CN1195743C - 二氢-1,3,5-三嗪的含氨基衍生物及其治疗应用 - Google Patents
二氢-1,3,5-三嗪的含氨基衍生物及其治疗应用 Download PDFInfo
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- CN1195743C CN1195743C CNB018041027A CN01804102A CN1195743C CN 1195743 C CN1195743 C CN 1195743C CN B018041027 A CNB018041027 A CN B018041027A CN 01804102 A CN01804102 A CN 01804102A CN 1195743 C CN1195743 C CN 1195743C
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- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
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Abstract
本发明涉及通式(I)的化合物,其中R1、R2、R3、R4、R5和R6的定义如权利要求1。所述化合物可用于治疗与胰岛素抗性症候群相关的病理。
Description
本发明涉及二氢-1,3,5-三嗪的含氨基衍生物,它们可用于治疗与胰岛素抗性症候群相关的病理状况。
JP-A-73 64 088和JP-A-79 14 986已公开了具有低血糖性能的二氢-1,3,5-三嗪的含氨基衍生物。
本发明的目的是提供具有改进性能的新型化合物。
因此,本发明的主题是通式(I)的化合物,及其互变异构、对映异构、非对映异构和差向异构形式和可药用的盐:
其中:
R1,R2,R3和R4独立地选自下列基团:
-H,
-用或不用卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C3-C8)环烷基取代的(C1-C20)烷基,
-用或不用卤素、(C1-C5)烷基、(C1-C5)烷氧基取代的(C2-C20)烯基,
-用或不用卤素、(C1-C5)烷基、(C1-C5)烷氧基取代的(C2-C20)炔基,
-用或不用(C1-C5)烷基、(C1-C5)烷氧基取代的(C3-C8)环烷基,
-含有一个或多个选自N、O、S的杂原子,并用或不用(C1-C5)烷基、(C1-C5)烷氧基取代的(C3-C8)杂环烷基,
-用或不用氨基、羟基、硫、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C1-C5)烷基氨基、(C6-C14)芳氧基、(C6-C14)芳基(C1-C5)烷氧基、氰基、三氟甲基、羧基、羧甲基或羧乙基取代的(C6-C14)芳基(C1-C20)烷基,
-用或不用氨基、羟基、硫、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C1-C5)烷基氨基、(C6-C14)芳氧基、(C6-C14)芳基(C1-C5)烷氧基、氰基、三氟甲基、羧基、羧甲基或羧乙基取代的(C6-C14)芳基,
-含有一个或多个选自N、O、S的杂原子,并用或不用氨基、羟基、硫、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C1-C5)烷基氨基、(C6-C14)芳氧基、(C6-C14)芳基(C1-C5)烷氧基、氰基、三氟甲基、羧基、羧甲基或羧乙基取代的(C1-C13)杂芳基,
也可以R1和R2在一面,R3和R4在另一面,与氮原子形成n-元环(n为3~8),该n-元环可以含有或不含有一个或多个选自N、O、S的杂原子,并可以被一个或多个下列基团取代:氨基、羟基、硫、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C1-C5)烷基氨基、(C6-C14)芳氧基、(C6-C14)芳基(C1-C5)烷氧基、氰基、三氟甲基、羧基、羧甲基或羧乙基,
R5和R6独立地选自下列基团:
-H,
-用或不用氨基、羟基、硫、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C1-C5)烷基氨基、(C6-C14)芳氧基、(C6-C14)芳基(C1-C5)烷氧基、氰基、三氟甲基、羧基、羧甲基或羧乙基取代的(C1-C20)烷基,
-用或不用氨基、羟基、硫、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C1-C5)烷基氨基、(C6-C14)芳氧基、(C6-C14)芳基(C1-C5)烷氧基、氰基、三氟甲基、羧基、羧甲基或羧乙基取代的(C2-C20)烯基,
-用或不用氨基、羟基、硫、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C1-C5)烷基氨基、(C6-C14)芳氧基、(C6-C14)芳基(C1-C5)烷氧基、氰基、三氟甲基、羧基、羧甲基或羧乙基取代的(C2-C20)炔基,
-用或不用氨基、羟基、硫、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C1-C5)烷基氨基、(C6-C14)芳氧基、(C6-C14)芳基(C1-C5)烷氧基、氰基、三氟甲基、羧基、羧甲基或羧乙基取代的(C3-C8)环烷基,
