CN1080919A - 作为酰基辅酶a-胆固醇酰基转移酶抑制剂的、新的n-芳基和n-杂芳基脲类衍生物 - Google Patents
作为酰基辅酶a-胆固醇酰基转移酶抑制剂的、新的n-芳基和n-杂芳基脲类衍生物 Download PDFInfo
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Abstract
式I化合物及其可药用盐,其中 Q,R17,R18和
R1的定义如文中所述。式I化合物中酰基辅酶A:
胆甾醇酰基转移酶(ACAT)抑制剂,并可用作降血脂
和抗动脉粥样硬化剂。
Description
本发明涉及新的N-芳基和N-杂芳基基脲衍生物、含有该类化合物的药用组合物、以及该类化合物在抑制胆固醇肠吸收、降低血清胆固醇和消除动脉粥样硬化形成中的应用。该类化合物是酰基辅酶A-胆固醇酰基转移酶(ACAT)的抑制剂。
饮食中被消耗的胆固醇(饮食胆固醇)由粘膜细胞和小肠以游离的胆固醇吸收。然后游离的胆固醇由酶ACAT酯化,组装到称为乳糜微粒的颗粒中,并释放到血流中。乳糜微粒是颗粒,在其中,饮食胆固醇被组装并被输送到血流中。通过抑制ACAT的作用,本发明化合物可以阻止肠吸收饮食胆固醇,因此可以降低血清胆固醇含量。所以本发明化合物可以用于预防动脉粥样硬化、心脏病发作和中风。
通过抑制ACAT的作用,本发明化合物还能够将胆固醇从血管壁除去。该作用使本发明化合物既可用于阻止或消除动脉粥样硬化的形成,又可防止心脏病发作和中风。
ACAT的其他抑制剂参见美国专利4,994,465,4,716,175和4,743,605(′175专利的分案申请),公布号为0242610、0245687、0252524、0293880、0297610、0335374、0335375、0386487、0399422、0415123、0421456和0439059的欧洲专利申请。在PCT出版物WO90/15048和WO91/04027中描述了其他的ACAT的抑制剂。作为抗动脉粥样硬化剂的某些脲类和硫脲类化合物参见美国专利4,623,662。
本发明涉及下式Ⅰ化合物
式中Q是氧或硫,
R17-(CH2)n-(CR19R20)z(CH2)r-ArⅩⅩⅩⅧ,其中n是0或1至3的整数,z是0或1;r是0或1至4的整数,
R19和R20独立地选自氢、任选卤化的(C1-12)烷基,任选取代的芳基(C1-5)烷基,(C3-8)环烷基-(C1-5)烷基和Ar;或者R19及R20与和它们相连接的碳原子形成(C4-7)环烷基环或苯稠合的(C5-7)环烷基或杂烷基环;其前提是R19和R20不能同时为氢;
Ar选自下述基团之一:
式中U是J,直接键-CH=CH-或-CH2-CH2-;
z,n和r的限定同前,X是3至10的整数,而W是0或1至X-1的整数。
R21,R22及各R23独立地选自:任选卤代的(C1-6)烷基,任选地卤代(C1-6)烷氧基,任选地卤代的(C1-6)烷硫基,苯基和卤素;其中,在所说烷基,烷氧基和烷硫基中的烷基可以是直链的,或者,如果含有3个或多个碳原子,可以是直链的,环状的,或者是环状和支链或直链残基的组合;
或者R21和R22一起形成下式基团:
-J(CH2)t-J-或-(CH2)q-
其中J是氧或硫;
t是1至3的整数;
q是3至5的整数;
k是J-或-CH=CH-;
L是-(CH2)u或-(CH2)vJ-;
u是3至5的整数;
v是2、3或4;
R18是氢,任选取代的(C1-8)烷基,任选取代的(3-8)环烷基,芳基或任选取代的芳基(C1-4)烷基,其前提是如果式ⅩⅩⅩⅧ中n,z或r中的任一个不是O,R18是氢;
R1选自下述基团之一:
式中m的限定同前;n是0或1。
每个Ⅰ独立地选自0至3。
R6和R15各自独立地选自下述基团:卤素,(C1-6)烷基,(C1-6)卤代烷基,任选地卤化(C1-6)烷氧基,任选地卤化(C1-6)烷硫基,(C5-7)环烷硫基,苯基(C1-6)烷硫基,取代的苯硫基,杂芳硫基,杂芳氧基,(C1-6)烷基亚硫酰基,(C1-6)烷基磺酰基,(C5-7)环烷基亚硫酰基,(C5-7)环烷基磺酰基,苯基(C1-6)烷基亚硫酰基,苯基(C1-6)烷基磺酰基,取代的苯基亚硫酰基,取代的苯基磺酰基,杂芳亚硫酰基,杂芳磺酰基,和NR10R11,其中R10和R11相同或不同,并且选自氢,(C1-6)烷基,苯基,取代苯基,(C1-6)烷酰基,芳酰基,和取代的芳酰基,其中所说取代苯基和取代芳酰基是由一个或多个独立地选自下述基团的取代基取代:(C1-6)烷基,(C1-6)烷氧基,(C1-6)烷硫基,卤素和三氟甲基,或者R10和R11与它们相连接的氮原子一起形成哌啶,吡咯烷或吗啉环;并且
B,D,E和G选自氮和碳,其前提是,B,D和E中的一个或多个是氮,其另一前提是,当G为氮时,基团ⅩⅥ以嘧啶环4或5位连接在式Ⅰ的氮上(4和5-位标为a和b),其中所有的所说氮原子都可被氧化;
或者R1是
