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CN1182109C - ((氨基亚氨基甲基)氨基)链烷羧酰胺及其在治疗中的应用 - Google Patents

((氨基亚氨基甲基)氨基)链烷羧酰胺及其在治疗中的应用 Download PDF

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CN1182109C
CN1182109C CNB998155640A CN99815564A CN1182109C CN 1182109 C CN1182109 C CN 1182109C CN B998155640 A CNB998155640 A CN B998155640A CN 99815564 A CN99815564 A CN 99815564A CN 1182109 C CN1182109 C CN 1182109C
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G·莫耐特
D·克拉沃
D·梅桑吉奥
L·多尔
M·克高特
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Abstract

本发明涉及包含通式(I)化合物作为活性组分的药物组合物,其中R1、R2、R3和A如权利要求1中所定义。这些组合物可用于治疗与胰岛素抗性综合征有关的病症。

Description

((氨基亚氨基甲基)氨基)链烷羧酰胺及其在治疗中的应用
本发明涉及((氨基亚氨基甲基)氨基)链烷羧酰胺类衍生物在治疗与胰岛素抗性综合征有关的病症中的应用。
本发明提供了药物组合物,其中包含通式(I)化合物、其溶剂化物和可药用盐作为活性组分
Figure C9981556400061
其中:
R1选自下述基团中的一个:
-H;
-未取代或者被一个或多个下述基团取代的(C1-C20)烷基:氨基、羟基、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷硫基、(C1-C5)烷基氨基、三氟甲基;
R2和R3独立地选自:
-H;
未取代或者被一个或多个下述基团取代的(C3-C8)环烷基:氨基、羟基、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷硫基、(C1-C5)烷基氨基、三氟甲基;
-含有一个或多个选自N、O和S的杂原子的(C3-C8)杂环烷基,所述杂环烷基未取代或者被一个或多个下述基团取代:氨基、羟基、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷硫基、(C1-C5)烷基氨基、三氟甲基;此外,氮原子还可被(C6-C14)芳基、(C6-C14)酰基或(C1-C5)烷基取代;-未取代或者被一个或多个下述基团取代的(C6-C14)芳基:氨基、羟基、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷硫基、(C1-C5)烷基氨基、三氟甲基、氰基;
-含有一个或多个选自N、O和S的杂原子的(C1-C13)杂芳基,所述杂芳基未取代或者被一个或多个下述基团取代:氨基、羟基、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C2-C5)烷硫基、(C1-C5)烷基氨基、三氟甲基、氰基;此外,氮原子还可被(C6-C14)芳基、(C6-C14)酰基或(C1-C5)烷基取代;
-未取代或者被一个或多个下述基团取代的(C6-C14)芳基-(C1-C5)烷基:氨基、羟基、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷硫基、(C1-C5)烷基氨基、三氟甲基、氰基;
以及A选自:
-CH2-,
-CH2-CH2-,
-CHR4-,
其中R4选自:
-H;
-未取代或者被一个或多个下述基团取代的(C1-C20)烷基:氨基、羟基、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷硫基、(C1-C5)烷基氨基、三氟甲基;
-未取代或者被一个或多个下述基团取代的(C3-C8)环烷基:氨基、羟基、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷硫基、(C1-C5)烷基氨基、三氟甲基;
-含有一个或多个选自N、O和S的杂原子的(C3-C8)杂环烷基,所述杂环烷基未取代或者被一个或多个下述基团取代:氨基、羟基、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷硫基、(C1-C5)烷基氨基、三氟甲基;此外,氮原子还可被(C6-C14)芳基、(C6-C14)酰基或(C1-C5)烷基取代。
杂芳基尤其选自吡啶基、嘧啶基、呋喃基、吡咯基、噻吩基、苯并噻唑基、苯并噁唑基、苯并咪唑基、苯并噻吩基、吲哚基、苯并呋喃基和咪唑基。
杂环烷基尤其选自哌啶基、吗啉基、哌嗪基、四氢呋喃基、四氢噻吩基、吡咯烷基和四氢吡喃基。
一组优选的式I化合物由其中R1是H或(C1-C6)烷基的式I化合物组成。