-含有一个或多个选自N、O、S的杂原子,并用或不用氨基、羟基、硫、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C1-C5)烷基氨基、(C6-C14)芳氧基、(C6-C14)芳基(C1-C5)烷氧基、氰基、三氟甲基、羧基、羧甲基或羧乙基取代的(C3-C8)杂环烷基,
-用或不用氨基、羟基、硫、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C1-C5)烷基氨基、(C6-C14)芳氧基、(C6-C14)芳基(C1-C5)烷氧基、氰基、三氟甲基、羧基、羧甲基或羧乙基取代的(C6-C14)芳基,
-含有一个或多个选自N、O、S的杂原子,并用或不用氨基、羟基、硫、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C1-C5)烷基氨基、(C6-C14)芳氧基、(C6-C14)芳基(C1-C5)烷氧基、氰基、三氟甲基、羧基、羧甲基或羧乙基取代的(C1-C13)杂芳基,
-用或不用氨基、羟基、硫、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C1-C5)烷基氨基、(C6-C14)芳氧基、(C6-C14)芳基(C1-C5)烷氧基、氰基、三氟甲基、羧基、羧甲基或羧乙基取代的(C6-C14)芳基(C1-C5)烷基,
R5和R6也可以与它们所连接的碳原子形成m-元环(m为3~8),该m-元环可以含有或不合有一个或多个选自N、O、S的杂原子,并可以被氨基、羟基、硫、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C1-C5)烷基氨基、(C6-C14)芳氧基、(C6-C14)芳基(C1-C5)烷氧基、氰基、三氟甲基、羧基、羧甲基或羧乙基取代;或者可以与碳原子形成C10-C30多环残基,该多环残基可以用或不用氨基、羟基、硫、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C1-C5)烷基氨基、(C6-C14)芳氧基、(C6-C14)芳基(C1-C5)烷氧基、氰基、三氟甲基、羧基、羧甲基或羧乙基取代,
杂环烷基或杂芳基的氮原子可以被(C1-C5)烷基、(C3-C8)环烷基、(C6-C14)芳基、(C6-C14)芳基(C1-C5)烷基或(C1-C6)酰基取代,
排除式I的下列化合物,其中:
a-R1=H,R2=H,R3=H,R5=CH3,R6=CH3,且R4=苯乙基、苯氧乙基、2-苯基硫代异丙基或苄基;
b-R1=H,R2=H,R3=H或CH3,R4=H、甲基、丁基或苯乙基,R5=H或乙基,且R6为3-甲基-5-异噁唑基、5-甲基-3-异噁唑基、3-甲基-5-吡唑基或(5-甲基-3-异噁唑基)甲基,
c-R1、R2、R3和R4代表氢原子。
由R5和R6形成的m-元环特别是指饱和环,例如环己基、哌啶基(piperidinyl)或四氢吡喃基。
由R5和R6形成的多环基是指任选取代的含碳多环基,特别是指甾族残基。
一组特别的式(I)的化合物是其中R5为氢的化合物。
另一组特别的式(I)的化合物是其中R5和R6与它们所连接的碳原子形成m-元环(m为3~8)的化合物,所述m-元环可以含有或不含有一个或多个选自N、O、S的杂原子,并可以被一个或多个下列基团取代:(C1-C5)烷基、氨基、羟基、(C1-C5)烷基氨基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C6-C14)芳基、(C6-C14)芳基(C1-C5)烷氧基,
或其中R5和R6与碳原子形成C10-C30多环残基的化合物,该多环残基用或不用氨基、羟基、硫、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C1-C5)烷基氨基、(C6-C14)芳氧基、(C6-C14)芳基(C1-C5)烷氧基、氰基、三氟甲基、羧基、羧甲基或羧乙基取代。
另一组特别的式(I)的化合物是其中R5和R6独立地选自如下基团的化合物:
-用或不用氨基、羟基、硫、卤素、(C1-C5)烷基、(C1-C5)烷氧基、(C1-C5)烷基硫、(C1-C5)烷基氨基、(C6-C14)芳氧基、(C6-C14)芳基(C1-C5)烷氧基、氰基、三氟甲基、羧基、羧甲基或羧乙基取代的(C1-C20)烷基。
一组更特别的式(I)的化合物是其中R1和R2独立地选自除氢原子以外的上述指定基团,并且R3和R4代表氢的化合物。更具体而言,优选的一组式(I)的化合物是其中R1和R2是烷基,有利地是甲基,并且R3和R4是氢的化合物。
本发明还涉及通式(I)化合物的互变异构、对映异构、非对映异构和差向异构形式。
通式(I)的化合物具有碱性氮原子,它们可以与有机或无机酸成单盐或二盐。
通式(I)的化合物可以通过使通式(II)的化合物:
其中R1、R2、R3和R4的定义如上,与通式(III)、(IV)或(V)的化合物:
其中R5和R6定义如上,R7为甲基或乙基,在极性溶剂(例如乙醇或二甲基甲酰胺)中,在有机酸(例如樟脑磺酸)或无机酸(例如盐酸)存在下反应制备。
通式(II)的化合物是双胍类,其合成对于本领域技术人员来说是常规的。本文引用部分描述这样的化合物合成的出版物作为实例:
(FR 1537604,FR 2132396;K.H.Slotta and R.Tschesche,
Ber.,1929(62b),1398;S.L.Shapiro,V.A.Parrino,
E.Rogow and L.Freedman,J.Org.Chem.,1959(81),
3725;S.L.Shapiro,V.A.Parrino and L.Freedman,J.