其中R7,R8和R9可以相同或不同,各自独立地选自:任选卤代(C1-5)烷氧基,任选卤代(C1-5)烷硫基,任选卤代(C1-5)烷基和卤素;其前提是,当R1是式ⅩⅩⅦ基团是,Ar是式ⅩⅩⅫ,ⅩⅩⅩⅢ或ⅩⅩⅩⅤ基团,并且,当Ar是ⅩⅩⅫ时,R19或R20不是烷基和卤代(C1-12)烷基,其前提是R19和R20不能同时为氢,并且在式ⅩⅩⅩⅧ中的r是0;本发明还涉及所说化合物的可药用盐。
除非另外指明,本文使用的术语“卤素”包括氟、氯、溴和碘。
除非另外指明,本文中使用的术语“烷基”可以是直链,支链或环状的,并且可以包括直链和环状部分以及支链和环状部分。
除非另外指明,本文中使用的术语“一个或多个取代基”意指以可利用成键位置计算,从1至最大可能数目的取代基。
本文所采用的术语“所说非芳香环中的1个或多个碳原子”意指所有前述芳基稠合或杂芳基稠合系统中非芳环部分,而不是所述芳基稠合系统的芳香环部分的1个至所有碳原子。
本文所采用的术语“所说芳环的1个或多个碳”意指前述所有芳香稠合和杂芳稠合系统的芳环部分的1个至所有的碳原子,或者是所说芳基稠合和杂芳稠合系统中所述芳香和非芳香环的1个至所有的碳原子。
式Ⅰ化合物可以具有光学中心,因此,可以不同的立体异构构型出现。本发明包括所述式Ⅰ化合物的所有立体异构体,并包括它们的混合物。
本发明还涉及下式ⅩⅩⅧ化合物
式中R21是(C1-3)烷基,R22是氢或(C1-3)烷基。
优选的式Ⅰ化合物为下述化合物,式中R1是2,4,6-三氟苯基,2,6-二异丙基苯基,2,4-二氟苯基,6-甲氧基喹啉-5-基,6-甲基喹啉-5-基,6-甲硫基喹啉-5-基,6-甲氧基异喹啉-5-基,6-甲硫基异喹啉-5-基,6-甲硫基-8-乙酰氨基喹啉-5-基,4,6-二(甲硫基)嘧啶-5-基,4,6-二(甲硫基)-2-甲基嘧啶-5-基,2,4-二(甲硫基)吡啶-3-基,2,4-二(甲硫基)-6-甲基吡啶-3-基,2,4-二(乙硫基)-6-甲基吡啶-3-基,2,4-二(甲硫基)吡啶-3-基和2,4-二(异丙硫基)-6-甲基吡啶-3-基。
特别优选的式Ⅰ化合物是:
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(4-异丙基苄基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,5-二甲基苄基)-N′-(2,3-二氢化茚-2-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,4-二甲基苄基)-N′-(2,3-二氢化茚-2-基)脲;
N-[4,6-二(甲硫基)-2-甲基嘧啶-5-基]-N′-(2,3-二氢化茚-2-基)-N′-(4-异丙基苄基)脲;
N-[4,6-二(甲硫基)-2-甲基嘧啶-5-基]-N′-(2,4-二甲基苄基)-N′-(2,3-二氢化茚-2-基)脲;
N-(2,5-二甲基苄基)-N-(2,3-二氢化茚-2-基)-N′-(6-甲硫基喹啉-5-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2-氯苄基)-N′-(2,3-二氢化茚-2-基)脲;
N-[4,6-二(甲硫基)-2-甲基嘧啶-5-基]-N′-(2,3-二氢化茚-2-基)脲;
N-[4,6-二(甲硫基)-2-甲基嘧啶-5-基]-N′-(2,3-二氢化茚-2-基)-N′-[4-(3-甲基丁基)苄基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-[4-(3-甲基丁基)苄基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-1-基)-N′-(萘-1-基甲基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-1-基)-N′-(萘-2-基甲基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-1-基)-N′-(4-叔丁基苄基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-1-基)-N′-(4-苯基苄基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(萘-1-基甲基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(萘-2-基甲基)脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-环庚基-N′-(4-苯基苄基)脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-环庚基-N′-(芴-2-基甲基)脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-环庚基-N′-(萘-2-基甲基)脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