CN101445504A - 二烷-2-烷基氨基甲酸酯衍生物 - Google Patents
二烷-2-烷基氨基甲酸酯衍生物 Download PDFInfo
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Abstract
本发明涉及二噁烷-2-烷基氨基甲酸酯衍生物,特别涉及通式(VI)和通式(III)表示的化合物,式(VI)中,R1代表可被一或多个卤素原子或者羟基、氰基、硝基、(C1-C3)-烷基、(C1-C3)-烷氧基、三氟甲基、三氟甲氧基、苄氧基或(C3-C6)-环烷基-(C1-C3)-烷氧基任意取代的苯基或萘基;R3代表氢原子或甲基;以及n代表1至3的数字。式(III)中,R2代表通式CHR3CONHR4表示的基团,其中,R3代表氢原子或甲基;以及R4代表氢原子或者(C1-C3)-烷基、(C3-C5)环烷基或者(吡啶-4-基)甲基;以及U代表氢原子或硝基。
Description
本发明专利申请是国际申请号为PCT/FR2003/002590,国际申请日为2003年8月27日,进入中国国家阶段的申请号为03824105.6的发明专利申请的分案申请。
发明领域
本发明涉及1,3-二噁烷-2-基烷基氨基甲酸酯衍生物、其制备及其在治疗学上的应用。
发明内容
本发明的化合物是通式(I)化合物:
式中,
R1代表可被一或多个卤素原子或者羟基、氰基、硝基、(C1-C3)-烷基、(C1-C3)-烷氧基、三氟甲基、三氟甲氧基、苄氧基、(C3-C6)环烷基-O-、或(C3-C6)-环烷基-(C1-C3)-烷氧基任意取代的苯基或萘基;
R2代表以通式CHR3CONHR4表示的基团,其中R3代表氢原子或甲基,R4代表氢原子或(C1-C3)-烷基、(C3-C5)-环烷基或(吡啶-4-基)甲基,
或者R2代表2,2,2-三氟乙基,
或者R2代表(咪唑-2-基)甲基,
或者R2代表(苯并咪唑-2-基)甲基,
或者R2代表可被一或多个卤素原子或者氰基、硝基、(C1-C3)-烷基、(C1-C3)-烷氧基、三氟甲基、三氟甲氧基任意取代的苯基;以及
n代表1至3的数字。
通式(I)化合物可包含一或多个不对称碳原子。它们可以对映体或非对映异构体形式存在。通式(I)化合物也可以顺式或反式立体异构体形式存在。这些对映体、非对映异构体和立体异构体,及其包括外消旋混合物在内的混合物是本发明的一部分。
通式(I)化合物可以碱的形式存在,或与酸的加成盐形式存在。这样的加成盐是本发明的一部分。
这些盐可用药学上可接受的酸来很好地制备,但用来例如纯化或分离通式(I)化合物的其他酸生成的盐,也是本发明的组成部分。通式(I)化合物可以水合物或溶剂化物形式存在,即该化合物与一个或多个水分子或一个溶剂分子缔合或结合。这些水合物和溶剂化物也是本发明的组成部分。
专利文献EP 0461958和FR 2714056描述了一些与本发明化合物相似的化合物,其中R2代表直链或支链(C1-C4)烷基,它们用作抗惊厥剂。
本发明上下文中,
术语“(Ct-Cz),其中t和z是1至6的数字”是指有t至z个碳原子的碳链,例如“(C1-C3)”是指有1至3个碳原子的碳链;
术语“烷基”是指直链或支链的饱和脂肪基团,如(C1-C3)烷基代表有1至3个碳原子的直链或支链碳链,更具体地说是甲基、乙基、丙基或异丙基;
术语“环烷基”是指环状烷基,如(C3-C5)环烷基代表有3至5个碳原子的环状碳链,更具体地说,是环丙基、环丁基或环戊基;
术语“烷氧基”是指含有直链或支链的饱和脂肪链的烷氧基;
术语“卤素原子”是指氟、氯、溴或碘。
在通式(I)化合物中,优选提到的化合物,其定义如下:
-R1代表可被一或多个卤素原子或者羟基、氰基、硝基、(C1-C3)-烷基、(C1-C3)-烷氧基、三氟甲基、三氟甲氧基、苄氧基、(C3-C6)环烷基-O-、或(C3-C6)-环烷基-(C1-C3)-烷氧基任意取代的萘基;和/或
-R2代表以通式CHR3CONHR4表示的基团,其中R3代表氢原子,而R4代表氢原子或(C1-C3)-烷基,优选甲基或乙基,或者(吡啶-4-基)甲基,
或者R2代表2,2,2-三氟乙基,
或者R2代表可被一或多个卤素原子或者氰基、硝基、(C1-C3)-烷基、(C1-C3)-烷氧基、三氟甲基或三氟甲氧基任意取代的苯基;
-n代表2或3。
R1、R2和n如上限定的化合物是特别优选的。
在优选的通式(I)化合物中,特别提到下列化合物:
反式-3-[5-(萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-氨基-2-氧乙酯;
反式-2-[5-(萘-1-基)-1,3-二噁烷-2-基]乙基氨基甲酸2-(甲氨基)-2-氧乙酯;
反式-3-[5-(萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-(甲氨基)-2-氧乙酯;
反式-2-[5-(萘-1-基)-1,3-二噁烷-2-基]乙基氨基甲酸2,2,2-三氟乙酯;
反式-3-[5-(萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2,2,2-三氟乙酯;
反式-2-[5-(萘-1-基)-1,3-二噁烷-2-基]乙基氨基甲酸苯酯;
反式-3-[5-(萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸苯酯;
反式-3-[5-(4-氯萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-氨基-2-氧乙酯;
反式-3-[5-(4-氯萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-(甲氨基)-2-氧乙酯;
反式-3-[5-(6-氯萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-(甲氨基)-2-氧乙酯;
反式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-氨基-2-氧乙酯;
