CN1922138A - 芳氧基烷基氨基甲酸酯类衍生物,它们的制备方法与治疗用途 - Google Patents
芳氧基烷基氨基甲酸酯类衍生物,它们的制备方法与治疗用途 Download PDFInfo
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Abstract
符合式(I)的化合物,式中:m代表0、1、2或3;n代表0、1、2或3;X代表氧或硫原子或SO或SO2基团;R1和R2彼此独自地代表氢原子或C1-3烷基,或R1和R2一起构成-(CH2) p-基团,其中p代表1-5的整数,以便n+p是2-5的整数;R3代表氢原子或氟原子或羟基或甲基;R4代表式CHR5CONHR6基团,其中:R5代表氢原子或C1-6-烷基和R6代表氢原子或C1-6-烷基、C3-7-环烷基、C3-7-环烷基-C1-6-亚烷基;Y代表选自苯基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、噻唑基、萘基、喹啉基、异喹啉基、2,3二氮杂萘基、喹唑啉基、喹喔啉基、萘啶基、噌啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、异吲哚基、二氢吲哚基、苯并咪唑基、苯并噻唑基、苯并异噻唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、苯并噻二唑基、苯并噻二唑基,这些基团任选地被取代。所述的化合物呈碱、与酸的加成盐、水合物或溶剂化物形式。在治疗上的应用。
Description
本发明的目的是芳氧基烷基氨基甲酸酯衍生物,它们的制备方法与治疗用途。
本发明的化合物符合下述式(I):
式中:
m代表0、1、2或3;
n代表0、1、2或3;
X代表氧或硫原子或SO或SO2基团;
R1和R2彼此独自地代表氢原子或C1-3烷基,或R1和R2一起构成-(CH2)p-基团,其中p代表1-5的整数,以便n+p是2-5的整数;
R3代表氢原子或氟原子或羟基或甲基;
R4代表通式CHR5CONHR6基团,其中:
R5代表氢原子或C1-6-烷基和
R6代表氢原子或C1-6-烷基、C3-7-环烷基、C3-7-环烷基-C1-6-亚烷基;
Y代表:
Y1基团特别地选自苯基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、噻唑基、萘基、喹啉基、异喹啉基、2,3二氮杂萘基(phtalazinyle)、喹唑啉基、喹喔啉基、萘啶基、噌啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、异吲哚基、二氢吲哚基、苯并咪唑基、苯并唑基、苯并异唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、苯并二唑基、苯并噻二唑基;Y1基团任选地被一个或多个彼此相同或不同的取代基Y2取代,或被Y3基团取代;
Y2代表卤素原子、氰基、硝基、C1-8-烷基、C1-8-烷氧基、C1-8-硫代烷基、C1-8-氟烷基、C1-8-氟烷氧基、C1-8-氟硫代烷基、C3-7-环烷基、C3-7-环烷氧基、C3-7-环烷基-C1-8-亚烷基、C3-7-环烷基-C1-8-烷氧基、羟基、NR7R8,NHCOR7,NHSO2R7,COR7,CO2R7,CONR7R8,SO2R7,SO2NR7R8,-O-(C1-3-亚烷基)-O-、苯氧基、苯硫基、苯基-C1-C8-亚烷基、苯基-C1-C8-烷氧基或苯基-C1-C8-烷硫代基;
Y3代表特别地选自苯基、吡啶基、嘧啶基、吡嗪基或哒嗪基的基团;这个或这些Y3基团可以被一个或多个彼此相同或不同的基团Y2取代;
R7和R8彼此独自地代表氢原子或C1-6-烷基,或与它们带的氮原子一起构成吖丁啶、吡咯烷、哌啶、吗啉、硫代吗啉、吖庚因、哌嗪的环,该环任选地被C1-3-烷基或苄基取代。
在式(I)化合物中,第一组化合物是,其中:
Y代表
Y1基团特别地选自苯基、吡啶基、嘧啶基、噻唑基、萘基、喹啉基、异喹啉基、苯并唑基;Y1基团任选地被一个或多个相同或不同的取代基,更特别地被一个或两个取代基Y2取代,或被Y3基团取代;Y2代表卤素原子,更特别地氯、氟或溴、氰基、C1-8-烷基,更特别地甲基、异丙基、丁基、叔丁基或四甲基丁基、C1-8-烷氧基,更特别地甲氧基、乙氧基或丙氧基、C1-8-氟烷基,更特别地三氟甲基,C1-8-氟烷氧基,更特别地三氟甲氧基、苯氧基、苯基-C1-C8-亚烷基,更特别地苯基-(1,1-二甲基亚甲基);
Y3代表苯基;Y3可以被一个或多个彼此相同或不同的基团,更特别地被一个或两个基团Y2取代。
在如前面定义的第一组化合物中,第二组化合物是,其中:
Y代表
Y1基团特别地选自苯基或萘基;Y1基团任选地被一个或多个彼此相同或不同的取代基,更特别地被一个或两个取代基Y2基团取代,或被Y3基团取代;
Y2代表卤素原子,更特别地氯、氟或溴,氰基、C1-8-烷基,更特别地甲基、异丙基、丁基、叔丁基或四甲基丁基、C1-8-烷氧基,更特别地甲氧基、乙氧基或丙氧基,C1-8-氟烷基,更特别地三氟甲基、C1-8-氟烷氧基,更特别地三氟甲氧基、苯氧基、苯基-C1-C8-亚烷基,更特别地苯基-(1,1-二甲基亚甲基);
Y3代表苯基;Y3可以被一个或多个彼此相同或不同的基团,更特别地被一个或两个Y2基团取代。
在式(I)化合物中,第三组化合物是,其中:
m代表0、1、2或3;和/或
n代表0、1、2或3;和/或
R1和R2彼此独自地代表氢原子或C1-3-烷基,或R1和R2一起构成-(CH2)p-基团,其中p代表1-5的整数,以便n+p是2-5的整数;
其条件是R1和R2彼此独自地代表氢原子或C1-3-烷基,而m+n>1。
在如前面定义的第三组化合物中,第四组化合物是,其中:
m代表0、1、2或3;和/或
n代表0、1、2或3;和/或
R1和R2一起构成-(CH2)p-基团,其中p代表1-4的整数,以致n+p等于4。
在式(I)化合物中,第五组化合物是,其中X代表氧原子。
在式(I)化合物中,第六组化合物是,其中R3代表氢原子。
第七组由其中R1、R2、R3、R4、R5、R6、R7、R8、X、Y、Y1、Y2、Y3、n和m同时如这些上述化合物小组中所定义的化合物组成。
式(I)化合物可以含有一个或多个非对称碳原子。它们能以对映异构体或非对映异构体形式存在。这些对映异构体和非对映异构体以及它们的混合物,其中包括外消旋混合物都是本发明的一部分。
式(I)化合物能以碱或与酸的加成盐形式存在。这样一些加成盐都是本发明的一部分。
使用在药学上可接受的酸制备这些盐很有利,而例如纯化或分离式(I)化合物时使用的其它酸盐也是本发明的一部分。式(I)化合物可以呈水合物或溶剂化物形式,即呈与一个或多个水分子或与溶剂缔合或化合的形式。这样一些水合物和溶剂化物也是本发明的一部分。
在本发明的范围内,应该理解:
-Ct-z,其中t和z可以取值1-8,含碳链可以有t-z个碳原子,例如C1-3含碳链,它可以有1-3个碳原子,
-烷基,直链或支链饱和脂族基团;例如C1-3烷基代表有1-3个碳原子的直链或支链含碳链,更特别地甲基、乙基、丙基、1-甲基乙基;
-亚烷基,直链或支链饱和二价烷基,例如C1-3-亚烷基代表有1-3个碳原子的直链或支链二价含碳链,更特别地亚甲基、亚乙基、1-甲基亚乙基、亚丙基、1,1-二甲基亚甲基;
-环烷基,环状烷基,例如C3-5环烷基代表有3-5个碳原子的环状含碳链,更特别地环丙基、环丁基、环戊基;
-亚烯基,二价不饱和的有2个碳的脂族基团,更特别地乙烯;
-烷氧基,具有直链或支链饱和脂肪链的-O-烷基;
-硫烷基,具有直链或支链饱和脂族链的-S-烷基;
-氟烷基,其中一个或多个氢原子已被氟原子取代的烷基;
-氟烷氧基,其中一个或多个氢原子已被氟原子取代的烷氧基;
-氟硫代烷基,其中一个或多个氢原子已被氟原子取代的硫烷基;
-卤素原子,氟、氯、溴或碘。
可以采用下面流程说明的不同方法制备本发明的化合物。
于是,制备方法(流程1)是在例如甲苯或二氯乙烷的溶剂中,在温度0-80℃下,让通式(II)胺(式中Y、X、R1、R2、R3、m和n如式(I)中所定义)与通式(III)的碳酸盐(式中Z代表氢原子或硝基,R5如式(I)中所定义和R代表甲基或乙基)进行反应。使用式R6NH2胺通过氨解作用将如此得到的式(IV)氨基甲酸酯再转化成式(I)化合物,其中R6如式(I)中所定义。这种氨解反应可以在例如甲醇或乙醇的溶剂中,或在甲醇与四氢呋喃的溶剂混合物中进行。
流程1
式中R2更特别地代表氢原子的式(I)化合物的其它制备方法(流程2),是让式(IIa)衍生物(式中W代表羟基、甲磺酸酯(mésylate)、甲苯磺酸酯基团或氯、溴和碘原子,和式中Y、X、R1、R3、m和n如式(I)中所定义)与通式结构(V)的唑烷-二酮(式中R5如式(I)中所定义)进行反应,得到通式结构(VI)的唑烷-二酮衍生物。在W代表羟基基团的情况下,根据Mitsunobu条件(《合成》(Synthesis),1981,1-28),例如在三苯基膦存在下通过偶氮二甲酸二乙酯或二异丙酯的作用,可以进行这个反应。在W代表氯、溴或碘原子或甲磺酸酯或甲苯磺酸酯基团的情况下,可以在例如1,1,3,3-四甲基胍、氢化钠或叔丁醇钠的碱存在下,在例如四氢呋喃、乙腈或二甲基甲酰胺的溶剂中,在温度0℃至溶剂回流温度下进行这个反应。然后,通过氨解作用,使用式R6NH2胺,其中R6如式(I)中所定义,将如此得到的式(VI)唑烷-二酮衍生物转化成式(I)化合物。
流程2
获得式(I)化合物(式中X更特别地代表氧原子)的另一个实施方案(流程3)在于,例如按照Mitsunobu反应条件(《合成》,1981,1-28)或改进的Mitsunobu反应条件(《四面体通讯》(TetrahedronLetters),1993,34,1639-1642),让式(VIIa)、(VIIb)或(VIIc)醇衍生物与通式结构YOH酚衍生物(式中Y如式(I)中所定义)进行反应,然后,通过氨解作用,使用式R6NH2胺,其中R6如式(I)中所定义,将氨基甲酸酯衍生物(IVa)和唑烷二酮(VIa)转化成式(I)化合物。
在式(VIIa)、(VIIb)和(VIIc)中,R1、R2、R3、R5、R6、m、n和R如前面所定义。
流程3