Org.Chem.,1959(81),3728;S.L.Shapiro,V.A.Parrino
和L.Freedman,J.Org.Chem.,1959(81),4636).
本发明的化合物可用于治疗与胰岛素抗性症候群(X症候群)相关的病理状况。
胰岛素抗性的特征在于胰岛素作用的降低(参见Presse Médicale,1997,26(No.14),671-677),并涉及很多病理状态,例如糖尿病,更具体而言非胰岛素依赖型糖尿病(non-insulin-dependent diabetes,II型糖尿病或NIDDM)、血脂异常、肥胖症、高血压,及某些微脉管和大脉管(macrovascular)并发症,如动脉粥样硬化、视网膜病变和神经病。
在这点上,可参考例如Diabètes,vol.37,1988,1595-1607;Journal ofDiabetes and its complications,1998,12,110-119或Horm.Res.,1992,38,28-32。
特别地,本发明的化合物具有高的低血糖活性。
本发明的化合物还可用于治疗慢性并发症,该慢性并发症的诱因特别是由于“高级糖基化最终产物”(被称为AGEs)的形成,AGEs源自葡萄糖、其氧化衍生物与蛋白质的氨基官能团间的葡萄糖氧化反应(glycoxidation reaction),包括用于例如乙二醛的糖化作用(glycation)的所谓的美拉德反应。
事实上,最近出版的数据清楚地显示了AGEs对肾并发症(Nephr.Dial.Transplant.,2000,15(suppl 2),7-11)、动脉粥样硬化、早老性痴呆和其它神经变性疾病(Glycoconj.J.,1998,15(10),1039-42;Brain Res.,2001,888(2),256)的影响。AGE的形成还可能是血管病,特别是糖尿病的重要发病原因,还可能是衰老的重要原因(J.Neuropathol.Exp.Neurol.,2000,59(12),1094)。
因此,本发明的主题还是含有本发明化合物作为活性成分的药物组合物。
这些药物组合物特别是用于治疗糖尿病、由于AGEs形成导致的病理状况如特别是肾并发症、动脉粥样硬化、血管病、早老性痴呆、神经变性疾病和衰老。
本发明的药物组合物可以以用于通过肠胃外、口服、直肠、经粘膜或经皮方式给药的形式提供。
因此它们可以以可注射溶液或悬浮体或多剂量小瓶的形式,以未包衣或包衣片剂、糖衣片剂、胶囊、明胶胶囊、丸剂、扁囊剂、粉剂、栓剂或直肠胶囊、用于经皮应用(在极性溶剂中)和用于经粘膜应用的溶液或悬浮体的形式提供。
适合这样的给药方式的赋形剂,对于固体形式来说是纤维素衍生物或微晶纤维素衍生物、碱土金属碳酸盐、磷酸镁、淀粉、改性淀粉、乳糖。
对于直肠应用,可可脂或聚乙二醇的硬脂酸酯是优选的赋形剂。
对于肠胃外应用,水、水溶液、生理盐水、等渗溶液是最通常使用的赋形剂。
根据治疗指征和给药方案,以及患者的年龄和体重,剂量可以在宽的范围(0.5mg~1000mg)内变化。
作为实例,此处给出数个可用于式I的衍生物合成的式II的双胍。
表I
下列实施例举例说明式I的化合物的制备。
实施例1
2-氨基-3,6-二氢-4-二甲基氨基-6-乙基-1,3,5-三嗪盐酸盐
将23ml丙醛和3.6g樟脑磺酸加入到化合物A(25.7g;0.155mol)在200ml DMF中的溶液中。回流2小时后,减压除去溶剂,并加入100ml乙腈。排干形成的固体并干燥(21.9g;69%)。
m·p·=218-220℃
1H NMR(DMSO-d6,200MHz):1.10(t,3H);1.80(m,2H);
3.20(s,6H);4.83(m,1H);7.57(m,2H);8.65(s,1H);
8.90(s,1H)
13C NMR(DMSO-d6,50MHz):6.41(CH3);27.59(CH2);
35.64(CH3);60.75(CH);155.01(C=N);156.67(C=N)
实施例2
2,4-二(二甲基氨基)-3,6-二氢-6-甲基-1,3,5-三嗪盐酸盐
将61ml乙缩醛和5g樟脑磺酸加入到化合物E(41.10g;0.212mol)在200ml无水乙醇中的溶液中。整个体系加热回流72小时,然后浓缩。粗产品用乙腈捣碎,排干形成的固体,然后在乙腈中重结晶。得到24g(51.5%)固体。