顺式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-氨基-2-氧乙酯;
反式-2-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]乙基氨基甲酸2-(甲氨基)-2-氧乙酯;
反式-2-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]乙基氨基甲酸4-氯苯酯;
反式-2-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]乙基氨基甲酸2,2,2-三氟乙酯;
反式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-(甲氨基)-2-氧乙酯;
反式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-(乙氨基)-2-氧乙酯;
反式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-[(吡啶-4-基)甲基氨基]-2-氧乙酯;
反式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2,2,2-三氟乙酯;
反式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸苯酯;
反式-3-[5-(6-环丙基甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-氨基-2-氧乙酯;
反式-3-[5-(6-环丙基甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸4-氯苯酯;
反式-3-[5-(6-环丙基甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2,2,2-三氟乙酯;
反式-3-[5-(6-苯基甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-氨基-2-氧乙酯;
反式-3-[5-(6-羟基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-氨基-2-氧乙酯;
反式-3-[5-(6-羟基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-(甲氨基)-2-氧乙酯;
反式-3-[5-(7-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-氨基-2-氧乙酯;
反式-3-[5-(7-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-(甲氨基)-2-氧乙酯;
反式-3-[5-(7-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2,2,2-三氟乙酯;
反式-3-[5-(7-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸苯酯;
反式-3-[5-(萘-2-基)-1,3-二噁烷-2-基]丙基氨基甲酸苯酯;
反式-3-[5-(萘-2-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-(甲氨基)-2-氧乙酯;
反式-3-[5-(萘-2-基)-1,3-二噁烷-2-基]丙基氨基甲酸2,2,2-三氟乙酯。
本发明的化合物可按照以下流程所示的各种方法制备。
因此,一种制备方法(流程1)包括将通式(II)的胺(其中R1和n如通式(I)所限定)与通式(III)的氨基甲酸酯(其中U代表氢原子或硝基,R2如通式(I)所限定)在溶剂如甲苯或二氯乙烷在0至80℃之间的温度下反应。
流程1
通式(III)的氨基甲酸酯可根据已有文献中描述的任何方法制备,例如将通式HOR2表示的醇与氯甲酸苯酯或氯甲酸4-硝基苯酯在碱例如三乙胺或二异丙乙胺存在下反应制成。
将上述限定的通式(II)的胺与通式(IIIa)的氯甲酸芳酯在溶剂如二氯甲烷或二氯乙烷中在碱例如三乙胺或二异丙乙胺存在下于0℃至溶剂回流温度之间的温度下反应,可特别制备R2代表可任意取代的苯基(Ar)的通式(I)化合物。
根据流程2,将上述限定的通式(II)的胺与二氧化碳在碱例如碳酸铯和相转移试剂例如四-正丁基碘化铵存在下,在溶剂例如N,N-二甲基甲酰胺或N-甲基吡咯烷酮中反应,然后与通式(IV)的卤代乙酰胺(其中V代表氯、溴或碘原子,R3和R4如通式(I)所限定)反应,可特别制备R2代表通式CHR3CONHR4基团的通式(I)化合物。
流程2
另一种获得R2代表通式CHR3CONHR4基团的通式(I)化合物的方法(流程3)包括将上述限定的通式(II)的胺与通式(IIIb)的碳酸盐(其中U代表氢原子或硝基,R3如通式(I)所限定,R5代表甲基或乙基)反应。然后,通过通式R4NH2的胺(其中R4如通式(I)所限定)直接氨解作用,或者通过通式(Ia)的酸(其中R5代表氢原子)的水解作用,再与通式R4NH2的胺(其中R4如通式(I)所限定)偶合,将所得到的通式(Ia)的氨基甲酸酯转化为通式(I)化合物。氨解反应可在溶剂如甲醇或溶剂混合物如甲醇与四氢呋喃的混合物中进行。偶合反应可按照文献记载的任何公知方法来进行,例如在碱如二异丙乙胺存在下采用氯甲酸异丁酯。
流程3
通式(IIIb)碳酸盐可参照通式(III)碳酸盐的制备方法来制备。