-庚基-N′-[萘-2-基甲基]脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-庚基-N′-(2,4,6-三甲基苄基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-环庚基-N′-(4-苯基苄基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-环庚基-N′-(芴-2-基甲基)脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-(4-异丙基苄基)-N′-(1,2,3,4-四氢化萘-2-基)脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-庚基-N′-(3-甲基苯并[b]噻吩-2-基甲基)脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-(1,2,3,4-四氢萘-2-基)-N′-(2,4,6-三甲基苄基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-环庚基-N′-(萘-2-基甲基)脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(4-异丙基苄基)脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-(2,4-二甲基苄基)-N′-(2,3-二氢化茚-2-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(4-异丙基苄基)-N′-(6,7,8,9-四氢-5H-苯并环庚烯-7-基)脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(2,4,6-三甲基苄基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(2,4,6-三甲基苄基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氯苄基)-N′-(2,3-二氢化茚-2-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2,2-二苯基乙基]脲;
N-(2,2-二苯基乙基)-N′-(6-甲硫基喹啉-5-基)脲;
N-[4,6-二(甲硫基)-2-甲基嘧啶-5-基]-N′-(2,2-二苯基乙基)脲;
N-[4,6-二(甲硫基)嘧啶-5-基]-N′-(2,2-二苯基乙基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(1-苯基环戊基)甲基]脲;
N-(6-甲硫基喹啉-5-基)-N′-[(1-苯基环戊基甲基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[{1-(4-甲基苯基)环戊基}甲基]脲;
N-[{1-(4-甲基苯基)环戊基}甲基]-N′-(6-甲硫基喹啉-5-基)脲;
N-(6-甲硫基喹啉-5-基)-N′-[(1-苯基环己基)甲基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(1-苯基环己基)甲基]脲;
N-[{1-(4-甲基苯基)环己基}甲基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[4,6-二(甲硫基)-2-甲基嘧啶-5-基]-N′-[{1-(4-甲基苯基)环己基}甲基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[{1-(4-甲基苯基)环己基}甲基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-乙基-2-苯基)丁基]脲;
N-[2,4-二(异丙硫基)-6-甲基吡啶-3-基]-N′-[(2-乙基-2-苯基)丁基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-乙基-2-{2-甲基苯基}丁基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-苯基-2-丙基)戊基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2-甲基苯基}-2-丙基)戊基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2-甲基苯基}-2-丁基)己基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2,5-二甲氧基苯基}-2-丙基)戊基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2,3-二甲氧基苯基}-2-丙基)戊基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2,5-二甲基苯基}-2-丙基)戊基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2-甲基苯基)己基]脲;
