下,将步骤3.1中得到的1.68g(4.3mmol)[3-(6-氯-2甲氧基羰基)-1-甲基-1H-吲哚-3-基]-3-氧代-1-丙基]-4-甲基哌嗪在80ml甲苯中的溶液在90摄氏度加热24小时。此混合物经冷却,过滤收集不溶物并用水、二异丙基醚洗涤,再用减压干燥。
分离得到1.43g(3.8mmol)化合物,为白色固体。
熔点:>300摄氏度。
3.3 盐酸4-甲基-1-[2-(7-氯-5-甲基-4-氧代-3-(吡啶-3-基)-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-基]乙酰-1-基]哌嗪(1:1)
将步骤3.2中得到的0.45g(1.2mmol)4-甲基-1-[2-(7-氯-5-甲基-4-氧代-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-基]乙酰-1-基]哌嗪溶于30ml N-甲基吡咯烷中。在环境温度下,氩气氛中加入0.2ml(2.4mmo1)吡啶,0.34ml(2.4mmol)三乙胺,0.30g分子筛,0.44g(2.4mmol)醋酸铜和0.39g(2.4mmol)2-(吡啶-3-基)-1,3,2-二氧杂硼烷。反应24小时后滤除不溶物,溶液与0.2ml(2.4mmol)吡啶,0.34ml(2.4mmol)三乙胺,0.30g分子筛,0.44g(2.4mmol)醋酸铜和0.39g(2.4mmol)2-(吡啶-3-基)-1,3,2-二氧杂硼烷混和。反应再搅拌进行24小时。过滤去除不溶物,滤液经减压除去溶剂而浓缩。加入二氯甲烷和水。水相用二氯甲烷萃取,合并有机相并用水洗涤。其用硫酸钠干燥,减压浓缩。残渣用硅胶色谱柱纯化(洗脱液:二氯甲烷/甲醇:100/0至90/10)。得到白色的固体。如下制得其盐酸盐,将上述所得到的固体溶解在2-丙醇和甲醇的混合物中,加入盐酸在2-丙醇中的0.1N溶液,在2-丙醇和甲醇混合物中重结晶后,分离得到0.34g(0.70mmol)化合物,为白色固体
熔点:287摄氏度(分解),M+H+:451。
实施例4(化合物8)
7-氯-N,N,5-三甲基-4-氧代-3-(6-甲基吡啶-3-基)-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺
将0.4g(1.25mmol)实施例2步骤2.3中得到的7-氯-N,N,5-三甲基-4-氧代-3,5-二氢-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺溶于45ml N-甲基吡咯烷酮中,在环境温度下,氩气氛中加入0.2ml(2.5mmol)吡啶,0.35ml(2.5mmol)三乙胺,0.40g分子筛,0.45g(2.5mmol)醋酸铜和0.80g(3.6mmol)4,4,5,5-四甲基-2-(6-甲基吡啶-3-基)-1,3,2-二氧杂硼烷。反应24小时后,溶液与0.2ml(2.5mmol)吡啶,0.35ml(2.5mmol)三乙胺,0.40g分子筛,0.45g(2.5mmol)醋酸铜和0.80g(3.6mmol)4,4,5,5-四甲基-2-(6-甲基吡啶-3-基)-1,3,2-二氧杂硼烷混合。反应再搅拌进行24小时。过滤去除不溶物,滤液经减压除去溶剂而浓缩。加入二氯甲烷和水。水相用二氯甲烷萃取,合并有机相并用水洗涤。其用硫酸钠干燥,减压过滤并浓缩。残渣用硅胶色谱柱纯化(洗脱液:二氯甲烷/甲醇:100/0至80/20)。得到的固体在异丙醇和甲醇混合物中重结晶后,分离得到0.12g(0.29mmol)化合物,为白色固体
熔点:253~255摄氏度,M+H+:410
下表列明了本发明中的一些化合物的化学结构和物理特性
在这些表格中“盐”的一栏里,“HCl”是指盐酸盐,“-”是指化合物是碱的形式。在后面也注明了酸:碱的摩尔比。缩写Dec表明在所给定的温度时,化合物已分解了。
表
本发明的化合物形成的制剂经测试显示有作为治疗活性物质的优点。