获得式(I)化合物(式中Y更特别地代表芳基-芳基、芳基-杂芳基、杂芳基-芳基或杂芳基-杂芳基类的Y1-Y3基团)的另一个实施方案(流程4)在于,例如按照Suzuki反应条件(《Chem.Rev.》,1995,95,2457-2483),让通式结构(VIII)芳基卤衍生物(式中U是溴原子或碘原子,而Y1、X、R1、R2、R3、R5、R6、n和m如式(I)中所定义)与式Y3B(OH)2的芳基-或杂芳基-硼酸衍生物进行反应(式中Y3如式(I)中所定义)或按照Stille反应条件(《Angew.Chem.Int.Ed.》,1986,25,504-524),与式Y3Sn(R′)3芳基-或杂芳基-三-烷基锡烷衍生物进行反应(式中Y3如式(I)中所定义,而R′是C1-4-烷基)。
流程4
通式结构(II)、(IIa)、(III)、(V)、(VIIa)、(VIIb)、(VIIc)、(VIII)化合物和通式结构YOH酚衍生物的制备方式没有描述过,它们可从市场上获得或在文献中已描述,或可以根据已描述的或本技术领域的技术人员已知的方法制备得到。
式R6NH2胺可从市场上获得。
下面的实施例说明本发明的一些化合物的制备方法。这些实施例不是限制性的,只是说明本发明。微量分析、红外光谱和NMR和/或LC-MS(液相色谱与质谱联用)证实所得到化合物的结构和纯度。
PF(℃)代表以摄氏度表示的熔点。
实施例标题中用括号表示的编号相应于下表第1栏的编号。
UICPA(国际纯化学与应用化学协会-英语为IUPAC)的缩写已用于下述实施例中化合物的命名。例如,对于联苯基,已遵守下述编号:
实施例1(第1号化合物)
{2-[(4-氯苯基)氧]乙基}氨基甲酸2-(甲基氨基)-2-氧代乙酯
1.1.[(苯氧基羰基)氧]乙酸乙酯
往25g(240mmol)羟乙酸乙酯和55ml(315mmol)二异丙基乙胺在500ml甲苯中的溶液,在室温下缓慢添加32ml(256mmol)氯甲酸苯酯。在室温下搅拌2小时。分离生成的盐,滤液在减压下浓缩。得到53.7g原样用于后续步骤的油状产物。
1.2.{[({2-[(4-氯苯基)氧]乙基}氨基)羰基]氧}乙酸乙酯
0.6g(3.5mmol)[(4-氯苯基)氧]乙胺(《Chim.Ther.》,1973,8,259-270)和1.3g(5.8mmol)在步骤1.1.制备的[(苯氧基羰基)氧]乙酸乙酯在30ml甲苯中的溶液在60℃加热一夜。蒸发至干,该产物采用硅胶柱色谱进行纯化,使用乙酸乙酯和环己烷30/70混合物洗脱。得到0.7g含有~10%唑烷-二酮成环产物的油状产物,它可原样用于后续步骤。
1.3.{2-[(4-氯苯基)氧]乙基}氨基甲酸2-(甲基氨基)-2-氧代乙酯
把3.5ml(7mmol)2M甲胺在四氢呋喃中的溶液添加到0.7g(2.3mmol)在步骤1.2.制备的{[({2-[(4-氯苯基)氧]乙基}氨基)羰基]氧}乙酸乙酯在5ml甲醇中的溶液。任其在室温下进行反应一夜。蒸发至干,残留的固体用己烷洗涤,然后用异丙醚洗涤,得到0.59g粉末状的产物。
熔点(℃):147-149
LC-MS:M+H=287
RMN-1H(DMSO)δ(ppm):7,75(m,1H),7,40(m,1H),7,25(d,2H),6,95(d,2H),4,35(s,2H),3,95(t,2H),3,35(m,2H),2,60(d,3H)
实施例2(第11号化合物)
(2-[(4-氰基苯基)氧]乙基)氨基甲酸2-氨基-2-氧代乙酯
2.1.3-(2-羟基乙基)-1,3-唑烷-2,4-二酮
在2小时内,往49ml(95mmol)1.9M碳酰氯在甲苯中的溶液(该溶液稀释在50ml四氢呋喃中并用冰浴冷却)滴加3ml(39.6mmol)乙醇酸甲酯在25ml四氢呋喃中的溶液。然后在室温下搅拌16小时和蒸发至干。与30ml二氯甲烷共蒸发4次。将该残留物溶于40ml乙腈中,再在1小时内将其滴加到3.4ml(59.4mmol)乙醇胺和30ml(178mmol)二异丙基乙胺在乙腈和二氯甲烷50/10混合物(已用冰浴冷却)中的溶液。然后,在室温下搅拌16小时。用硅藻土过滤,蒸发至干,该产物采用硅胶柱色谱进行纯化,使用乙酸乙酯和n-己烷混合物(先70/30,后80/20)洗脱,得到4.9g白色固体状的产物。
2.2.(2-[(4-氰基苯基)氧]乙基)氨基甲酸2-氨基-2-氧代乙酯
往0.13g(0.88mmol)在步骤2.1.制备的3-(2-羟基乙基)-1,3-唑烷-2,4-二酮、0.35g(1.35mmol)三苯基膦和0.10g(0.89mmol)4-羟基苯并腈在2ml用冰浴冷却的苯中的溶液,滴加0.61ml(1.35mmol)2.2M偶氮二甲酸二乙酯在甲苯中的溶液。然后,该反应混合物在室温下搅拌16小时。蒸发至干,该产物采用硅胶柱色谱进行纯化,使用二氯甲烷和乙酸乙酯混合物(先99/1,后98/2)洗脱。该产物溶于1.5ml7M(10.5mmol)氨在甲醇中的溶液。搅拌一小时。过滤沉淀,用乙酸乙酯洗涤,得到0.035g白色固体。
熔点(℃):204-206
LC-MS:M+H=264
RMN-1H(DMSO)δ(ppm):7,55(d,2H),7,05(m,1H),6,90-6,80(m+d,4H),4,35(s,2H),4,05(t,2H),3,45(m,2H)
实施例3(第58号化合物)
[4-(1-萘氧基)丁基]氨基甲酸2-氨基-2-氧代乙酯
3.1.3-[4-(1-萘氧基)丁基]-1,3-唑烷-2,4-二酮
往3.1g(11.1mmol)1-[(4-溴丁基)氧]萘(《Eur.J.Med.Chem.》,1997,32,175-179)和1.35g(13.3mmol)1,3-唑烷-2,4-二酮(《J.Med.Chem.》,1991,34,1542-1543)在30ml四氢呋喃中的溶液,滴加2.55g(22.2mmol)1,1,3,3-四甲基胍在15ml四氢呋喃中的溶液。加热回流8小时。再添加0.28g(2.7mmol)1,3-唑烷-2,4-二酮和0.32g(2.7mmol)1,1,3,3-四甲基胍,再加热回流4小时。该反应混合物使用冰浴冷却,添加100ml乙酸乙酯,然后添加50ml 1M盐酸水溶液。倾析,该含水相用2×80ml乙酸乙酯提取。然后,这些有机相先用80ml水,再用80ml饱和氯化钠水溶液洗涤。它们用硫酸钠干燥,再蒸发至干。该产物采用硅胶柱色谱进行纯化,使用环己烷和乙酸乙酯80/20混合物洗脱,得到2.0g产物,它可原样用于后续步骤。
3.2.[4-(1-萘氧基)丁基]氨基甲酸2-氨基-2-氧代乙酯
将1.50g(5.0mmol)在步骤3.1.制备的3-[4-(1-萘氧基)丁基]-1,3-唑烷-2,4-二酮溶于10ml四氢呋喃和28ml 7N(200mmol)氨甲醇溶液的混合物中。让其在室温下反应一夜,然后蒸发至干。这种产物采用硅胶柱色谱进行纯化,使用二氯甲烷和甲醇97/3混合物洗脱。在乙酸乙酯中重结晶,然后用乙醚洗涤,得到0.73g白色固体状的产物。
熔点(℃):80-82
LC-MS:M+H=317
RMN-1H(CDCl3)δ(ppm):8,25(dd,1H),7,80(dd,1H),7,55-7,30(m,4H),6,80(d,1H),6,00(m,1H),5,65(m,1H),5,05(m,1H),4,65(s,2H),4,20(t,2H),3,35(m,2H),2,00(m,2H),1,90(m,2H)
实施例4(第85号化合物)
4-[(4′-氟-4-联苯基)氧]-1-哌啶甲酸2-(甲基氨基)-2-氧代乙酯
4.1.4-[(4-溴苯基)氧]-1-哌啶甲酸1,1-二甲基乙酯
往2.01g(10mmol)4-羟基-1-哌啶甲酸1,1-二甲基乙酯在20ml二甲基甲酰胺中的溶液,添加7g(40mmol)1-溴-4-氟苯和2.5g(50mmol)50%在矿物油中的氢化钠。该混合物在100℃搅拌3小时,然后蒸发至干。该残留物用50ml冰水溶解,用二氯甲烷提取。将这些有机提取物蒸发至干,得到3.5g油状产物,它可原样用于后续步骤。
4.2.4-[(4-溴苯基)氧]哌啶
往3.5g(9.83mmol)在步骤4.1.制备的4-[(4-溴苯基)氧]-1-哌啶甲酸1,1二甲基乙酯在20ml二氯甲烷中的溶液,添加10ml三氟乙酸,该溶液在室温下搅拌1小时。蒸发至干,该残留物然后用30ml甲苯溶解,将它再蒸发至干。然后,该残留物先用戊烷洗涤,然后将其溶于60ml二氯甲烷和20ml 4N氨水溶液的混合物中。激烈搅拌15分钟,然后倾析该有机相,用硫酸钠干燥和蒸发至干,得到2.7g油状产物,它可原样用于后续步骤。
4.3.4-[(4-溴苯基)氧]-1-哌啶甲酸2-(乙基氧)-2-氧代乙酯
在40ml甲苯中,将2.7g(7.58mmol)在步骤4.2.制备的4-[(4-溴苯基)氧]哌啶与1.70g(7.6mmol)根据实施例1.1制备的{[(苯氧基)羰基]氧}乙酸乙酯混合起来,该溶液在50℃加热20小时。冷却后,蒸发至干,该产物采用硅胶柱色谱进行纯化,使用乙酸乙酯和环己烷40/60混合物洗脱.然后在异丙醚中研磨得到2.9g粉末状的产物。
熔点(℃):87-88
4.4.4-[(4-溴苯基)氧]-1-哌啶甲酸2-(甲基氨基)-2-氧代乙酯
2.9g(7.5mmol)在步骤4.3.制备的4-[(4-溴苯基)氧]-1-哌啶甲酸2-(乙基氧)-2-氧代乙酯溶于10ml 33%甲胺乙醇溶液在室温下搅拌20小时。在蒸发后,该产物采用硅胶柱色谱进行纯化,用乙酸乙酯洗脱,得到0.8g呈树胶状的产物,它可原样用于后续步骤。
4.5.4-[(4′-氟-4-联苯基)氧]-1-哌啶甲酸2-(甲基氨基)-2-氧代乙酯
在带塞的玻璃管中,放入0.1g(0.27mmol)在步骤4.4.制备的4-[(4-溴苯基)氧]-1-哌啶甲酸2-(甲基氨基)-2-氧代乙酯,0.01g四(三苯基膦)钯(O)和0.057g(0.4mmol)4-氟苯基硼酸。添加4ml甲苯、2ml2N碳酸钠水溶液和0.5ml乙醇。在搅拌下在80℃加热2小时。冷却后,添加1ml水和2ml甲苯。抽取有机相,该产物采用硅胶柱色谱进行纯化,使用二氯甲烷和甲醇95/5混合物洗脱。将该产物再溶于1ml乙醇中。然后添加2ml水使其再沉淀,得到0.031g粉末状的产物。
熔点(℃):117-119
LC-MS:M+H 387
RMN-1H(CDCl3)δ(ppm):7,70(dd,2H);7,65(d,2H);7,30(dd,2H);7,20(d,2H);6,25(s large,1H),4,80(s+m,3H);4,00-3,70(m,4H);3,05(d,3H);2,25-2,00(m,4H)
实施例5(第120号化合物)
4-{[(4-溴苯基)氧]甲基}-1-哌啶甲酸2-(甲基氨基)-2-氧代乙酯
5.1.4-{[(4-溴苯基)氧]甲基}-1-哌啶甲酸1,1-二甲基乙基酯