N-[2-(2-甲基苯基)乙基]-N′-[6-甲硫基喹啉-5-基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(4-甲基苯基)庚基]脲;
N-[2-(4-甲基苯基)庚基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3-甲基苯基)庚基]脲;
N-[2-(3-甲基苯基)庚基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[2-(3-甲基苯基)庚基]-N′-(6-甲氧基喹啉-5-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)己基]脲;
N-[2-(2,5-二甲基苯基)己基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[2-(2,5-二甲基苯基)己基]-N′-(6-甲氧基喹啉-5-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,4-二甲基苯基)己基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3-甲基苯基)己基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,4-二甲基苯基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(萘-1-基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(萘-1-基)己基]脲;
N-(6-甲硫基喹啉-5-基)-N′-[2-(萘-1-基)己基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,3-二甲氧基苯基)庚基]脲;
N-[2-(2,3-二甲氧基苯基)庚基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3-甲基苯基)辛基]脲;
N-[2-(3-甲基苯基)辛基]-N′-(6-甲氧基喹啉-5-基)脲;
N-[2-(3-甲基苯基)辛基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[2-(萘-1-基)庚基]-N′-(6-甲氧基喹啉-5-基)脲;
N-[2-(萘-1-基)庚基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[2-(2,4-二甲基苯基)庚基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[2-(2,4-二甲基苯基)庚基]-N′-(6-甲氧基喹啉-5-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3,4,5-三甲氧基苯基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基-4-甲氧基苯基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲氧基苯基)庚基]脲;
N-[2-(2,5-二甲氧基苯基)庚基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[2-(2,5-二甲氧基苯基)庚基]-N′-(6-甲氧基喹啉-5-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3,5-二甲氧基苯基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲氧基苯基)辛基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-2-[2-(3-甲基苯基)-6,6,6-三氟己基]脲;