本发明的化合物还显示出水溶性,其能提高体内的活性。
在[3H]Ro5-4864存在下孵育大鼠肾细胞膜时,可选择性标记p位点受体。在与这些受体亲和力的体外研究中,本发明化合物作为研究对象。
所用的动物是雄性SD大鼠(Iffa Cerdo),体重180至300克(mg)。断头后,将肾剥离,在4摄氏度下用Polytron匀浆机将组织匀浆,在6/10最高速度下作用2分钟,缓冲液为35倍体积的50mM Na2HPO4磷酸盐缓冲液,用Na2HPO4将pH调至7.5,用纱布过滤细胞膜匀浆,并用10倍体积的缓冲液稀释。
将100微升细胞膜匀浆与浓度为0.5nM的[3H]Ro5-4864(比强度:70~90Ci/mmol,新英格兰核子公司)一起孵育,用含待测化合物的缓冲液将终体积调为1ml。
在0摄氏度下孵育3小时后,用Whatman GF/B过滤器过滤收集细胞膜,用4.5ml冷(0摄氏度)的孵育缓冲液洗涤两次。过滤器截留的放射性活性用液体闪烁仪测定。
对于待测化合物的每一浓度,均进行[3H]Ro5-4864结合的抑制百分率的测定,并进行IC50(抑制50%比结合力的浓度)的测定。本发明中最好的化合物的IC50介于1nM~200nM之间。
亲神经性活性的研究
4日龄大鼠面神经切断后运动神经元存活的测试
在未发育的大鼠的面神经受损害后,面神经的运动神经元因凋亡而发生神经元死亡。用组织学和神经元计数法的方法来评价神经元的存活。
未发育的4日龄的大鼠用戊巴比妥麻醉(3mg/kg i.p.)。在茎突乳突孔出口处暴露并切断右颊的面神经。苏醒后,幼小的大鼠被送回到它们的妈妈处,治疗7天,每日给药一次或两次,口腹或腹膜内注射,剂量为1~10mg/kg。损伤后7天,动物被断头。其脑在-40摄氏度异戊烷中冰冻。面神经用冷冻切割机切成10微米的切片。运动神经元用甲苯基紫染色再用Histo软件(BiocomTM)计数。
在这个模型中,本发明的化合物提高神经元生存10~30%。
本次测试的结果表明本发明的化合物是有促进神经再生的功能的。
因此,本发明化合物可用于制造药物产品。
因此,根据本发明的另一方面,本发明还提供了含有通式(I)或其与药学上可接受的酸形成的加成盐或通式(I)化合物的水合物或溶剂化物的医药用产品。
这些医药产品可用于治疗,尤其是用于预防和/或治疗多种类型的外周神经疾病,如创伤性或缺血型神经疾病,感染性、酒精性、药物性或遗传性神经疾病,以及运动神经元病症,如脊柱萎缩症和肌萎缩性(脊髓)侧索硬化。这些医药用产品还被发现用于治疗中枢神经系统的神经退化疾病,既可以是急性的(如脑血管意外以及颅损伤和脊髓损伤),也可以是慢性的(如自身免疫疾病(多发性硬化)阿尔茨海默病和帕金森病和任何其他一些被认为施用神经营养因子具有治疗作用的疾病)。
根据本发明的化合物还可以用于治疗急性或慢性肾功能不全,肾小球肾炎,糖尿病肾病,缺血性心脏病和心脏功能不全,心肌梗死,下肢缺血,冠状动脉血管痉挛,心绞痛,和心脏瓣膜相关的疾病,炎性心脏疾病,心脏毒性药物造成的副作用或心脏手术后的副作用,动脉粥样硬化及其血栓栓塞并发症,再狭窄,移植排斥,或与平滑肌细胞不正确的增殖或不正确的迁移相关的疾病。
在人星形细胞瘤中,外周苯二氮受体的表达程度与肿瘤的恶性程度、增殖指数和病人的存活相关。在人脑瘤中,外周苯二氮受体数量的增加被用作医学成像的诊断指征和作为偶联物的治疗靶目标,其中该偶联物由苯二氮受体的配体和细胞增殖抑制药物构成。在卵巢癌和乳房癌中也观察到高密度的苯二氮受体。关于后者,已表明外周苯二氮受体的表达程度与肿瘤的发展可能性有关;此外,外周苯二氮受体激动剂的存在,会刺激哺乳动物癌细胞系的生长。
本化合物还因此可用于治疗肿瘤和癌症。
外周苯二氮受体也在皮肤中存在,这样,根据本发明使用的化合物可以用于预防或治疗皮肤的应激(stresses)。