另一种获得R2特别代表通式CH3CONHR4基团的通式(I)化合物的变换方法(流程4)是将通式(IIa)的衍生物(其中Z代表羟基、甲磺酸盐或甲苯磺酸盐基团、或者氯、溴或碘原子,R1和n如通式(I)所限定)与通式(V)的恶唑烷二酮(其中R3如通式(I)所限定)反应,生成通式(VI)的恶唑烷二酮衍生物。当Z代表羟基时,反应可在Mitsunobu条件(Synthesis,1981,1-28)下进行,例如在偶氮二甲酸二乙酯或二异丙酯作用下并在三苯基膦存在下进行反应。当Z代表氯、溴或碘原子,或者甲磺酸盐或甲苯磺酸盐基团时,反应可在碱例如1,1,3,3-四甲基胍、氢化钠或叔丁氧化钠存在下进行,需要的溶剂比如四氢呋喃、乙腈或二甲基甲酰胺,温度在0℃至溶剂回流温度之间。再用通式R4NH2的胺(其中R4如通式(I)所限定)进行氨解作用,将由此得到的通式(VI)恶唑烷二酮衍生物转化为通式(I)化合物。
流程4
通式(II)的胺可参照专利申请EP 0461958、WO 97/20836和WO 98/55474中描述的制备方法制备,任选地可根据本领域技术人员公知的技术作调整。
通式(IIa)、(IIIa)、(IV)和(V)的化合物以及胺R4NH2,若没有描述它们的制备方法,一般可通过商业途径获得,或在文献中已有描述,或者可用文献中描述的方法或本领域技术人员已知的方法制备。
通式(Ia)化合物(其中R1、R3和n如通式(I)所限定,R5代表氢原子或甲基或乙基)和通式(VI)化合物(其中R1、R3和n如通式(I)所限定)是新颖化合物,构成本发明的一部分。它们可用作制备通式(I)化合物的合成中间体。
下面实施例叙述了本发明一些化合物的制备。这些实施例仅用来说明本发明,而本发明不受这些实施例的限制。微量分析、IR和NMR谱和/或LC-MS(液相色谱和质谱联用)验证所得化合物的结构和纯度。
实施例标题中括号内标示的数字对应于下表第一栏的数字。
具体实施方式
实施例1:(化合物61号)
反式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-(环丙基氨基)-2-氧乙酯
1.1[(苯氧基羰基)氧基]乙酸乙酯
室温下将13.5ml(105.6mmol)氯甲酸苯酯滴入10g(96.15mmol)乙醇酸乙酯和27ml(192.3mmol)三乙胺在20ml甲苯的溶液中,该混合物室温搅拌2小时。分离出生成的盐,滤液减压浓缩。
得到20g油状产物,无需改性可用在下一步骤中。
1.2反式-[[[[3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基]氨基]羰基]氧基]乙酸乙酯
将10g(33mmol)反式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙胺和上一步骤得到的[(苯氧基羰基)氧基]乙酸乙酯8.9g(39.8mmol)溶解在500ml甲苯中,该溶液在50℃加热12小时。使混合物返回室温,滤出不溶性物质,而滤液在减压下浓缩。残余物收集在二氯甲烷和水中,分离出水相并用二氯甲烷萃取三次,有机相合并,用饱和氯化钠水溶液洗涤,硫酸钠干燥。蒸去溶剂后,残余物经硅胶色谱法纯化,洗脱液为乙酸乙酯和环己烷的20/80混合物。
最后得到7g纯产物,为结晶油状。
熔点:74—76℃。
1.3反式-[[[[3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基]氨基]羰基]氧基]乙酸
向4g(9.27mmol)步骤1.2得到的反式-[[[[3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基]氨基]羰基]氧基]乙酸乙酯在40ml二甲氧基乙烷中的溶液加入40ml1N氢氧化钠溶液,混合物室温搅拌2小时。减压浓缩该混合物,残余物溶解在最小量水中,加入1N盐酸直至pH为4,水相用二氯甲烷萃取三次,分离出有机相,用硫酸钠干燥,减压浓缩,得到3g标题酸。
熔点:114-116℃。
1.4反式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-(环丙基氨基)-2-氧乙酯
惰性气氛下,将0.169g(1.24mmol)氯甲酸异丁酯在5ml四氢呋喃中的溶液滴入0.5g(1.24mmol)步骤1.3得到的反式-[[[[3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基]氨基]羰基]氧基]乙酸和0.65ml(3.70mmol)N,N-二异丙乙胺在10ml四氢呋喃中的溶液(该溶液被冷却至约-20℃),同时保留反应物质的温度保持在-15℃以下。在该温度下搅拌1小时,然后缓慢加入0.078g(1.36mmol)环丙胺在5ml四氢呋喃中的溶液,在-15℃继续搅拌1小时,然后20℃搅拌10小时。减压浓缩,残余物收集在乙酸乙酯和水中,分离出有机相并用饱和氯化钠水溶液洗涤,硫酸钠干燥。减压浓缩,在乙醇中重结晶析出固体。
最后得到0.258g纯产物。
熔点:176℃。
1H NMR:(CDCl3)δ(ppm)8.10(d,1H);7.65(d,1H);7.35(dd,1H);7.25(d,1H);7.15(dd,1H);7.05(d,1H);6.20(broad m,1H);5.05(broad m,1H);4.70(t,1H);4.55(s,2H);4.35(m,2H);3.95-3.90(m,6H);3.30(m,2H);2.75(m,1H);1.75(m,4H);0.80(m,2H);0.55(m,2H)。
实施例2:(化合物49号)
反式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-氨基-2-氧乙酯
将20g(66mmol)反式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙胺、64g(198mmol)碳酸铯和73.14g(198mmol)四丁基碘化铵在400ml N,N-二甲基甲酰胺中的悬液倒入置于惰性气氛下的1升三颈圆底烧瓶中。在强烈搅拌条件下使二氧化碳气流通过该悬液2小时。然后,滴入18.5g(198mmol)氯乙酰胺在70mlN,N-二甲基甲酰胺中的溶液,持续通入二氧化碳气流5小时,室温搅拌过夜。滤出盐,减压浓缩滤液,残余物收集在乙酸乙酯和水中,分离出有机相并先后用0.1N盐酸水溶液、饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗涤。该有机相用硫酸钠干燥,减压浓缩滤液,残余物经硅胶色谱法纯化,洗脱液为乙酸乙酯和甲醇的95/5混合物,得到的固体在乙酸乙酯中重结晶。