N-[2-(3-甲基苯基)庚基]-N′-(6-戊硫基喹啉-5-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-{2-(5-氯苯并[b]噻吩-3-基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3,5-二甲基苯基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)辛基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[5-甲基-2-{3-甲基苯基}己基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2,5-二甲基苯基}-4-苯基丁基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)-5-苯基戊基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(萘-1-基)-6-甲基戊基]脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(萘-1-基)-6-甲基庚基]脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)-6-甲基庚基]脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(萘-1-基)庚基]脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)-6-苯基己基]脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)-6-庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,4,6-三甲基苯基)辛基]脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)-6,6,6-三氟己基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(5-甲基苯并[b]噻吩-3-基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2-氯苯并[b]噻吩-3-基)庚基]脲;
N-[2-(2,5-二甲基苯基)庚基]-N′-(6-甲硫基喹啉-5-基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)-6-甲基庚基]脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)-5-苯基戊基]脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)辛基]脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)-5-甲基己基]脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2-氯苯并[b]噻吩-3-基)-6-甲基庚基]脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(5,6,7,8-四氢萘-1-基)庚基]脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(3,5-二甲基苯基)庚基]脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2-氯苯并[b]噻吩-3-基)庚基]脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(3,5-二甲基苯基)辛基]脲;
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基-4-甲氧基苯基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(5-甲基苯并[b]噻吩-3-基)庚基]脲;
N-[2-(2-氯苯并[b]噻吩-3-基)-5-甲基己基]-N′-(2,6-二异丙基)脲;
N-(2,6-二异丙基苯基)-N′-[2-(5-甲基苯并[b]噻吩-3-基)-5-甲基己基]脲;
N-[2-(苯并[b]噻吩-3-基)庚基]-N′-(2,6-二异丙基苯基)脲;
N-[2-(苯并[b]噻吩-3-基)-6-甲基庚基]-N′-(2,6-二异丙基苯基)脲;
N-[2-(2-氯苯并[b]噻吩-3-基)-6-甲基庚基]-N′-(2,6-二异丙基苯基)脲;
N-(2,6-二异丙基苯基)-N′-[2-(5-甲基苯并[b]噻吩-3-基)-6,6,6-三氟己基]脲;
N-[2-(2-氯苯并[b]噻吩-3-基)-6,6,6-三氟己基]-N′-(2,6-二异丙基苯基)脲;
N-(2,6-二异丙基苯基)-N′-[2-(萘-2-基)-6,6,6-三氟己基]脲;
N-[7,7-二氟-2-(萘-1-基)庚基]-N′-(2,6-二异丙基苯基)脲;