如实施例4.1所描述的那样进行。使用2.5g(11.6mmol)4-(羟基甲基)-1-哌啶甲酸1,1-二甲基乙酯和8.13g(46.4mmol)1-溴-4-氟苯,得到5.75g呈油状的粗制产物。
5.2.4-{[(4-溴苯基)氧]甲基}哌啶
如实施例4.2所描述的那样进行。使用5.75g在步骤5.1.制备的4-{[(4-溴苯基)氧]甲基}-1-哌啶甲酸1,1-二甲基乙基酯,得到3g呈油状的产物。
5.3.4-{[(4-溴苯基)氧]甲基}-1-哌啶甲酸2-(乙氧基)-2-氧代乙酯
如实施例4.3所描述的那样进行。使用1.6g(5.9mmol)在步骤5.2.制备的4-{[(4-溴苯基)氧]甲基}哌啶和1.32g(5.9mmol)根据实施例1.1制备的{[(苯氧基)羰基]氧}乙酸乙酯,得到呈油状的产物。
5.4.4-{[(4-溴苯基)氧]甲基}-1-哌啶甲酸2-(甲基氨基)-2-氧代乙酯
如实施例4.4.所描述的那样进行。使用在步骤5.3.制备的4-{[(4-溴苯基)氧]甲基}-1-哌啶甲酸2-(乙基氧)-2-氧代乙酯,得到1.1g粉末状的产物。
熔点(℃):163-165
LC-MS:M+H=386
RMN-1H(CDCl3)δ(ppm):7,35(d,2H);6,75(d,2H);6,05(s large,1H);4,70-4,50(m,2H);4,30-4,10(m,2H);3,80(d,2H);3,00-2,75(m,2H);2,85(d,3H);2,10-1,80(m,3H);1,45-1,20(m,2H)
实施例6(第154号化合物)
4-([(4′-(三氟甲基)-4-联苯基)氧]甲基)-1-哌啶甲酸2-(甲基氨基)-2-氧代乙酯
如实施例4.5.所描述的那样进行。使用0.1g(0.26mmol)按照实施例5制备的4-{[(4-溴苯基)氧]甲基}-1-哌啶甲酸2-(甲基氨基)-2-氧代乙酯,和0.074g(0.389mmol)4-三氟甲基苯基硼酸,得到0.049g粉末状的产物。
熔点(℃):197-199
LC-MS:M+H=451
RMN-1H(DMSO)δ(ppm):7,85-7,65(m,7H),7,05(d,2H),4,35(s,2H),4,05(d large,2H),3,90(d,2H),2,85(m,2H),2,60(d,3H),2,00(m,1H),1,80(d large,2H),1,35-1,10(m,2H)。
实施例7(第137号化合物)
4-[(1-萘氧基)甲基]-1-哌啶甲酸2-氨基-2-氧代乙酯
7.1.4-[(1-萘氧基)甲基]-1-哌啶甲酸1,1-二甲基乙酯
往5.0g(23.2mmol)4-(羟基甲基)-1-哌啶甲酸1,1-二甲基乙酯,4.3g(29.8mmol)1-萘甲醇和7.82g(29.8mmol)三苯基膦在120ml四氢呋喃中的溶液,该溶液在氮气下使用冰浴冷却,滴加6.03g(29.8mmol)偶氮二甲酸二异丙酯溶液。让该反应混合物返回到室温,再搅拌一夜。添加2ml甲醇,然后蒸发至干。该残留物溶于200ml二氯甲烷中,相继地用10%硫酸氢钾水溶液,水和1M氢氧化钠水溶液洗涤。用硫酸钠干燥和蒸发至干。该产物采用硅胶柱色谱进行纯化,使用环己烷和二氯甲烷混合物(先用80/20,然后70/30和50/50)洗脱,得到7.96g回固化的油状产物。
熔点(℃):97-100
7.2.4-[(1-萘氧基)甲基]哌啶
7.96g(29.1mmol)在步骤7.1.制备的4-[(1-萘氧基)甲基]-1-哌啶甲酸1,1-二甲基乙酯在120ml甲醇和28ml 35%盐酸水溶液中的溶液,在60℃加热6小时。冷却到室温,蒸发至干,然后与乙醇一起共蒸发2次。该固体残留物用乙醚洗涤,然后在五氧化二磷存在下真空干燥得到3.1g白色固体。
将这种固体溶于80ml水中,再添加30%氢氧化钠水溶液,直到碱性pH,然后用150ml乙醚提取2两。这些提取物用硫酸钠干燥,浓缩至干得到2.75g油样产物,它可原样用于后续步骤。
7.3.4-[(1-萘氧基)甲基]-1-哌啶甲酸2-(乙氧基)-2-氧代乙酯
2.75g(11.4mmol)在步骤7.2.制备的4-[(1-萘氧基)甲基]哌啶和2.56g(11.4mmol)按照实施例1.1.制备的[(苯氧基羰基)氧]乙酸乙酯在80ml甲苯中的溶液,在50℃加热一夜。蒸发至干,该残留物用水、二氯甲烷和饱和碳酸氢钠水溶液混合物溶解。倾析该有机相,用硫酸钠干燥和蒸发至干。这种产物采用硅胶柱色谱进行纯化,先使用环己烷和二氯甲烷50/50混合物洗脱,然后用二氯甲烷,再用二氯甲烷和乙酸乙酯95/5混合物洗脱。得到2.05g呈油状的产物,它原样用于后续步骤。
7.4.4-[(1-萘氧基)甲基]-1-哌啶甲酸2-氨基-2-氧代乙酯
将1.0g(2.69mmol)在步骤7.3.制备的4-[(1-萘氧基)甲基]-1-哌啶甲酸2-(乙基氧)-2-氧代乙酯溶于12ml 7N(84mmol)氨在甲醇中的溶液。在室温下反应3天。蒸发至干,这种残留物采用硅胶柱色谱进行纯化,使用二氯甲烷和乙酸乙酯混合物(先90/10,然后80/20、70/30和50/50)洗脱,再使用乙酸乙酯和甲醇95/5混合物洗脱。然后在乙酸乙酯中重结晶得到0.77g产物。
熔点(℃):135-136
LC-MS:M+H=343
RMN-1H(DMSO)δ(ppm):8,15(dd,1H),7,80(dd,1H),7,50-7,30(m,4H),7,30(m,1H),7,15(m,1H),6,95(d,1H),4,35(s,2H),4,15-4,00(m+d,4H),4,90(m,2H),2,10(m,1H),1,90(d,2H),1,45-1,25(m,2H)
实施例8(第148号化合物)
4-[(7-喹啉基氧基)甲基]-1-哌啶甲酸2-氨基-2-氧代乙酯
8.1.4-(羟基甲基)-1-哌啶甲酸2-(甲基氧)-2-氧代乙酯
如实施例2.1.所描述的那样进行。使用6.84g(59.4mmol)4-(羟基甲基)哌啶,代替乙醇胺得到7.85g产物,为无色油状。
8.2.4-[(7-喹啉基氧基)甲基]-1-哌啶甲酸2-氨基-2-氧代乙酯
往0.16g(0.69mmol)在步骤8.1.制备的4-(羟基甲基)-1-哌啶甲酸2-(甲基氧)-2-氧代乙酯、0.26ml(1.03mmol)三-n-丁基膦和0.13g(0.90mmol)7-羟基喹啉在2.5ml用冰浴冷却的苯中的溶液,添加0.26g(1.03mmol)在步骤8.1.制备的1,1′-(偶氮二羰基)二哌啶(ADDP)。该混合物在0℃下搅拌15分钟,然后在室温下搅拌16小时。用硅藻土过滤,用乙醚漂洗。这些滤液蒸发至干,这种残留物采用硅胶柱色谱进行纯化,使用乙酸乙酯和n-己烷70/30混合物洗脱。将得到的产物溶于3ml(21mmol)7M氨甲醇溶液。搅拌3小时,然后蒸发至干。该产物采用硅胶柱色谱进行纯化,使用乙酸乙酯和乙醇90/10混合物洗脱,在乙酸乙酯中再结晶得到0.115g呈白色固体状的产物。
熔点(℃):137-139
LC-MS:M+H=344
RMN-1H(CDCl3)δ(ppm):7,80(dd,1H),8,05(dd,1H),7,70(d,1H),7,40(d,1H),7,30-7,15(m,2H),6,05(m,1H),5,65(m,1H),4,60(s,2H),4,25(m,2H),4,00(d,2H),2,90(m,2H),2,10(m,1H),1,95(d,2H),1,50-1,30(m,2H)
实施例9(第168号化合物)
4-{2-[(4-溴苯基)氧]乙基}-1-哌啶甲酸2-(甲基氨基)-2-氧代乙酯
9.1.4-{2-[(4-溴苯基)氧]乙基}-1-哌啶甲酸1,1-二甲基乙酯
如实施例4.1.所描述的那样进行。使用1.93g(8.4mmol)4-(2-羟基乙基)-1-哌啶甲酸1,1-二甲基乙酯和5.88g(33.6mmol)1-溴-4-氟苯,得到4.1g呈油状的粗制产物。
9.2.4-{2-[(4-溴苯基)氧]乙基}哌啶
如实施例4.2.所描述的那样进行。使用在步骤9.1.制备的4-{2-[(4-溴苯基)氧]乙基}-1-哌啶甲酸1,1-二甲基乙酯,得到1.79g呈粉末状的产物。
熔点(℃):100-102
9.3.4-{2-[(4-溴苯基)氧]乙基}-1-哌啶甲酸2-(乙基氧)-2-氧代乙酯
如实施例4.3.所描述的那样进行。使用1.76g(6.19mmol)在步骤9.2制备的4-{2-[(4-溴苯基)氧]乙基}哌啶和1.39g(6.19mmol)在实施例1.1.制备的{[(苯氧基)羰基]氧}乙酸乙酯,得到1.4g油状产物。
9.4.4-{2-[(4-溴苯基)氧]乙基}-1-哌啶甲酸2-(甲基氨基)-2-氧代乙酯
如实施例4.4.所描述的那样进行。使用1.3g(3.14mmol)在步骤9.3.制备的4-{2-[(4-溴苯基)氧]乙基}-1-哌啶甲酸2-(乙基氧)-2-氧代乙酯,0.95g粉末状的产物。
熔点(℃)-101-103
LC-MS:M+H=400
RMN-1H(CDCl3)δ(ppm):7,55(d,2H);7,00(d,2H);6,25(s large,NH);4,90-4,70(m,2H);4,50-4,25(m,2H);4,20(t,2H);3,20-2,90(m,2H);3,10(d,3H);2,05-1,90(m,5H);1,55-1,30(m,2H)
实施例10(第186号化合物)
4-{2-[(4′-氯-4-联苯基)氧]乙基}-1-哌啶甲酸2-(甲基氨基)-2-氧代乙酯
如实施例4.5.所描述的那样进行。使用0.1g(0.25mmol)按照实施例9制备的4-{2-[(4-溴苯基)氧]乙基}-1-哌啶甲酸2-(甲基氨基)-2-氧代乙酯和0.117g(0.75mmol)4-氯苯基硼酸,得到0.087g粉末状的产物。
熔点(℃):104-106
LC-MS:M+H=431
RMN-1H(CDCl3)δ(ppm):7,70-7,50(m,6H);7,10(d,2H);6,20(s large,NH);4,85-4,60(m,2H);4,45-4,15(m,2H);4,20(t,2H);3,15-2,95(m,2H);3,05(d,3H);2,10-1,85(m,5H),1,50-1,25(m,2H)
实施例11(第183号化合物)
4-[2-(7-异喹啉基氧基)乙基]-1-哌啶氨基甲酸2-氨基-2-氧代乙酯
11.1.4-(2-羟基乙基)-1-哌啶甲酸2-(甲基氧)-2-氧代乙酯
如实施例2.1.所描述的那样进行,使用7.6g(59.4mmol)4-(2-羟基乙基)哌啶,代替乙醇胺,得到7.1g呈无色油状的产物。