m.p.=200-202℃
1H NMR(DMSO-d6,200MHz):1.34(d,3H);3.02(s,6H);
4.72(m,1H);4.83(m,1H);8.80(s,2H)
13C NMR(DMSO-d6,50MHz):22.59(CH3);37.76(CH3);
59.02(CH);156.35(C=N)
下表II中给出了这些化合物和其它的式I化合物的表征。
表II
下面将给出药理学研究结果。
在NOSTZ大鼠中进行的抗糖尿病活性研究
在由链脲霉素诱导的非胰岛素依赖型糖尿病大鼠试验模型上测定口服给药的式(I)化合物的抗糖尿病活性。
所述非胰岛素依赖型糖尿病模型是在大鼠中通过新生期注射(在出生当天)链脲霉素而得到的。
所使用的糖尿病大鼠8周龄。所述的动物从其出生当天到进行试验的当天,一直保持在温度控制为21~22℃的动物房中,并经受固定的光照(从早7点到晚7点)和黑暗(从晚7点到早7点)循环。它们的饮食由维生饮食、水组成,并且食物“ablibitum”提供,只是在试验前撤掉食物禁食2小时(后吸收状态)。
所述大鼠通过口服给药方案,用所测试的产品治疗1天(D1)或4天(D4)。在所述产品最后一次给药后2小时,和用戊巴比妥钠(Nembutal)使所述动物麻醉后30分钟,从尾端取300微升血样。
作为实例,得到的结果汇集在表III。这些结果显示了式(I)的化合物在降低糖尿病动物的糖血症方面的功效。这些结果表示为在D1和D4(治疗天数)的糖血相对于DO(治疗前)的变化百分比。
表III
化合物 | 20mg/kg/D | 200mg/kg/D | ||
D1 | D4 | D1 | D4 | |
123471517181921222526272831323334373940424344 | -7-11-100-8-8-12-6-10-7-23-4-6-14-4-52-7-5-7-6-8-5-4-7 | -2-10-8-1-11-9-8-4-6-2-16-11-11-9-1-110-6-15-8-6-12-4-16-6 | -13-12-18-20-10-4-8-29-4-21-13-7-14-12-4-3-22-9-6-10-4-18-26-12-22 | -15-12-22-10-16-5-14-28-14-240-6-9-13-13-15-18-14-21-15-7-18-17-17-25 |
抗糖化活性的研究
化合物(1)还能够通过对含α-二羰基的衍生物如乙二醛的“捕获作用”抑制所谓的美拉德反应,这就是抗糖化作用。本发明化合物的这种美拉德反应抑制作用,是通过体外分析***(“果糖胺”)来进行研究的,所述***是在或不在本发明的式(I)化合物存在下,用甲基乙二醛培养白蛋白过程中产生的。
将牛白蛋白在0.2M的磷酸盐缓冲溶液中的,浓度为6.6mg/ml,pH为7.4的溶液,在或不在浓度为10mM的本发明化合物存在下,用1mM的甲基乙二醛培养。所述培养在无菌条件下,于37℃进行6天。在培养结束时,用市售的果糖胺分析盒(“ FRA”盒,产品号:0757055,Roche S.A.产品),按照制造商的指示测定***的量。
作为实例,在这些试验条件下得到的结果汇集于表IV:在本发明化合物(I)存在下用甲基乙二醛培养白蛋白后的果糖胺水平,与无本发明化合物(I)存在下用甲基乙二醛培养白蛋白的果糖胺水平相比较。
表IV
化合物(I) | 果糖胺含量的降低(%) |
1 | 62 |
10 | 80 |
11 | 89 |
12 | 90 |
13 | 95 |
18 | 69 |
33 | 79 |
34 | 64 |
36 | 66 |
37 | 65 |
40 | 66 |
43 | 68 |
45 | 67 |
Claims (14)
1.通式(I)的化合物,及其互变异构、对映异构、非对映异构和差向异构形式和可药用的盐:
其中:
R1和R2独立地选自下列基团:
-H,
-(C1-C20)烷基,
-(C6-C14)芳基(C1-C20)烷基,
R3和R4独立地选自下列基团:
-H,
-(C1-C20)烷基,
-(C2-C20)烯基,
R3和R4可以与氮原子形成3至8-元环,
R5和R6独立地选自下列基团:
-H,
-用或不用羟基、卤素或(C6-C14)芳氧基取代的(C1-C20)烷基,
-用或不用(C6-C14)芳基(C1-C5)烷氧基取代的(C3-C8)环烷基,