最后得到6.5g纯产物。
熔点:148-150℃。
1H NMR:(DMSO)δ(ppm)8.15(d,1H);7.75(d,1H);7.4(dd,1H);7.35(d,1H);7.25(m,4H);7.15(broad m,1H);4.75(t,1H);4.35(s,2H);4.25(dd,2H);3.95(dd,2H);3.90(s+m,4H);3.05(m,2H);1.60(m,4H)。
实施例3:(化合物3号)
反式-2-(5-苯基-1,3-二噁烷-2-基)乙基氨基甲酸2-(甲氨基)-2-氧乙酯
3.1反式-[[[[2-(5-苯基-1,3-二噁烷-2-基)乙基]氨基]羰基]氧基]乙酸乙酯
采用实施例1.2的方法。以1g(4.8mmol)反式-2-(5-苯基-1,3-二噁烷-2-基)乙胺和1.1g(4.8mmol)的[(苯氧基羰基)氧基]乙酸乙酯为起始材料,得到0.740g油状的标题酯。
3.2反式-2-(5-苯基-1,3-二噁烷-2-基)乙基氨基甲酸2-(甲氨基)-2-氧乙酯
在0.70g(2.1mmol)步骤3.1得到的反式-[[[[2-(5-苯基-1,3-二噁烷-2-基)乙基]氨基]羰基]氧基]乙酸乙酯在4ml甲醇中的溶液中滴入3.3ml(6.7mmol)甲胺溶液(2M,溶剂为四氢呋喃),混合物室温搅拌12小时。减压浓缩该混合物,残余物经硅胶色谱法纯化,洗脱液为二氯甲烷和甲醇的90/10混合物。将得到的油与二异丙醚研磨,得到0.450g纯产物。
熔点:89℃。
1H NMR:(CDC13)δ(ppm)7.35-7.20(m,3H);7.15(dd,2H);6.15(broadm,1H);5.45(broad m,1H);4.75(t,1H);4.60(s,2H);4.20(dd,2H);3.80(dd,2H);3.40(m,2H);3.20(m,1H);2.85(d,3H);1.90(m,2H)。
实施例4:(化合物63号)
反式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸1H-咪唑-2-基甲酯
4.1(1-三苯基甲基-1H-咪唑-2-基)甲基碳酸苯酯
采用实施例1.1中描述的方法。以3g(8.80mmol)1-三苯基甲基-1H-咪唑-2-甲醇(J.Het.Chem.,(1995),32,903-906)和1.1ml(8.80mmol)的氯甲酸苯酯为起始材料,得到3.9g产物,它无需改性可用于下一个步骤中。
4.2反式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸(1-三苯基甲基-1H-咪唑-2-基)甲酯
采用实施例1.2中描述的方法。以2.5g(8.28mmol)反式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙胺和3.8g(8.28mmol)步骤4.1得到的(1-三苯基甲基-1H-咪唑-2-基)甲基碳酸苯酯为起始材料,得到3.2g无定形固体。
4.3反式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸1H-咪唑-2-基甲酯
室温下,向1.9g(2.83mmol)步骤4.2得到的反式-3-[5-(6-甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸(1-三苯基甲基-1H-咪唑-2-基)甲酯在150ml二氯甲烷中的溶液滴入0.6ml(2.83mmol)三氟乙酸在2ml二氯甲烷中的溶液,混合物室温搅拌12小时。减压浓缩该混合物,残余物收集在二氯甲烷和饱和碳酸氢钠水溶液中,分离出有机相并用饱和氯化钠水溶液洗涤,硫酸钠干燥,减压浓缩滤液,残余物经硅胶色谱法纯化,洗脱液为二氯甲烷、甲醇和氨水的98/2/0.2混合物。在乙酸乙酯中重结晶后,最后得到0.820g纯产物。
熔点:130-132℃。
1H NMR:(CDCl3)δ(ppm)10.0(broad m,1H);8.10(d,1H);7.65(d,1H);7.35(dd,1H);7.25(d,1H);7.15(dd,1H);7.05(dd,1H);7.00(s,2H);5.15(m+s,3H);4.70(t,1H);4.30(m,2H);3.95-3.90(m,6H);3.30(m,2H);1.85(m,4H)。
实施例5:(化合物46号)
反式-3-[5-(4-氯萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-氨基-2-氧乙酯
5.1反式-3-[5-(4-氯萘-1-基)-1,3-二噁烷-2-基]丙醇
依次将0.75ml(10mmol)2,3-二氢呋喃和0.25ml浓盐酸水溶液(37%)加入到1.18g(5mmol)2-(4-氯萘-1-基)-1,3-丙醇在10ml二噁烷的溶液中。混合物室温下反应过夜,然后加入5ml水。该混合物搅拌5小时,再用25ml水和50ml二氯甲烷稀释。沉降后分离混合物,水相用50ml二氯甲烷萃取。有机相用25ml饱和氯化钠水溶液洗涤,硫酸钠干燥,减压浓缩。残余物经硅胶色谱法纯化,洗脱液先是环己烷和乙酸乙酯的70/30混合物,再是60/40混合物。在二异丙醚中重结晶后,得到0.557g产物,为白色晶体。
5.2反式-3-[5-(4-氯萘-1-基)-1,3-二噁烷-2-基]丙基甲烷磺酸酯
惰性气氛下,向0.530g(1.72mmol)步骤5.1制备的反式-3-[5-(4-氯萘-1-基)-1,3-二噁烷-2-基]丙醇和0.48ml(3.45mmol)三乙胺在8ml二氯甲烷中的溶液(冷却至0℃)滴入0.256g(2.23mmol)甲磺酰氯在2ml二氯甲烷中的溶液。反应混合物在0℃搅拌1小时。加入25ml水和50ml二氯甲烷。沉降后分离混合物,水相用50ml二氯甲烷萃取。有机相用25ml饱和氯化钠水溶液洗涤,硫酸镁干燥,真空浓缩,得到0.66g产物,为白色固体,它无需改性可用在下一个步骤中。