11.2.4-[2-(7-异喹啉基氧基)乙基]-1-哌啶氨基甲酸2-氨基-2-氧代乙酯
如实施例8.2.所描述的那样进行,使用在4ml苯中的0.46g(1.84mmol)ADDP、0.30g(1.24mmol)在步骤11.1.制备的4-(2-羟基乙基)-1-哌啶甲酸2-(甲基氧)-2-氧代乙酯、0.46ml三-n-丁基膦和0.26g(1.84mmol)7-羟基异喹啉。该产物采用硅胶柱色谱进行纯化,使用乙酸乙酯洗脱,然后使用乙酸乙酯和乙醇95/5混合物洗脱,得到0.25g白色固体状的产物。
熔点(℃):179-181
LC-MS:M+H=358
RMN-1H(CDCl3)δ(ppm):9,15(s,1H),8,45(d,1H),7,60(d,1H),7,35(dd,1H),7,20(d,1H),6,05(m,1H),5,75(m,1H),4,60(s,2H),4,20(t,4H),2,90(m,2H),1,90-1,70(m,5H),1,40-1,20(m,2H)
实施例12(第83号化合物)
3-[(1-萘氧基)甲基]-1-吡咯烷甲酸2-氨基-2-氧代乙酯
12.1.3-[(1-萘氧基)甲基]-1-吡咯烷甲酸1,1-二甲基乙酯
往1.0g(4.9mmol)3-(羟基甲基)-1-吡咯烷甲酸1,1-二甲基乙酯(在WO 0066557中描述的)、0.95g(6.4mmol)1-萘甲醇和1.4g(6.9mmol)三-n-丁基膦在40ml甲苯和20ml四氢呋喃中的溶液,该溶液在氮气下使用冰浴冷却,再滴加1.74g(6.9mmol)ADDP溶液。让该反应混合物回升到室温,再搅拌24小时。过滤该混合物,沉淀用甲苯漂洗。蒸发至干。该残留物溶于二氯甲烷,用1M氢氧化钠水溶液洗涤。用硫酸钠干燥和蒸发至干,该残留物采用硅胶柱色谱进行纯化,使用二氯甲烷洗脱,然后使用二氯甲烷和甲醇98/2混合物洗脱,得到0.80g呈无色油状的产物。
12.2.3-[(1-萘氧基)甲基]吡咯烷
0.42g(1.28mmol)在步骤12.1.制备的3-[(1-萘氧基)甲基]-1-吡咯烷甲酸1,1-二甲基乙酯在10ml 1,4-二氧杂环己烷和6ml 2N盐酸水溶液中的溶液搅拌6小时。蒸发至干,然后与甲苯共蒸发2次。固体残留物用乙醚洗涤。将该固体溶于二氯甲烷中,再添加浓氨水溶液直到pH碱性。用Whatman PTFE滤芯过滤,该有机相浓缩得到0.21g油样产物,它可原样用于后续步骤。
12.3.3-[(1-萘氧基)甲基]-1-吡咯烷甲酸2-(乙氧基)-2-氧代乙酯
0.20g(0.88mmol)在步骤12.2.制备的3-[(1-萘氧基)甲基]吡咯烷和0.35g(1.5mmol)按照实施例1.1制备的[(苯氧基羰基)氧]乙酸乙酯在6ml甲苯中的溶液在60℃加热一夜。蒸发至干,该残留物用水、二氯甲烷和饱和碳酸氢钠水溶液混合物溶解。倾析该有机相,用硫酸钠干燥和蒸发至干。该残留物采用硅胶柱色谱进行纯化,先使用二氯甲烷洗脱,然后使用二氯甲烷和甲醇99/1混合物洗脱。得到0.24g油状产物,它可原样用于后续步骤。
12.4.3-[(1-萘氧基)甲基]-1-吡咯烷甲酸2-氨基-2-氧代乙酯
将0.24g(0.67mmol)在步骤12.3.制备的3-[(1-萘氧基)甲基]-1-吡咯烷甲酸2-(乙基氧)-2-氧代乙酯溶于15ml 7N(105mmol)氨甲醇溶液中。在塞紧的管中在室温下搅拌3天。蒸发至干,该残留物采用硅胶柱色谱进行纯化,使用二氯甲烷和甲醇混合物(先97/3,后94/6)洗脱。得到的固体在乙醚中研磨,过滤得到0.15g产物。
熔点(℃):161-163
LC-MS:M+H=329
RMN-1H(DMSO)δ(ppm):8,15(m,1H),7,75(m,1H),7,50-7,30(m,4H),7,10-6,90(s,2H),6,80(m,1H),4,40(s,2H),4,20-4,05(m,2H),3,90-3,30(m,4H),2,90-2,70(m,1H),2,30-2,10(m,1H),2,05-1,85(m,1H)。
下表说明了本发明某些化合物的化学结构和物理性能。
表
n° | Y | X | m | n | R1 | R2 | R3 | R4 | PF℃(或M+H) |
1. | 4-氯苯基 | O | 0 | 1 | H | H | H | CH2CONHCH3 | 147-149 |
2. | 4-氯苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 128-130 |
3. | 4-氯苯基 | O | 0 | 2 | H | H | H | CH2CONH2 | 108-110 |
4. | 4-氯苯基 | O | 0 | 3 | H | H | H | CH2CONH2 | 116-118 |
5. | 3-氯苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 114-116 |
6. | 3-氯苯基 | O | 0 | 2 | H | H | H | CH2CONH2 | 90-92 |
7. | 3-氯苯基 | O | 0 | 3 | H | H | H | CH2CONH2 | 114-116 |
8. | 2-氯苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 128-130 |
9. | 2-氯苯基 | O | 0 | 2 | H | H | H | CH2CONH2 | 128-130 |
10. | 2-氯苯基 | O | 0 | 3 | H | H | H | CH2CONH2 | 110-112 |
11. | 4-氰基苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 204-206 |
12. | 4-氰基苯基 | O | 0 | 2 | H | H | H | CH2CONH2 | 173-175 |
13. | 4-氰基苯基 | O | 0 | 3 | H | H | H | CH2CONH2 | 169-171 |
14. | 3-氰基苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 142-143 |
15. | 3-氰基苯基 | O | 0 | 2 | H | H | H | CH2CONH2 | 129-131 |
16. | 3-氰基苯基 | O | 0 | 3 | H | H | H | CH2CONH2 | 123-125 |
17. | 4-异丙基苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 95-97 |
18. | 4-异丙基苯基 | O | 0 | 2 | H | H | H | CH2CONH2 | (295) |
19. | 4-异丙基苯基 | O | 0 | 3 | H | H | H | CH2CONH2 | 103-105 |
20. | 3-异丙基苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 96-98 |
21. | 3-异丙基苯基 | O | 0 | 2 | H | H | H | CH2CONH2 | (295) |
22. | 3-异丙基苯基 | O | 0 | 3 | H | H | H | CH2CONH2 | 88-90 |
23. | 4-叔丁基苯基 | O | 0 | 2 | H | H | H | CH2CONH2 | 90-92 |
24. | 4-叔丁基苯基 | O | 0 | 3 | H | H | H | CH2CONH2 | (323) |
25. | 3-叔丁基苯基 | O | 0 | 2 | H | H | H | CH2CONH2 | (309) |
26. | 3-叔丁基苯基 | O | 0 | 3 | H | H | H | CH2CONH2 | (323) |
27. | 4-(1,1,3,3-四甲基丁基)苯基 | O | 0 | 2 | H | H | H | CH2CONH2 | (365) |
28. | 4-(1,1,3,3-四甲基丁基)苯基 | O | 0 | 3 | H | H | H | CH2CONH2 | (379) |
29. | 4-(1,1-二甲基苯基甲基)苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | (357) |
30. | 4-(1,1-二甲基苯基甲基)苯基 | O | 0 | 2 | H | H | H | CH2CONH2 | (371) |
31. | 4-(1,1-二甲基苯基甲基)苯基 | O | 0 | 3 | H | H | H | CH2CONH2 | (385) |
32. | 4-苯基苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 196-198 |
33. | 4-苯基苯基 | O | 0 | 2 | H | H | H | CH2CONH2 | 187-189 |
n° | Y | X | m | n | R1 | R2 | R3 | R4 | PF℃(或M+H) |
34. | 4-苯基苯基 | O | 0 | 3 | H | H | H | CH2CONH2 | 192-194 |
35. | 4-(4-氯苯基)苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 193-195 |
36. | 4-(3-氯苯基)苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 168-170 |
37. | 4-(2-氯苯基)苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 114-116 |
38. | 4-(4-甲氧基苯基)苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 194-196 |
39. | 4-(3-甲氧基苯基)苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | (345) |
40. | 4-(2-甲氧基苯基)苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 127-129 |