一组优选的式I化合物由定义如下的式I化合物组成:
R2选自:
-未取代或者被一个或多个下述基团取代的(C3-C8)环烷基:氨基、羟基、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷硫基、(C1-C5)烷基氨基、三氟甲基;
-未取代或者被一个或多个下述基团取代的(C6-C14)芳基:氨基、羟基、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷硫基、(C1-C5)烷基氨基、三氟甲基、氰基;
-含有一个或多个选自N、O和S的杂原子的(C1-C13)杂芳基,所述杂芳基未取代或者被一个或多个下述基团取代:氨基、羟基、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷硫基、(C1-C5)烷基氨基、三氟甲基、氰基;此外,氮原子还可被(C6-C14)芳基、(C6-C14)酰基或(C1-C5)烷基取代。
尤其优选的一组式I化合物由其中R2选自可如上所述被取代的(C6-C14)芳基的式I化合物组成。
据本申请人所知,除了Mazundar(Indan Drugs 1989,27,5,292)描述了α-胍基乙酰苯胺,即其中R1=H、R2=苯基以及R3=H的式I化合物以外,其余式(I)化合物都是新的。
本发明还涉及通式(I)化合物的互变异构形式、对映体、非对映体和差向异构体。
通式(I)化合物包含碱性氮原子,因此可以与无机酸或有机酸形成单盐或二盐。
式(I)化合物可通过式(II)化合物
与式(III)或(IV)化合物反应来制备
Figure C9981556400092
其中:
R5选自-SCH3、吡唑基或-SO3H,和
T是叔丁氧羰基或苄氧羰基保护基。
式(II)化合物可依据下述方法制得,其中:
a)使式(V)化合物
Figure C9981556400094
其中R2和R3如上所定义,
与通式(VI)酰卤反应
Figure C9981556400095
其中:
A如上所定义,
L代表氯或溴原子或活化酯形式,
Z代表氯或溴原子或保护的氨基,
从而形成通式(VII)化合物:
其中R2、R3、A和Z如上所定义;
b)将通式(VII)化合物与邻苯二甲酰亚氨化钾反应,然后与肼一水合物或者与氮化物反应,之后进行还原以生成其中R1=H的通式(II)化合物。
当Z是保护的氨基时,在此步骤可适当地将其脱保护以生成通式(II)化合物。
其中R1不是H的通式(II)化合物可通过将通式(VII)化合物与通式(VIII)胺反应而制得:
R1NH2(VIII)
本发明组合物可用于治疗与胰岛素抗性综合征(综合征X)有关的病症。
胰岛素抗性的特征是胰岛素的作用下降(参见PresseMédicale,1997,26(No.14),671-677),并且涉及大量病症,例如糖尿病、尤其是非胰岛素依赖型糖尿病(II型糖尿病或NIDDM),血脂异常,肥胖症,动脉高血压,和一些微血管和大血管并发症例如动脉粥样硬化、视网膜病和神经病。
在本申请上下文,可参考例如《糖尿病》(Diabetes),37卷,1988,1595-1607;《糖尿病及其并发症杂志》(Journal ofDiabetes and its complications),1998,12,110-119,或Horm.Res.,1992,38,28-32。
本发明组合物特别表现出很强的降血糖活性。
本发明组合物还可用于治疗由于形成“高级葡糖基化终产物”(AGEs)所致的慢性并发症,AGEs是由于葡萄糖、其氧化衍生物与蛋白的氨基官能团之间的葡萄糖氧化反应、包括例如乙二醛糖化的美拉德反应而形成的。
本发明组合物可以呈适于非胃肠道、口服、直肠、经粘膜或经皮给药的形式。
因此,本发明组合物可以呈注射用溶液或悬浮剂或装有多次剂量的小瓶的形式,素片剂或包衣片剂、膜包衣片剂、糯米纸胶囊剂、明胶胶囊剂、丸剂、扁囊剂、粉剂、栓剂或直肠用胶囊,或者在极性溶剂中的经皮给药用或经粘膜给药用溶液或悬浮剂。
对于固体剂型,适用于这样的给药的赋形剂有纤维素或微晶纤维素的衍生物、碱土金属碳酸盐、磷酸镁、淀粉、改性淀粉、和乳糖。
对于直肠施用,可可脂或聚乙二醇硬脂酸酯是优选的赋形剂。
对于非胃肠道施用,水、水溶液、生理盐水和等渗溶液是合适的载体。
根据治疗适应征和给药途径、以及个体的年龄和体重,剂量可在很宽的范围内(0.5mg-1000mg)变化。
下述实施例举例说明了式(I)化合物的制备和各种中间体。
A-式(VII)化合物的制备实施例
制备N-(2,6-二甲基苯基)-3-氯丙酰胺
向2升三颈烧瓶中加入121.8g2,6-二甲基苯胺、300ml异丙醚和150ml水。以使内温介于5-10℃之间的速度加入126.5g3-氯丙酰氯。加入完成后,将该反应混合物搅拌3小时。过滤出所形成的沉淀,依次用异丙醚和水洗涤,然后干燥。获得了126g白色结晶。
m.p.=134-136℃
1H NMR(DMSO-d6,200MHz):
2.18(s,6H);2.81(t,2H);3.88(t,2H);7.03(c,3H);9.40(s,1H)
式(VII)化合物的结构式和特征数据如表1所示。
表1
Figure C9981556400131
B-式(II)化合物的制备实施例
制备N-(2,6-二甲基苯基)-3-氨基丙酰胺