5.3反式-3-[3-(5-(4-氯萘-1-基)-1,3-二噁烷-2-基)丙基]-1,3-恶唑烷-2,4-二酮
在惰性气氛下,使0.660g(1.71mmol)步骤5.2得到的反式-3-[5-(4-氯萘-1-基)-1,3-二噁烷-2-基]丙基甲烷磺酸酯、0.208g(2.05mmol)1,3-恶唑烷-2,4-二酮(J.Med.Chem.,1991,34,1542-1543)和0.396g(3.43mmol)1,1,3,3-四甲基胍与10ml四氢呋喃的混合物回流过夜。残余物收集在100ml乙酸乙酯和25ml水中。沉降后进行分离操作。有机相用25ml水和25ml饱和氯化钠水溶液洗涤。水相用50ml乙酸乙酯再萃取。合并有机相,硫酸钠干燥,减压浓缩。残余物经硅胶色谱法纯化,洗脱液先是环己烷和乙酸乙酯的70/30混合物,再是60/40混合物,得到0.483g产物,为白色固体。
熔点:125-127℃。
5.4反式-3-[5-(4-氯萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2-氨基-2-氧乙酯
将0.470g(1.20mmol)步骤5.3得到的反式-3-[3-(5-(4-氯萘-1-基)-1,3-二噁烷-2-基)丙基]-1,3-恶唑烷-2,4-二酮溶解在3.5ml四氢呋喃中,加入7ml 7N氨水的甲醇溶液。混合物室温反应过夜,然后蒸干,在异丙醇和二异丙醚的混合物中重结晶,得到0.388g产物,为白色晶体。
熔点:176-178℃。
LC-MS:M+H=407
1H NMR(DMSO)δ(ppm):8.35(d,1H);8.25(d,1H);7.8(m,3H);7.4
(d,1H);7.25(m,2H);7.15(s,1H);4.75(t,1H);4.3(s,2H);4.2(m,2H);4.0-3.9(m,3H);3.05(t,2H);1.65(m,2H);1.6(m,2H)。
实施例6:(化合物67号)
反式-3-[5-(6-环丙基甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸4-氯苯酯
室温下,将0.205g(0.60mmol)反式-3-[5-(6-环丙基甲氧基萘-1-基)-1,3-二噁烷-2-基]丙胺分小批加入到0.110ml(0.78mmol)氯甲酸4-氯苯酯和0.205ml(1.2
mmol)N,N-二异丙乙胺在6ml二氯甲烷中的溶液中。混合物室温搅拌16小时,再用5ml饱和碳酸氢钠溶液洗涤。分离两相,通过疏水性烧结玻璃漏斗滤出有机相。减压浓缩滤液,残余物经硅胶色谱法纯化,洗脱液为环己烷和乙酸乙酯的80/20混合物。用5ml二异丙醚洗涤后,得到0.176g白色固体。
LC-MS:M+H=496
熔点:159-162℃
1H NMR(CDCl3)δ(ppm):8.10(d,1H);7.65(d,1H);7.45-7.20(m,4H);7.20-7.00(m,4H);5.30(broad m,1H);4.75(t,1H);4.35(dd,2H);4.10-3.80(m,5H);3.50-3.25(m,2H);1.95-1.70(m,4H);1.45-1.20(m,1H);0.80-0.65(m,2H);0.50-0.30(m,2H)。
实施例7:(化合物68号)
反式-3-[5-(6-环丙基甲氧基萘-1-基)-1,3-二噁烷-2-基]丙基氨基甲酸2,2,2-三氟乙酯
室温下,将0.075ml(1.01mmol)2,2,2-三氟乙醇滴入0.205g(1.01mmol)氯甲酸4-硝基苯酯和0.555g(2.02mmol)N,N-二异丙基氨基乙基聚苯乙烯(Ps-DIEA,2%DVB,滴度=3.66mmol/g)在7.1ml二氯甲烷中的悬液。混合物以轨道摇动在室温搅拌16小时。通过装有烧结玻璃漏斗的滤筒滤出树脂,用4ml二氯甲烷冲洗。减压浓缩滤液,得到的油状残余物收集在3.5ml1,2-二氯乙烷中。依次加入0.134ml(0.78mmol)N,N-二异丙乙胺和0.205g(0.6mmol)3-[5-(6-环丙基甲氧基萘-1-基)-1,3-二噁烷-2-基]丙胺。该反应混合物在60℃加热16小时。冷却后,用20ml 1N氢氧化钠溶液洗涤。分离两相,通过疏水性烧结玻璃漏斗滤出有机相。减压浓缩滤液,残余物经硅胶色谱法纯化,洗脱液为环己烷和乙酸乙酯的80/20混合物。用5ml二异丙醚洗涤后,得到0.076g白色固体。
LC-MS:M+H=468
熔点:105-107℃
1H NMR:(CDCl3)δ(ppm):8.15(d,1H);7.65(d,1H);7.35(dd,1H);7.25(m,1H);7.15(d,1H);7.10(d,1H);5.15(broad m,1H);4.75(t,1H);4.50(q,2H);4.30(dd,2H);4.10-3.80(m,5H);3.40-3.20(m,2H);1.90-1.65(m,4H);1.45-1.20(m,1H);0.75-0.60(m,2H);0.50-0.35(2H)。
下表说明本发明一些实施例化合物的化学结构与物理性质。表中的化合物在二噁烷环上具有反式相对构型,但化合物37和50号为顺式相对构型以及化合物6、9、11、13、18、20、21和43为顺式和反式立体异构体混合物形式除外。表中化合物全部是碱形式。
表
编号 | R1 | n | R2 | M+H | 熔点(℃) |
1. | 苯基 | 2 | CH2CONH2 | - | 172-174 |
2. | 苯基 | 3 | CH2CONH2 | - | 116-118 |
3. | 苯基 | 2 | CH2CONHCH3 | - | 89 |
4. | 苯基 | 3 | CH2CONHCH3 | - | 116 |
5. | 苯基 | 2 | CH2CF3 | 334 | 77-80 |
6. | 苯基 | 3 | CH2CF3 | 348 | 83-85 |