41. | 3-苯基苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 126-128 |
42. | 3-苯基苯基 | O | 0 | 2 | H | H | H | CH2CONH2 | 110-112 |
43. | 3-苯基苯基 | O | 0 | 3 | H | H | H | CH2CONH2 | 127-129 |
44. | 3-(4-氯苯基)苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 137-139 |
45. | 3-(3-氯苯基)苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 90-92 |
46. | 3-(2-氯苯基)苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 55-57 |
47. | 3-(4-甲氧基苯基)苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 168-170 |
48. | 3-(3-甲氧基苯基)苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 86-88 |
49. | 2-苯基苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 92-94 |
50. | 2-苯基苯基 | O | 0 | 2 | H | H | H | CH2CONH2 | (329) |
51. | 2-苯基苯基 | O | 0 | 3 | H | H | H | CH2CONH2 | (343) |
52. | 2-(4-氯苯基)苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 130-132 |
53. | 2-(3-氯苯基)苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 88-90 |
54. | 2-(2-氯苯基)苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | (349) |
55. | 2-(4-甲氧基苯基)苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 74-76 |
56. | 萘-1-基 | O | 0 | 1 | H | H | H | CH2CONH2 | (289) |
57. | 萘-1-基 | O | 0 | 2 | H | H | H | CH2CONH2 | (303) |
58. | 萘-1-基 | O | 0 | 3 | H | H | H | CH2CONH2 | 80-82 |
59. | 萘-1-基 | O | 0 | 3 | H | H | H | CH2CONHCH3 | 90-92 |
60. | 4-氯-萘-1-基 | O | 0 | 3 | H | H | H | CH2CONH2 | 142-144 |
61. | 4-氯-萘-1-基 | O | 0 | 3 | H | H | H | CH2CONHCH3 | 108-110 |
62. | 萘-2-基 | O | 0 | 1 | H | H | H | CH2CONH2 | (289) |
n° | Y | X | m | n | R1 | R2 | R3 | R4 | PF℃(或M+H) |
63. | 萘-2-基 | O | 0 | 2 | H | H | H | CH2CONH2 | 158-160 |
64. | 萘-2-基 | O | 0 | 3 | H | H | H | CH2CONH2 | 171-173 |
65. | 4-苯氧基苯基 | O | 0 | 1 | H | H | H | CH2CONH2 | 158-160 |
66. | 4-苯氧基苯基 | O | 0 | 2 | H | H | H | CH2CONH2 | 141-143 |
67. | 4-苯氧基苯基 | O | 0 | 3 | H | H | H | CH2CONH2 | 144-146 |
68. | 吡啶-3-基 | O | 0 | 1 | H | H | H | CH2CONH2 | 135-137 |
69. | 吡啶-3-基 | O | 0 | 2 | H | H | H | CH2CONH2 | 119-121 |
70. | 吡啶-3-基 | O | 0 | 3 | H | H | H | CH2CONH2 | 96-98 |
71. | 5-氯喹啉-8-基 | O | 0 | 1 | H | H | H | CH2CONH2 | 232-234 |
72. | 5-氯喹啉-8-基 | O | 0 | 2 | H | H | H | CH2CONH2 | 183-185 |
73. | 5-氯喹啉-8-基 | O | 0 | 3 | H | H | H | CH2CONH2 | 184-186 |
74. | 苯基 | O | 1 | 0 | H | H | CH3 | CH2CONH2 | 90-92 |
75. | 4-CF3-苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONH2 | 115-117 | |
76. | 4-Cl-苯基 | SO2 | 0 | 2 | (CH2)2 | H | CH2CONH2 | 164-166 | |
77. | 4-Cl-苯基 | SO2 | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | 168-170 | |
78. | 3-CF3-苯基 | SO2 | 0 | 2 | (CH2)2 | H | CH2CONH2 | 148-150 | |
79. | 3-CF3-苯基 | SO2 | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | 163-165 | |
80. | 萘-1-基 | O | 0 | 1 | (CH2)2 | H | CH2CONHCH3 | 111-113 | |
81. | 萘-1-基 | O | 1 | 1 | CH2 | H | CH2CONH2 | 176-178 | |
82. | 萘-1-基 | O | 1 | 1 | CH2 | H | CH2CONHCH3 | 112-114 | |
83. | 萘-1-基 | O | 1 | 1 | (CH2)2 | H | CH2CONH2 | 161-163 | |
84. | 萘-1-基 | O | 1 | 1 | (CH2)2 | H | CH2CONHCH3 | 99-101 | |
85. | 4-(4-F-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | 117-119 | |
86. | 4-(4-Cl-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | 134-136 | |
87. | 4-(4-CH3-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | 121-123 | |
88. | 4-(4-正-丁基-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | 105-107 | |
89. | 4-(4-CF3-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | 141-143 | |
90. | 4-(4-CH3O-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | 152-154 | |
91. | 4-(4-C2H5O-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | 145-147 | |
92. | 4-(4-CF3O-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | 131-133 | |
93. | 4-(3-F,4-CH3O-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | (417) | |
94. | 4-(3-Cl,4-F-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | 124-126 | |
95. | 4-(3,4-Cl2-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | (438) | |
96. | 3-(4-F-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | (387) | |
97. | 3-(4-Cl-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | (403) | |
98. | 3-(4-CH3-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | (383) |
n° | Y | X | m | n | R1 | R2 | R3 | R4 | PF℃(或M+H) |
99. | 3-(4-正-丁基苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | (425) | |
100 | 3-(4-CF3-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | (437) | |
101 | 3-(4-CH3O-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | (399) | |
102 | 3-(4-C2H5O-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | (413) | |