-含有一个或多个选自N、O、S的杂原子的(C3-C8)杂环烷基,
-用或不用羟基或(C1-C5)烷氧基取代的(C6-C14)芳基,
-(C6-C14)芳基(C1-C5)烷基,
R5和R6也可以与它们所连接的碳原子形成3至8-元环,该3至8-元环可以含有或不含有一个或多个选自N、O、S的杂原子,并可以被羟基、(C1-C5)烷基或(C6-C14)芳基(C1-C5)烷氧基取代,
其中,当R1和R2表示氢原子,或R3和R4表示氢原子时,R3和R4或R1和R2具有上面定义的除氢以外的含义。
2.如权利要求1的式(I)的化合物,其中R5为氢。
3.如权利要求1的式(I)的化合物,其中R5和R6与它们所连接的碳原子形成3至8-元环,所述3至8-元环可以含有或不含有一个或多个选自N、O、S的杂原子,并可以被(C1-C5)烷基取代。
4.如权利要求1的式(I)的化合物,其中R5是被羟基取代的(C2-C20)烷基。
5.如权利要求1的式(I)的化合物,其中R5和R6选自用或不用羟基取代的(C1-C20)烷基。
6.如权利要求1的式(I)的化合物,其中R1和R2独立地选自除氢原子以外的权利要求1中指定的基团,并且R3和R4是氢。
7.如权利要求6的式(I)的化合物,其中R1和R2是甲基,而R3和R4是氢。
9.药物组合物,该药物组合物含有如权利要求1所述的化合物作为活性成分。
10.如权利要求1所述的化合物在制备用于治疗与胰岛素抗性症候群相关的病理状况的药物中的应用。
11.如权利要求1所述的化合物在制备用于治疗糖尿病的药物中的应用。
12.如权利要求1所述的化合物在制备用于治疗由于高级糖基化最终产物形成所导致的病理状况的药物中的应用。
13.如权利要求1所述的化合物在制备用于治疗选自肾并发症、动脉粥样硬化、血管病、早老性痴呆、神经变性疾病和衰老的病理状况的药物中的应用。
14.如权利要求1所述的化合物在制备用于治疗选自血脂异常、肥胖症、高血压、视网膜病变和神经病的病理状况的药物中的应用。
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FR2804113B1 (fr) * | 2000-01-26 | 2004-06-18 | Lipha | Derives animes de dihydro-1,3,5-triazine et leurs applications en therapeutique |
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DE102007054416A1 (de) * | 2007-11-13 | 2009-05-14 | Studiengesellschaft Kohle Mbh | Verfahren zur Herstellung von 3,6-Dihydro-1,3,5- Triazin-Derivaten für die Behandlungen von Erkrankungen, die mit dem Insulinresistenz-Syndrom assoziiert sind |
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FR2948026B1 (fr) * | 2009-07-17 | 2011-12-02 | Merck Sante Sas | Derives amines de dihydro-1,3,5-triazine |
TWI436768B (zh) | 2010-06-09 | 2014-05-11 | Poxel | 第2型糖尿病之治療 |
ES2577930T3 (es) * | 2010-06-09 | 2016-07-19 | Poxel | Derivados de triazina para retrasar el inicio de la diabetes tipo 1 |
WO2012072663A1 (en) | 2010-12-01 | 2012-06-07 | Poxel | Separation of triazine derivatives enantiomers using tartaric acid |
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