7. | 苯基 | 2 | 苯基 | 328 | 131-134 |
8. | 苯基 | 3 | 苯基 | 342 | 100-103 |
9. | 苯基 | 2 | 2-氯苯基 | 362 | 95-98 |
10. | 苯基 | 3 | 2-氯苯基 | 376 | 129-131 |
11. | 苯基 | 2 | 4-氯苯基 | 362 | 134-136 |
12. | 苯基 | 3 | 4-氯苯基 | 376 | 117-121 |
13. | 苯基 | 2 | 4-氟苯基 | 346 | 132-134 |
14. | 苯基 | 3 | 4-氟苯基 | 360 | 106-109 |
15. | 苯基 | 2 | 4-甲基苯基 | 342 | 112-115 |
16. | 苯基 | 3 | 4-甲基苯基 | 356 | 87-90 |
17. | 苯基 | 2 | 2-甲氧基苯基 | 358 | - |
18. | 苯基 | 3 | 2-甲氧基苯基 | 372 | 84-87 |
19. | 苯基 | 2 | 4-甲氧基苯基 | 358 | 130-132 |
20. | 苯基 | 3 | 4-甲氧基苯基 | 372 | 99-101 |
21. | 苯基 | 2 | 3-三氟甲基苯基 | 396 | 87-90 |
22. | 苯基 | 3 | 3-三氟甲基苯基 | 410 | 128-131 |
23. | 4-氟苯基 | 1 | 4-氯苯基 | - | 139-141 |
24. | 4-氟苯基 | 2 | CH2CONHCH3 | - | 124-126 |
编号 | R1 | n | R2 | M+H | 熔点(℃) |
25. | 4-氟苯基 | 3 | CH2CONHCH3 | - | 150-152 |
26. | 3-氯苯基 | 2 | 4-氯苯基 | - | 123-125 |
27. | 3-氯苯基 | 3 | 4-氯苯基 | - | 89-91 |
28. | 4-氯苯基 | 1 | 4-氯苯基 | - | 146-148 |
29. | 4-氯苯基 | 1 | CH2CF3 | - | 99-101 |
30. | 2-甲氧基苯基 | 2 | 4-氯苯基 | - | 144-146 |
31. | 3-甲氧基苯基 | 2 | 4-氯苯基 | - | 116-118 |
32. | 4-甲氧基苯基 | 3 | 4-氯苯基 | - | 128-131 |
33. | 3-三氟甲基苯基 | 1 | 4-氯苯基 | - | 116-119 |
34. | 3-三氟甲基苯基 | 1 | CH2CF3 | - | 66-67 |
35. | 3-三氟甲基苯基 | 3 | 4-氯苯基 | - | 93-96 |
36. | 3-三氟甲基苯基 | 2 | CH2CONHCH3 | - | 118-120 |
37. | 3-三氟甲基苯基 | 2 | CH2CONHCH3 | - | 82-84 |
38. | 萘-1-基 | 3 | CH2CONH2 | - | 112-114 |
39. | 萘-1-基 | 2 | CH2CONHCH3 | - | 86-88 |
40. | 萘-1-基 | 3 | CH2CONHCH3 | - | 154 |
41. | 萘-1-基 | 2 | CH2CF3 | 384 | 111-113 |
42. | 萘-1-基 | 3 | CH2CF3 | 398 | 89-92 |
43. | 萘-1-基 | 2 | CH2-苯并咪唑-2-基 | 432 | - |
44. | 萘-1-基 | 2 | 苯基 | 378 | 131-133 |
45. | 萘-1-基 | 3 | 苯基 | 392 | 125-127 |
46. | 4-氯-萘-1-基 | 3 | CH2CONH2 | 407 | 176-178 |
47. | 4-氯-萘-1-基 | 3 | CH2CONHCH3 | - | 190-192 |
48. | 6-氯-萘-1-基 | 3 | CH2CONHCH3 | - | 182-184 |
49. | 6-甲氧基-萘-1-基 | 3 | CH2CONH2 | - | 148-150 |
50. | 6-甲氧基-萘-1-基 | 3 | CH2CONH2 | - | 144-147 |
51. | 6-甲氧基-萘-1-基 | 1 | CH2CONHCH3 | - | 194-196 |
52. | 6-甲氧基-萘-1-基 | 1 | 4-氯苯基 | - | 133-136 |
53. | 6-甲氧基-萘-1-基 | 1 | CH2CF3 | - | 142-144 |
编号 | R1 | n | R2 | M+H | 熔点(℃) |
54. | 6-甲氧基-萘-1-基 | 2 | CH2CONHCH3 | - | 136-138 |
55. | 6-甲氧基-萘-1-基 | 2 | 4-氯苯基 | - | 129-131 |
56. | 6-甲氧基-萘-1-基 | 2 | CH2CF3 | - | 93-95 |
57. | 6-甲氧基-萘-1-基 | 3 | CH2CONHCH3 | - | 128-130 |
58. | 6-甲氧基-萘-1-基 | 3 | CH2CONHCH2CH3 | - | 170-172 |
59. | 6-甲氧基-萘-1-基 | 3 | CH(CH3)CONHCH3 | - | 154 |
60. | 6-甲氧基-萘-1-基 | 3 | CH2CONHCH2-吡啶-4-基 | - | 152 |
61. | 6-甲氧基-萘-1-基 | 3 | CH2CONH-环丙基 | - | 176 |
62. | 6-甲氧基-萘-1-基 | 3 | CH2CF3 | - | 111 |
63. | 6-甲氧基-萘-1-基 | 3 | CH2-咪唑-2-基 | - | 130-132 |
64. | 6-甲氧基-萘-1-基 | 3 | CH2-苯并咪唑-2-基 | - | 175-176 |