103 | 3-(4-CF3O-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | (453) | |
104 | 3-(3-F,4-CH3O-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | (417) | |
105 | 3-(3-Cl,4-F-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | (421) | |
106 | 3-(3,4-Cl2-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | (438) | |
107 | 3-(2,4-Cl2-苯基)苯基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | (438) | |
108 | 萘-1-基 | O | 0 | 2 | (CH2)2 | H | CH2CONH2 | 137-138 | |
109 | 萘-1-基 | O | 0 | 2 | (CH2)2 | H | CH2CONHCH3 | 121-122 | |
110 | 萘-2-基 | O | 0 | 2 | (CH2)2 | H | CH2CONH2 | 118-120 | |
111 | 喹啉-8-基 | O | 0 | 2 | (CH2)2 | H | CH2CONH2 | (330) | |
112 | 苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 123-125 | |
113 | 4-Cl-苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 152-154 | |
114 | 4-Cl-苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 166-168 | |
115 | 4-Cl-苯基 | S | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 130-132 | |
116 | 4-Cl-苯基 | SO2 | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 131-133 | |
117 | 3-Cl-苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHx | 131-133 | |
118 | 3-Cl-苯基 | S | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 94-96 | |
119 | 3-Cl-苯基 | SO2 | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 100-102 | |
120 | 4-Br-苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 163-165 | |
121 | 4-CH3O-苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 128-130 | |
122 | 3-CH3O-苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 119-121 | |
123 | 4-正-丙氧基-苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 141-143 | |
124 | 4-CF3-苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 134-136 | |
125 | 4-CF3-苯基 | S | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 129-131 | |
126 | 4-CF3-苯基 | SO2 | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 103-105 | |
127 | 3-CF3-苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 120-121 | |
128 | 3-CF3-苯基 | S | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 167-169 | |
129 | 3-CF3-苯基 | SO2 | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 141-143 | |
130 | 4-CF3O-苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 118-120 | |
131 | 3-CF3O-苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 132-134 | |
132 | 4-异丙基苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 113-115 | |
133 | 3-异丙基苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 119-121 | |
134 | 2,3-Cl2-苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 160-162 | |
135 | 2,4-Cl2-苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 144-146 | |
136 | 3,4-Cl2-苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 113-115 |
n° | Y | X | m | n | R1 | R2 | R3 | R4 | PF℃(或M+H) |
137 | 萘-1-基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 135-136 | |
138 | 萘-1-基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 151-152 | |
139 | 萘-1-基 | O | 1 | 1 | (CH2)3 | H | CH2CONH2 | 149-151 | |
140 | 萘-1-基 | O | 1 | 1 | (CH2)3 | H | CH2CONHCH3 | (357) | |
141 | 萘-1-基 | S | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 127-129 | |
142 | 萘-1-基 | SO2 | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 154-156 | |
143 | 萘-2-基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 142-144 | |
144 | 萘-2-基 | S | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 111-113 | |
145 | 萘-2-基 | SO2 | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 105-107 | |
146 | 4-氯-萘-1-基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 166-168 | |
147 | 4-氯-萘-1-基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 163-165 | |
148 | 喹啉-7-基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 137-139 | |
149 | 异喹啉-7-基 | O | 1 | 2 | (CH2)2 | H | CH2CONH2 | 162-164 | |
150 | 4-(4-F-苯基)苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 150-152 | |
151 | 4-(4-Cl-苯基)苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 167-169 | |
152 | 4-(4-CH3-苯基)苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 164-166 | |
153 | 4-(4-正-丁基苯基)苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 171-173 | |
154 | 4-(4-CF3-苯基)苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 197-199 | |
155 | 4-(4-CH3O-苯基)苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 172-174 | |
156 | 4-(4-C2H5O-苯基)苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 173-175 | |
157 | 4-(4-CF3O-苯基)苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 152-154 | |
158 | 4-(3-F,4-CH3O-苯基)苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 156-158 | |