向三颈烧瓶中加入400mlDMF、100gN-(2,6-二甲基苯基)-3-氯丙酰胺和95.7g邻苯二甲酰亚氨化钾。在回流状态下搅拌3小时后,将该反应混合物冷却至室温,并加入600ml水。继续搅拌1.5小时。抽滤出所形成的沉淀,并用水洗涤。获得了140g白色结晶(m.p.>260℃)。
将该结晶置于含有800ml 95°乙醇和23.7g肼一水合物的三颈烧瓶中。在回流状态下搅拌3小时后,加入39ml浓盐酸,并继续搅拌1小时。过滤出所形成的沉淀,用乙醇洗涤,将乙醇相浓缩。将所获得的粗产物用水处理;过滤出剩余的不溶物,将水相浓缩,获得了108g乳白色固体。
m.p.=239-241℃
1H NMR(DMSO-d6,200MHz):
2.22(s,6H);2.44(t,2H);2.88(t,2H);7.07(s,3H);9.50(s,1H).
式(II)化合物的结构式和特征数据如表2所示。
                                     表2
Figure C9981556400151
Figure C9981556400161
Figure C9981556400171
C-式(II)化合物的制备实施例
制备N-(2,6-二甲基苯基)-2-甲基氨基乙酰胺
向密闭的不锈钢反应器中加入80gN-(2,6-二甲基苯基)-2-氯乙酰胺和600ml40%甲基胺水溶液。在搅拌下将该混合物在80℃加热4小时,然后真空浓缩。将粗产物用水处理,并用二氯甲烷洗涤。用氢氧化钠溶液将该水溶液碱化,并用二氯甲烷萃取。用硫酸钠将有机相干燥,浓缩,获得了60g无色油状物。
1H NMR(DMSO-d6,200MHz):
2.15(s,6H);2.44(s,3H);3.50(s,2H);6.50(s,1H);7.70(s,3H);9.58(s,1H)
化合物的结构式和特征数据如表3所示。
                                     表3
D-式(I)化合物的制备实施例
制备2-氨基亚氨基甲基氨基-N-(环己基)-乙酰胺
向园底烧瓶中加入15g2-氨基-N-(环己基)-乙酰胺、14.6g1-氨基亚氨基甲基吡唑盐酸盐和100ml二氧杂环己烷。在回流状态下搅拌18小时后,将该反应混合物冷却至室温,抽滤出所形成的沉淀。获得了16g白色固体。
m.p.=232-234℃
1H NMR(DMSO-d6,200MHz):1.19(m,5H);1.62(m,5H);3.46(m,1H);3.78(d,2H);7.21(s,4H);7.68
式(I)化合物的结构式和特征数据如表4所示。
                                 表4
Figure C9981556400211
下文中给出药理实验的结果。
在Nostz大鼠中进行的抗糖尿病活性实验
在用链脲霉素诱导的非胰岛素依赖型糖尿病大鼠实验模型中测定口服的式(I)化合物的抗糖尿病活性。
通过给新生大鼠(在出生的当天)注射链脲霉素来获得非胰岛素依赖型糖尿病模型。
所用的糖尿病大鼠是8周大小。从出生当天到实验这天期间,将大鼠保持在动物房中,给动物房提供21-22℃的调控温度和固定的光照(从早晨7点到晚上7点)与黑暗(从晚上7点到早晨7点)循环。大鼠的饮食是维持饮食;让它们随意摄取水和食物,只是在测试前取走食物让它们禁食2小时(吸收后状态)。
给大鼠口服1天(d1)或4天(d4)的测试产物来进行治疗。最后一次给药2小时后,和用戊巴比妥钠(Nembutal)麻醉30分钟后,从尾末端采集300ml血样。
实验结果如表5所示。这些结果证实了式(I)化合物在糖尿病动物中降血糖的效力。这些结果以相对于在d0(治疗前),在d1和d4(治疗的天数)血糖的改变百分数表示。
                    表5
 实施例 20mg/kg/d  200mg/kg/d
d1 d4  d1  d4
 1345 -3+7-1-2 -7-7-11-7  -20-5-13-16  -24-4-15-25
  化合物     20mg/kg/d     200mg/kg/d
    d1     d4     d1     d4
  6789101112     +8-9-11-4-13-14-9     -3-9-14-15-15-9-13     -4-3-8+7-3-3-14     -18-10-10-4-16-16-27
抗葡萄糖氧化活性的实验
式(I)化合物还通过对α-二羰基衍生物例如乙二醛的“清除”作用—即抗糖化作用而能抑制美拉德反应。通过将白蛋白与甲基乙二醛在有或没有式(I)化合物存在下培养,并测定在温育期间生成的氯胺酮(“果糖胺”)来在体外分析式(I)化合物抑制美拉德反应的作用。
将6.6mg/ml牛血清蛋白在0.2M磷酸盐缓冲液pH 7.4中的溶液与1mM甲基乙二醛在有或没有1mM本发明化合物存在下温育。在无菌条件下于37℃温育6天。温育期结束时,用市售果糖胺试剂盒(试剂盒“FRA”,产品号:0757055,Roche S.A.的产品),依据生产商的使用说明,测定氯胺酮的量。在这些实验条件下,与在没有式(I)化合物存在下将清蛋白与甲基乙二醛温育后所测定的果糖胺水平相比,清蛋白与甲基乙二醛在式(I)化合物存在下温育后的果糖胺水平下降了30-50%。