65. | 6-甲氧基-萘-1-基 | 3 | 苯基 | - | 128 |
66. | 6-环丙基-甲氧基萘-1-基 | 3 | CH2CONH2 | - | 137-139 |
67. | 6-环丙基-甲氧基萘-1-基 | 3 | 4-氯苯基 | 496 | 159-162 |
68. | 6-环丙基-甲氧基萘-1-基 | 3 | CH2CF3 | 468 | 105-107 |
69. | 6-苯基甲氧基-萘-1-基 | 1 | CH2CONH2 | - | 154-156 |
70. | 6-羟基-萘-1-基 | 3 | CH2CONH2 | - | 166-170 |
71. | 6-羟基-萘-1-基 | 3 | CH2CONHCH3 | - | 140-148 |
72. | 7-甲氧基-萘-1-基 | 3 | CH2CONH2 | - | 156-158 |
73. | 7-甲氧基-萘-1-基 | 3 | CH2CONHCH3 | - | 144-146 |
74. | 7-甲氧基-萘-1-基 | 3 | CH2CF3 | 428 | 93-96 |
75. | 7-甲氧基-萘-1-基 | 3 | 苯基 | 422 | 151-153 |
76. | 萘-2-基 | 3 | 苯基 | 392 | 130-131 |
77. | 萘-2-基 | 3 | CH2CONHCH3 | - | 144-146 |
78. | 萘-2-基 | 3 | CH2CF3 | 398 | 130-132 |
本发明化合物是药理试验的对象,用来确定它们对酶FAAH(脂肪酸酰氨基水解酶)的抑制作用。
这种抑制活性在放射酶学测定法中得到确认,该测定法基于测量FAAH水解anandamide[乙醇胺1-3H]过程的水解产物(Life Science(1995),56,1999-2005 and Journal of Pharmacology and Experimented Therapeutics(1997),283,729-734)。所以,切除小鼠脑(去掉小脑),储存于-80℃。用Polytron均化组织即场制备膜均浆,均化采用10mM Tris-HCl缓冲液(pH8.0),它含有150mMNaCl和1mM EDTA。然后,在70μl不带脂肪酸但含有牛血清白蛋白的缓冲液(1mg/ml)中进行酶反应。依次加入各种浓度的测试化合物、用非放射性标记的anandamide稀释至10μM的anandamide[乙醇胺1-3H](比活性为15-20Ci/mmol)和膜制品(每次测定为400μg冷冻组织)。在25℃反应15分钟后,加入140μl氯仿/甲醇(2:1)终止酶反应。混合物搅拌10分钟,再以3500g离心15分钟。用液相闪烁法计算含有乙醇胺[1-3H]的水相等分试样(30μl)。
在这样的条件下,本发明大部分活性化合物的IC50值(抑制一半FAAH对照酶活性的浓度)在0.005至1μM范围内。
因此看来,本发明的化合物对酶FAAH具有抑制活性。
本发明化合物的体内活性在镇痛试验中评估。
所以,将PBQ(苯基苯醌,在含5%乙醇的0.9%氯化钠溶液中为2mg/kg)腹腔内(i.p.)给予重25至30g雄性OF1小鼠,引起腹部肌肉牵拉,注射后5至15分钟内平均扭动或收缩30次。给予PBQ之前30分钟、60分钟或120分钟口服或腹腔内给予在0.5%Tween80悬液中的测试化合物。在此条件下,本发明最有效的化合物在1至30mg/kg范围内能使PBQ诱导的牵拉次数减少50%至70%。
酶FAAH(Chemistry and Physics of Lipids,(2000),108,107-121)对内源性酰胺衍生物和各种脂肪酸的酯(如N-花生四烯酰基乙醇胺(anandamide)、N-棕榈酰基乙醇胺、N-油酰基乙醇胺、油酰胺或2-花生四烯酰基甘油)的水解作用具有催化活性。这些衍生物尤其通过与大麻素和辣椒素受体相互作用来表现各种药理活性。本发明的化合物阻断该降解通道并增加这些内源物质的组织水平。为此,它们可用来预防或治疗涉及通过酶FAAH代谢内源大麻素和/或任何其他物质的任何病理病症。
例如,以下提到的疾病和病症:
疼痛,特别是神经类急性或慢性疼痛:偏头痛,包括疱疹性病毒和糖尿病相关的各种形式在内的神经痛;
炎性疾病相关的急性或慢性疼痛:关节炎、类风湿关节炎、骨关节炎、脊椎炎、痛风、血管炎、克隆氏症(Crohn′s Disease)、肠道易激综合征;
急性或慢性末梢性疼痛;
晕动症、呕吐、恶心,特别是由化疗引起的恶心;
饮食失调,特别是各类厌食症和恶病质引起的饮食失调;
神经系统病症和精神病理病症:震颤、运动障碍、肌张力障碍、痉挛、强迫症、图雷特氏综合征、任何性质和病因引起的全部形式的抑郁症和焦虑、情绪紊乱、精神病;
急性或慢性神经系统退化性疾病:帕金森氏症、阿耳茨海默氏病、老年性痴呆、亨廷顿舞蹈症、脑缺血相关的以及颅和髓创伤相关的损伤;
癫痫症;
睡眠紊乱症,包括睡眠呼吸暂停;
心血管疾病,特别是高血压、心律不齐、动脉硬化、心脏病发作、心脏缺血;
肾脏缺血;
癌症:良性皮肤肿瘤、乳突淋瘤和脑瘤、前列腺肿瘤、脑瘤(神经胶母细胞瘤、髓上皮瘤、成神经管细胞瘤、成神经细胞瘤、胚胎源肿瘤、星细胞瘤、成星形细胞瘤、室管膜细胞瘤、少突神经胶质细胞瘤、丛肿瘤、神经上皮瘤、骨骺瘤、成骨管膜细胞瘤、恶性脑膜瘤、肉瘤病、恶性黑素瘤、神经鞘瘤);
免疫系统疾病,特别是自身免疫疾病:牛皮癣、红斑狼疮症、结缔组织疾病或胶原疾病、斯耶格伦氏综合征、强直性脊椎关节炎、未分化脊椎关节炎、贝切特氏病(Behcet’s disease)、溶血性自身免疫贫血症、多发性硬化症、肌萎缩性侧索硬化症、直链淀粉、移植排斥、影响浆细胞系的疾病;
过敏性疾病:速发型和迟发型过敏反应、过敏性鼻炎或结膜炎、接触性皮炎;
寄生性、病毒性或细菌性感染疾病;AIDS:脑膜炎
炎症疾病,特别是关节的炎症疾病:关节炎、类风湿关节炎、骨关节炎、脊椎炎、痛风、血管炎、克隆氏症、肠道易激综合征;
骨质疏松症;
眼病:眼内高压、青光眼;
肺部疾病:呼吸道疾病、支气簵痉挛、咳嗽、哮喘、慢性支气管炎、慢性呼吸道阻塞、肺气肿;