159 | 4-(3-Cl,4-F-苯基)苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 132-134 | |
160 | 4-(3,4-Cl2-苯基)苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 163-165 | |
161 | 4-(2,4-Cl2-苯基)苯基 | O | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 177-179 | |
162 | 嘧啶-2-基 | S | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | 109-111 | |
163 | 5-苯基-噻唑-2-基 | S | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | (406) | |
164 | 苯并唑-2-基 | S | 1 | 2 | (CH2)2 | H | CH2CONHCH3 | (364) | |
165 | 苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | 136-138 | |
166 | 4-Cl-苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | 115-117 | |
167 | 3-Cl-苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | 91-93 | |
168 | 4-Br-苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONHCH3 | 101-103 | |
169 | 4-CH3O-苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | 108-110 |
n° | Y | X | m | n | R1 | R2 | R3 | R4 | PF℃(或M+H) |
170 | 3-CH3O-苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | (337) | |
171 | 4-正-丙氧基-苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | 121-123 | |
172 | 4-CF3-苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | 112-114 | |
173 | 3-CF3-苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | 94-96 | |
174 | 4-CF3O-苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | 79-81 | |
175 | 3-CF3O-苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | (391) | |
176 | 4-异丙基-苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | 75-77 | |
177 | 3-异丙基-苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | (349) | |
178 | 3,4-Cl2-苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | 103-105 | |
179 | 萘-1-基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | 134-135 | |
180 | 萘-1-基 | O | 2 | 2 | (CH2)2 | H | CH2CONHCH3 | 108-109 | |
181 | 萘-2-基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | (357) | |
182 | 喹啉-7-基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | 164-166 | |
183 | 异喹啉-7-基 | O | 2 | 2 | (CH2)2 | H | CH2CONH2 | 179-181 | |
184 | 4-苯基-苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONHCH3 | 124-126 | |
185 | 4-(4-F-苯基)苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONHCH3 | 120-122 | |
186 | 4-(4-Cl-苯基)苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONHCH3 | 104-106 | |
187 | 4-(4-CF3-苯基)苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONHCH3 | 137-139 | |
188 | 4-(3-CF3-苯基)苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONHCH3 | 98-100 | |
189 | 4-(4-CH3O-苯基)苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONHCH3 | 141-143 | |
190 | 4-(4-CF3O-苯基)苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONHCH3 | 116-118 | |
191 | 4-(4-异丙基-苯基)苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONHCH3 | 121-123 | |
192 | 4-(2,4-Cl2-苯基)苯基 | O | 2 | 2 | (CH2)2 | H | CH2CONHCH3 | 112-114 |
本发明的化合物构成了能够确定其FAAH酶(脂肪酸酰氨基水解酶)抑制剂作用的药理试验主题。
在基于使用FAAH的花生四烯酸乙醇酰胺[乙醇胺1-3H]水解产物(乙醇胺[1-3H])测量结果的放射酶学试验中证明了这种抑制活性[《生命科学》(Life Sciences),1995,56,1999-2005和《药理学和实验治疗学杂志》(Journal of Pharmacology and ExperimentalTherapeutics),1997,283,729-734]。于是,取出鼠的脑(比小脑少),并保存在-80℃。临时地,在含有150mM NaCl和1mM EDTA的10mMTris-HCl缓冲液(pH8.0)中,使用Polytron使组织均浆化,制备这些膜匀浆。然后在70μl含有无脂肪酸的牛血清(1mg/ml)的缓冲液中进行该酶反应。相继添加不同浓度的试验化合物,用冷花生四烯酸乙醇酰胺稀释到10μM的花生四烯酸乙醇酰胺[乙醇胺1-3H](比活性15-20Ci/mmol)和该膜制剂(每个试验400μg冷冻组织)。在25℃下15分钟后,添加140μL氯仿/甲醇(2∶1)停止其酶反应。该混合物搅拌10分钟,然后以3500g离心15分钟。采用液体闪烁法计算含有乙醇胺[1-3H]的含水相试样量(30μL)。
在这些条件下,本发明这些活性最强化合物的CI50(抑制50%FAAH控制酶活性的浓度)是0.001-1μM。例如,该表第58号化合物的CI50是0.047μM。
因此,显然本发明的化合物对FAAH酶具有抑制活性。
通过痛觉缺失试验评价了本发明化合物的活体内活性。
于是,给体重25-30g OF1雄性鼠腹膜内给药(i.p.)PBQ(苯基苯并醌,在含有5%乙醇的0.9%氯化钠溶液中2mg/kg),在注射后5-15分钟期间内会引起腹部牵张,平均30次扭转或收缩。给药PBQ前60分钟或120分钟,口服给药0.5%试验化合物在Tween 80中的悬混剂。在这些条件下,本发明的最强化合物在剂量范围1-30mg/kg内可使由PBQ引起的牵张数减少35-70%。例如,该表第58号化合物在2小时内在剂量1mg/kg下可使由PBQ引起的牵张数减少51%。FAAH酶[《类脂化学和物理学》(Chemistry and Physics of Lipids),2000,108,107-121]催化不同脂肪酸酯的酰胺和酯内源性衍生物水解,例如N-花生四烯酰基乙醇胺(花生四烯酸乙醇酰胺)、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。这些衍生物特别在与大麻素和香草素
相互作用时产生了不同的药学活性。
本发明的化合物阻断这个降解途径,提高了这些内源物质的组织比率(taux tissulaire)。基于这一点,它们可以用于预防和治疗下述病理学,其中涉及FAAH酶所代谢的内源大麻素和/或任何其它的物质。
例如可以列举下述疾病和病症:
疼痛,特别地神经性类的急性或慢性疼痛:偏头痛,神经病疼痛,其中包括与疱疹病毒和糖尿病相关的形式;与炎性病相关的急性或慢性疼痛:关节炎,类风湿性关节炎、骨关节炎、脊椎炎、痛风性关节炎、血管炎、克罗恩病(maladie de Crohn)、过敏性肠综合症;
外周急性或慢性疼痛;
眩晕、呕吐、恶心,特别是在化疗后的恶心;
进食行为障碍,特别是各种性质的食欲缺乏和恶病质;
神经病学和精神病学病理学:哆嗦、运动障碍、张力异常(dystonies)、痉挛状态、强制性的和纠缠不休的行为、图雷特综合症、任何性质和起源的所有形式抑郁症和焦虑、情感障碍、精神病;急性或慢性神经变性疾病:帕金森病、阿尔茨海默病、老年性痴呆、亨廷顿舞蹈病、与脑局部缺血和与颅和脊髓外伤相关的病变;
癫痫;
睡眠障碍,其中包括睡眠呼吸暂停;
心血管疾病,特别是高血压、心律不齐、动脉硬化症、心脏病发作、心脏缺血;