Claims (8)

1.药物组合物,其中包含通式(I)化合物或其可药用盐作为活性组分
其中:
R1选自下述基团中的一个:
-H或C1-C6烷基;
R2选自:
-未取代的C3-C8环烷基;
-未取代或者被一个或多个下述基团取代的C6-C14芳基:
卤素、C1-C5烷基;
-未取代或者被一个或多个下述基团取代的吡啶基:
C1-C5烷基、C1-C5烷硫基;
-未取代的C6-C14芳基-C1-C5烷基;
R3选自:
-H;
-未取代的C3-C8环烷基;
-未取代或者被一个或多个下述基团取代的吡啶基:
C1-C5烷基、C1-C5烷硫基;
-未取代或者被一个或多个下述基团取代的C6-C14芳基:
卤素、C1-C5烷基;
-未取代的C6-C14芳基-C1-C5烷基;
以及A选自:
-CH2-,
-CH2-CH2-,
-CHR4-,
R4选自:
-C1-C20烷基。
2.权利要求1的组合物,包含通式(I)化合物作为活性组分,其中R2选自如权利要求1所述的可被取代的C6-C14芳基。
3.通式(I)化合物或其可药用盐:
Figure C998155640003C1
其中:
R1选自下述基团中的一个:
-H或C1-C6烷基;
R2选自:
-未取代的C3-C8环烷基;
-未取代或者被一个或多个下述基团取代的C6-C14芳基:
卤素、C1-C5烷基;
-未取代或者被一个或多个下述基团取代的吡啶基:
C1-C5烷基、C1-C5烷硫基;
-未取代的C6-C14芳基-C1-C5烷基;
R3选自:
-H;
-未取代的C3-C8环烷基;
-未取代或者被一个或多个下述基团取代的吡啶基:
C1-C5烷基、C1-C5烷硫基;
-未取代或者被一个或多个下述基团取代的C6-C14芳基:
卤素、C1-C5烷基;
-未取代的C6-C14芳基-C1-C5烷基;
以及A选自:
-CH2-,
-CH2-CH2-,
-CHR4-,
R4选自:
-C1-C20烷基;
不包括其中R1=H、R2=苯基以及R3=H的式(I)化合物。
4.权利要求3的化合物或其可药用盐,其中R2选自如权利要求1所述的可被取代的C6-C14芳基。
5.制备权利要求3的化合物或其可药用盐的方法,包括使式(II)化合物
Figure C998155640004C1
其中R1、R2、R3和A如权利要求3中所定义,
与式(III)或(IV)化合物反应,
Figure C998155640004C2
Figure C998155640004C3
其中:
R5选自-SCH3、吡唑基或-SO3H,以及
T是叔丁氧羰基或苄氧羰基保护基。
6.权利要求3的化合物或其可药用盐在制备用于治疗与胰岛素抗性综合征有关的病症的药物中的应用。
7.权利要求3的化合物或其可药用盐在制备具有降血糖活性的药物中的应用。
8.权利要求3的化合物或其可药用盐在制备抗葡萄糖氧化药物中的应用。
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