胃肠疾病:肠道易激综合征、肠内炎症疾病、溃疡、腹泻、胃食管反流;
尿失禁和膀胱发炎。
本发明化合物在制备打算用来预防或治疗上述病症的医药产品中的用途,是本发明的一个完整部分。
本发明的一个主题是医药产品,该产品含有通式(I)化合物,或者通式(I)化合物的药学上可接受的盐、或水合物或溶剂化物。这些医药产品可用于治疗学上,特别是预防和治疗上述病症。
另一方面,本发明涉及药物组合物,它们含有本发明至少一种化合物作为活性成份。这些药物组合物包含有效剂量的本发明化合物,或者所述化合物药学上可接受的盐、水合物或溶剂化物,任选地并且包含一或多种药学上可接受的赋形剂。
根据药物形式和给药方法,所述赋形剂从已知的常用赋形剂中进行选择。
在供口服,舌下,皮下,肌内,静脉,表面,局部,气管内,鼻腔内,经皮、肺部、眼睛或直肠途径给药的本发明药物组合物中,上述通式(I),或其可能的盐、溶剂物或水合物的活性成份,可以与常规药用赋形剂一起,以单剂量给药形式供动物用和人用,用于预防或治疗上述的失调或疾病。
适宜的单剂量给药形式包括口服给药形式,比如片剂、软或硬胶囊、粉剂、颗粒剂、口香糖和口服溶液或混悬剂,舌下、口腔、气管内、眼内或鼻腔内给药形式,吸入给药形式,皮下、肌内、静脉或鞘内给药形式,直肠和阴道内给药形式。对于局部表面给药,本发明化合物可以其霜剂、软膏剂或洗剂使用。
举例说明,本发明化合物的单剂量给药形式,以片剂为例,可能含有以下组分:
本发明化合物 50.0mg
甘露醇 223.75mg
交联羧甲基纤维素钠 6.0mg
玉米淀粉 15.0mg
羟丙甲基纤维素 2.25mg
硬脂酸镁 3.0mg
根据药物形式,所述单剂形式可含有的活性成份日剂量为0.01~20mg/kg体重。
可以有适宜使用更高或更低剂量的特殊情况;这样的剂量没有脱离本发明的范围。常规的做法是,每个病人的合适剂量由医生根据给药方式、病人体重和用药后反应来决定。
另一方面,本发明也涉及治疗上述病症的方法,包含将本发明化合物、或其可药用的盐或溶剂化物或水合物中的一种的有效剂量给予病人。
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FR02/10707 | 2002-08-29 | ||
FR0210707A FR2843964B1 (fr) | 2002-08-29 | 2002-08-29 | Derives de dioxane-2-alkylcarbamates, leur preparation et leur application en therapeutique |
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CNB038241056A Expired - Fee Related CN100491368C (zh) | 2002-08-29 | 2003-08-27 | 二烷-2-烷基氨基甲酸酯衍生物,其制备及其在治疗学上的应用 |
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FR2854633B1 (fr) * | 2003-05-07 | 2005-06-24 | Sanofi Synthelabo | Derives de piperidinyl-et piperazinyl-alkylcarbamates, leur preparation et leur application en therapeutique |
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FR2866884B1 (fr) * | 2004-02-26 | 2007-08-31 | Sanofi Synthelabo | Derives d'aryl-et d'heteroaryl-piperidinecarboxylates, leur preparation et leur application en therapeutique |
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WO2008063714A1 (en) * | 2006-11-20 | 2008-05-29 | N.V. Organon | Metabolically-stabilized inhibitors of fatty acid amide hydrolase |
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FR2941696B1 (fr) * | 2009-02-05 | 2011-04-15 | Sanofi Aventis | Derives d'azaspiranyl-alkylcarbamates d'heterocycles a 5 chainons, leur preparation et leur application en therapeutique |
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JP5738766B2 (ja) | 2009-09-09 | 2015-06-24 | 大日本住友製薬株式会社 | 8−オキソジヒドロプリン誘導体 |
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EP2545914A1 (en) | 2011-07-11 | 2013-01-16 | Sanofi | 2-amino-2-oxoethyl trans-3-[5-(6-methoxy-naphtalen-1-yl)-1,3-dioxan-2-yl]propyl-carbamate for use in the treatment of persistent cancer pain |
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