皮肤的应激是指会引起损伤(尤其是对表皮的损伤)的多种状况,而并不管引起这些应激的因子是什么。对机体而言,这些因子可以是外部的和/或内部的,如化学因子或自由基因子,或还有外部的,如紫外线辐射。因此,根据本发明使用的化合物可用于预防和对抗皮肤的刺激,干燥斑,红斑,感觉迟钝(disesthesic sensations),感觉发热,皮肤和/或粘膜骚痒,或老化,还可以用于皮肤疾病,如:银屑病、痒疹疾病、疱疹、光皮肤病(photodermatoses)、特应性皮炎、接触性皮炎、苔癣、骚痒、虫咬、纤维变性和其他胶原化脓性疾病,免疫性疾病和其他皮肤性症状,如湿疹。
本发明的化合物还可以用于预防和治疗慢性炎性疾病,尤其是类风湿性关节炎。
根据另一方面,本发明还提供了含至少一种通式(I)化合物为活性物质的药物组合物。这些药物组合物含有一份有效剂量的至少一种本发明的化合物(其形式为碱、药学上可接受的盐、溶剂化物或水合物),和可选的至少一种药学上可接受的赋形剂。所述的赋形剂是根据剂型和所需的给药方法,从常规赋形剂中选出,这些都是有经验的工作人员熟知的。
在本发明用于口服、舌下、皮下、肌内、静脉内、表面局部、病灶局部或动脉给药的药物组合物中,上述通式(I)的活性成分或其盐、溶剂化物或水合物,如果合适,可以用单位给药剂型,作为一种与至少一种常规药物赋形剂相混的混合物形式,施用于动物和人类,从而预防或治疗上述失调和疾病。
单位给药剂型可以是,例如片剂、胶囊、颗粒剂、粉剂、口服的或可注射的溶液或混悬液、透皮贴剂,用于舌下、颊面、气管内、眼内、鼻内给药形式或通过吸入、局部、透皮、皮下、肌内或静脉给药形式施用的剂型。对于表面局部用药,可以是霜剂、凝胶、软膏、洗液或洗眼剂。这些药物制剂是根据所述领域常规方法进行制备。
所述单位剂型的剂量是保证每日施用量为0.001-20mg活性成分/千克体重,依剂型而定。
也可能有适宜用较高或较低的剂量的特殊情况;这样的剂量没有超出本发明的范围。根据常规的实践,对于每个患者的合适剂量是医生依据给药方式、病人的体重和反应而确定的。
根据另一方面,本发明还提供了一种治疗上述病症的方法,包括向患者施用有效剂量的本发明化合物或其药学上可接受的盐或水合物或溶剂化物。
Claims (1)
1.通式(III)化合物,
其中
X为卤素原子,
R1为一个(C1~C4)烷基,
R’和R”,每个相互独立地为一个(C1~C4)烷基。
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CNB2006101003182A Expired - Fee Related CN100543016C (zh) | 2002-04-03 | 2003-04-02 | 3-杂芳基-3,5-二氢-4-氧代-4H-哒嗪并[4,5-b]吲哚-1-乙酰胺衍生物的中间体化合物 |
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JP2009504752A (ja) * | 2005-08-19 | 2009-02-05 | シェーリング コーポレイション | 治療剤としての縮合三環式mGluR1アンタゴニスト |
JP2012516327A (ja) * | 2009-01-30 | 2012-07-19 | アストラゼネカ アクチボラグ | カルボキシ含有ピラゾールアミド化合物を製造するための新規な方法 |
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FR2766823B1 (fr) * | 1997-07-30 | 1999-10-08 | Synthelabo | Derives de 4-oxo-3,5-dihydro-4h-pyridazino[4,5-b] indole-1-acetamide, leur preparation et leur application en therapeutique |
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