肾脏缺血;
癌:皮肤良性肿瘤、乳突状瘤和脑瘤、前列腺瘤、脑瘤(成胶质细胞瘤、髓上皮瘤、髓母细胞瘤、成交感神经细胞瘤、胚胎源瘤、星形细胞瘤、成星形细胞瘤、室管膜瘤、少突神经胶质细胞瘤、丛瘤、神经上皮瘤、骨骺瘤、成室管膜细胞瘤、恶性脑膜瘤、肉瘤病、恶性黑色素瘤、神经鞘瘤(schwénnomes);
免疫系统疾病,特别地自身免疫疾病:牛皮癣、红斑狼疮、结缔组织或胶原疾病、斯耶格伦综合症(syndrome de Sjgrer’s)、强直脊椎关节炎、无差别脊椎关节炎、贝切特病(maladie de Behcet’s)、溶血性自身免疫贫血、多发性硬化、肌萎缩性脊髓侧索硬化、淀粉样变性、排斥移植物、影响浆细胞系的疾病;
变应性疾病:即刻或延迟的超敏性、变应性鼻炎或结膜炎、接触性皮炎;
寄生虫、病毒或细菌感染疾病:SIDA、脑膜炎;炎性疾病,特别地关节病:关节炎、风湿性关节炎、骨关节炎、脊椎炎、痛风性关节炎、血管炎、克罗恩病、过敏性肠综合症;骨质疏松症;
眼部情况:眼高血压、青光眼;
肺部情况:呼吸道病、支气管痉挛、咳嗽、哮喘、慢性支气管炎、慢性呼吸道梗塞、肺气肿;
胃-肠疾病:过敏性肠综合症、肠炎病、溃疡、腹泻;
尿失禁和膀胱炎。
呈在药学上可接受的碱、盐、水合物或溶剂化物形式的式(I)化合物在用于制备用于治疗上述病理学的药物中的用途是本发明的组成部分。
本发明另一个目的是药物,它们含有呈在药学上可接受的式(I)化合物或其盐、水合物或溶剂化物。这些药物在治疗中有应用,特别地在治疗上述疾病中有应用。
根据其另一个方面,本发明涉及药物组合物,它们含有至少一种式(I)化合物作为活性组分。这些药物组合物含有有效剂量的本发明的化合物,或所述化合物的在药学上可接受的盐、水合物或溶剂化物,以及任选地一种或多种在药学上可接受的赋形剂。
根据药物剂型和期望的给药方式,所述的赋形剂选自本技术领域的技术人员已知的通常赋形剂。
在口、舌下、皮下、肌内、静脉内、外部、局部、气管内、鼻内、经皮、肺、眼或直肠给药的本发明药物组合物中,上述式(I)的活性组分、其任选的盐、溶剂化物或水合物,以与通常药物赋形剂混合的给药单位剂型,可以给动物和人给药,用于预防或治疗上述的障碍或疾病。
合适的给药单位剂型包括口服剂型,例如片剂、软或硬胶囊、粉剂、颗粒剂、嚼咀剂(chewing-gums)和口服液或悬混剂,舌下、含服(buccale)、气管内、眼内、鼻内、吸入给药剂型,皮下、肌内或静脉内给药剂型和直肠或阴道给药剂型。对于外部涂敷,可以使用膏、软膏或洗剂状的本发明化合物。
作为实例,本发明化合物的片剂给药单位剂型可以含有下述组分:
本发明化合物 50.0mg
甘露醇 223.75mg
交联甲羧纤维素钠(croscaramellose sodique) 6.0mg
玉米淀粉 15.0mg
羟丙基-甲基纤维素 2.25mg
硬脂酸镁 3.0mg
根据药学形式,为了能达到日给药为每kg体重0.01-20mg活性组分配制所述的单位剂型。
有剂量适当高些或低些的特定情况,这样一些剂量也属于本发明。按照一般实践,医生根据给药方式、每个病人的体重和反应确定所述病人的合适剂量。
根据其它方面,本发明还涉及上面指出病理学的治疗方法,该方法包括给药有效剂量的本发明化合物,所述化合物在药学上可接受的盐、溶剂化物或水合物。
Claims (12)
1.符合下述式(I)的化合物:
式中:
m代表0、1、2或3;
n代表0、1、2或3;
X代表氧或硫原子或SO或SO2基团;
R1和R2彼此独自地代表氢原子或C1-3烷基,或R1和R2一起构成-(CH2)p-基团,其中p代表1-5的整数,以便n+p是2-5的整数;
R3代表氢原子或氟原子或羟基或甲基;
R4代表通式CHR5CONHR6基团,其中:
R5代表氢原子或C1-6-烷基和
R6代表氢原子或C1-6-烷基、C3-7-环烷基、C3-7-环烷基-C1-6-亚烷基;
Y代表:
Y1基团特别地选自苯基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、噻唑基、萘基、喹啉基、异喹啉基、2,3二氮杂萘基、喹唑啉基、喹喔啉基、萘啶基、噌啉基、苯并呋喃基、二氢苯并呋喃基、苯并噻吩基、二氢苯并噻吩基、吲哚基、异吲哚基、二氢吲哚基、苯并咪唑基、苯并唑基、苯并异唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、苯并二唑基、苯并噻二唑基;Y1基团任选地被一个或多个彼此相同或不同的取代基Y2取代,或被Y3基团取代;
Y2代表卤素原子、氰基、硝基、C1-8-烷基、C1-8-烷氧基、C1-8-硫代烷基、C1-8-氟烷基、C1-8-氟烷氧基、C1-8-氟硫代烷基、C3-7-环烷基、C3-7-环烷氧基、C3-7-环烷基-C1-8-亚烷基、C3-7-环烷基-C1-8-烷氧基、羟基、NR7R8,NHCOR7,NHSO2R7,COR7,CO2R7,CONR7R8,SO2R7,SO2NR7R8,-O-(C1-3-亚烷基)-O-、苯氧基、苯硫基、苯基-C1-C8-亚烷基、苯基-C1-C8-烷氧基或苯基-C1-C8-烷硫代基;
Y3代表特别地选自苯基、吡啶基、嘧啶基、吡嗪基或哒嗪基的基团;这个或这些Y3基团可以被一个或多个彼此相同或不同的基团Y2取代;
R7和R8彼此独自地代表氢原子或C1-6-烷基,或与它们带的氮原子一起构成吖丁啶、吡咯烷、哌啶、吗啉、硫代吗啉、吖庚因、哌嗪的环,该环任选地被C1-3-烷基或苄基取代,
它们呈碱、与酸的加成盐、水合物或溶剂化物形式。
2.根据权利要求1所述的式(I)化合物,其特征在于:
Y代表
Y1基团特别地选自苯基、吡啶基、嘧啶基、噻唑基、萘基、喹啉基、异喹啉基、苯并唑基;Y1基团任选地被一个或多个彼此相同或不同的取代基Y2取代,或被Y3基团取代;Y2代表卤素原子、氰基、C1-8-烷基、C1-8-烷氧基、C1-8-氟烷基、C1-8-氟烷氧基、苯氧基、苯基-C1-C8-亚烷基;
Y3代表苯基;Y3可以被一个或多个彼此相同或不同的基团Y2取代,
它们呈碱、与酸的加成盐、水合物或溶剂化物形式。
3-根据权利要求1或2所述的式(I)化合物,其特征在于:
Y代表
Y1基团特别地选自苯基或萘基;Y1基团任选地被一个或多个彼此相同或不同的取代基Y2基团取代,或被Y3基团取代;
Y2代表卤素原子、氰基、C1-8-烷基、C1-8-烷氧基、C1-8-氟烷基、C1-8-氟烷氧基、苯氧基、苯基-C1-C8-亚烷基;
Y3代表苯基;Y3可以被一个或多个彼此相同或不同的基团Y2取代,
它们呈碱、与酸的加成盐、水合物或溶剂化物形式。
4.根据权利要求1-3中任一权利要求所述的式(I)化合物,其特征在于:
m代表0、1、2或3;
n代表0、1、2或3;
R1和R2彼此独自地代表氢原子或C1-3-烷基,或R1和R2一起构成-(CH2)p-基团,其中p代表1-5的整数,以便n+p是2-5的整数,其条件是R1和R2彼此独自地代表氢原子或C1-3-烷基,而m+n>1;
它们呈碱、与酸的加成盐、水合物或溶剂化物形式。
5.根据权利要求1-4中任一权利要求所述的式(I)化合物,其特征在于:
m代表0、1、2或3;和/或
n代表0、1、2或3;和/或
R1和R2一起构成-(CH2)p-,其中p代表1-4的整数,以致n+p等于4;
它们呈碱、与酸的加成盐、水合物或溶剂化物形式。
6.根据权利要求1-5中任一权利要求所述的式(I)化合物,其特征在于X代表氧原子;
它们呈碱、与酸的加成盐、水合物或溶剂化物形式。
7.根据权利要求1-6中任一权利要求所述的式(I)化合物,其特征在于R3代表氢原子;
它们呈碱、与酸的加成盐、水合物或溶剂化物形式。
9.药物组合物,它含有至少一种根据权利要求1-7中任一权利要求所述的式(I)化合物,它们呈在药学上可接受的碱、盐、水合物或溶剂化物形式,和任选地一种或多种在药学上可接受的赋形剂。
10.根据权利要求1-7中任一权利要求所述的式(I)化合物,它们呈在药学上可接受的碱、盐、水合物或溶剂化物形式,作为药物的用途。
11.根据权利要求1-7中任一权利要求所述的式(I)化合物,它们呈在药学上可接受的碱、盐、水合物或溶剂化物形式,在制备用于预防或治疗下述病理学的药物中的应用,这些病理学涉及FAAH酶所代谢的内源大麻素和/或任何其它的物质。
12.根据权利要求1-7中任一权利要求所述的式(I)化合物,它们呈在药学上可接受的碱、盐、水合物或溶剂化物形式,在制备用于预防或治疗急性或慢性疼痛、头晕、呕吐、恶心、进食行为障碍、神经系统病理学和精神病病理学、急性或慢性神经变性病、癫痫、睡眠障碍、心血管病、肾缺血、癌、免疫系统紊乱、变应性疾病、寄生虫、病毒或细菌性感染病、炎性疾病、骨质疏松症、眼部情况、肺部情况、胃-肠疾病或尿失禁的药物中的应用。
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KR20050088992A (ko) * | 2002-10-07 | 2005-09-07 | 더 리전트 오브 더 유니버시티 오브 캘리포니아 | 아난드아미드 가수분해 차단을 통한 불안감의 조절 |
AU2003275493A1 (en) * | 2002-10-08 | 2004-05-04 | The Scripps Research Institute | Inhibitors of fatty acid amide hydrolase |
FR2850377B1 (fr) * | 2003-01-23 | 2009-02-20 | Sanofi Synthelabo | Derives d'arylalkylcarbamates, leur preparation et leur application en therapeutique |
FR2865205B1 (fr) * | 2004-01-16 | 2006-02-24 | Sanofi Synthelabo | Derives de type aryloxyalkylcarbamates, leur preparation et leur application en therapeutique |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN105837565A (zh) * | 2010-01-20 | 2016-08-10 | 赛诺菲 | 烷基-杂环氨基甲酸酯衍生物,它们的制备和治疗应用 |
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