N-[7,7-二氟-2-(2-氯苯并[b]噻吩-3-基)庚基]-N′-(2,6-二异丙基苯基)脲;
N-[2-(5-氯苯并[b]噻吩-3-基)庚基]-N′-(2,6-二异丙基苯基)脲;
N-[2-(2-氯苯并[b]噻吩-3-基)庚基]-N′-(2,6-二异丙基苯基)脲;
N-[2-(5-氯苯并[b]噻吩-3-基)-6,6,6-三氟己基]-N′-(2,6-二异丙基苯基)脲;
N-(2,6-(二异丙基苯基)-N′-[2-(5-甲基苯并[b]噻吩-3-基)庚基]脲;
N-[2-(5-氯苯并[b]噻吩-3-基)-6-甲基庚基]-N′-(2,6-二异丙基苯基)脲;
N-(2,6-二异丙基苯基)-N′-[2-(2,5-二甲基苯基)-6,6,6-三氟己基]脲;
N-[7,7-二氟-2-(2,5-二甲基苯基)庚基]-N′-(2,6-二异丙基苯基)脲;
N-(2,6-二异丙基苯基)-N′-[2-(萘-1-基)庚基]脲;
N-(2,6-二异丙基苯基)-N′-[6-甲基-2-(萘-1-基)庚基]脲。
本发明也涉及式Ⅰ,Ⅱ和ⅩⅩⅧ的放射性同位素示踪标记形式的化合物。所述放射性同位素示踪标记的化合物可用作为动物和人的药代动力学分析和结合试验中研究与特性鉴别的工具。
本发明还涉及在哺乳动物(包括人)中抑制ACAT、抑制胆固醇的肠吸收、消除或延缓动脉粥样硬化形成或降低血清胆固醇浓度的药用组合物,该组合物包括抑制ACAT、抑制胆固醇的肠吸收、消除或延缓动脉粥样硬化形成或降低血清胆固醇浓度有效剂量的式Ⅰ化合物或其药学上适用的盐以及药用载体。
本发明也涉及在哺乳动物(包括人)中抑制ACAT、抑制胆固醇的肠吸收、消除或延缓动脉粥样硬化形成或降低血清胆固醇的方法,该方法包括给哺乳动物服用抑制ACAT、抑制胆固醇的肠吸收、消除或延缓动脉粥样硬化形成或降低血清胆固醇浓度有效剂量的式Ⅰ化合物或其药学上适用的盐。
式Ⅰ化合物的药学上适用的酸加成盐的实例有与盐酸、对甲苯磺酸、富马霜清胆固醇浓度有效剂量的式Ⅰ化合物或其药学上适用的盐。
式Ⅰ化合物的药学上适用的酸加成盐的实例有与盐酸、对甲苯磺酸、富马酸、柠檬酸、琥珀酸、水杨酸、草酸、氢溴酸、磷酸、甲磺酸、酒石酸、二-对甲苯酰基酒石酸和偏桃酸形成的盐。
下述反应式解释了在实施本发明过程中使用的某些5-氨基喹啉及5-氨基异喹啉的合成。
除特别指明外,反应式及讨论中的Q,R1,R6,R7,R8,R9,R15,R17,R18,n,m,o,p,A,B,D,E和G遵循前述的定义。
本发明中采用的氨基嘧啶和氨基吡啶中间体是文献中的已知的化合物,或者可由文献中已知的或买得到的中间体按本领域已知方法制得。D.J.Brown的专著“嘧啶类化合物”(1962),及R.A.Abramovitch的专著“吡啶及其衍生物”(1961)(Interscience Publishers,Inc.,New York,N.Y.及它们的补充材料中提到了许多有关制备嘧啶和吡啶中间体的文献。下文将更加详细地介绍这些中间体中某些中间体的制备。
在约15℃至约40℃的温度下,使适宜取代的4,6-二羟基嘧啶与硝化剂(例如,在乙酸中的发烟硝酸)反应约1至5小时,可以制得2,6-二取代的-5-硝基-嘧啶衍生物。用氯化剂(如:磷酰氯,单独或在碱(优选二乙基苯胺)存在下使用)将所得5-硝基嘧啶转化为2,4-二氯-5-硝基嘧啶中间体,反应温度约为100~115℃,反应时间约为0.5~2小时。实施这些转化的方法详见于J.Chem.Soc.,3832(1954)。
可以制备2,6-二(烷硫基)-5-硝基嘧啶衍生物的方法是:在溶剂(如:二甲基甲酰胺或,优选甲醇)中,在约0~30℃下,优选在环境温度下,使适宜的二氯中间体与两当量的烷基硫醇钠反应,反应时间约为4~16小时。在隋性溶剂(如:二甲基甲酰胺或四氢呋喃)中,采用一当量的亲核性试剂,根据该亲核性试剂的活性,在约0~100℃下反应约4~16小时,完成二氯中间体的单取代反应。
所得的单氯衍生物然后再与一当量的不同的亲核试剂反应,得到在2-和4-位碳原子上带有不同取代基的二取代衍生物。采用还原剂(如:在浓盐酸中的氯化锡或氢气/适宜催化剂)将2,6-二取代-5-硝基嘧啶还原,得到相应的5-氨基嘧啶衍生物。
新的式ⅩⅩⅧ吡啶和其他2,4-二取代-3-氨基吡啶衍生物可按下法制备:使适宜的2,4-二羟基吡啶与硝化剂(如:浓硝酸)在80-100℃下反应15-60分钟。例如,“J.Heterocyclic Chem.,(1970),7,389”中描述了2,4-二羟基-6-甲基-3-硝基吡啶的制备方法。采用类似于前文叙及的有关嘧啶系列的反应条件,依次将所得2,4-二羟基-3-硝基吡啶转化为2,4-二氯-3-硝基吡啶,2,4-二取代-3-硝基吡啶和2,4-二取代-3-氨基吡啶衍生物。
反应式Ⅰ描述了某些5-氨基喹啉和5-氨基异喹啉的制备。参照反应式Ⅰ,按如下方法可以制得式ⅩⅤ和ⅩⅦ5-氨基喹啉和异喹啉类化合物。分别使式ⅩⅢ喹啉或异喹啉在5-位硝化的方法是:在约0~100℃下,使之与硝化剂(如:硝酸或加或不加酸催化剂(如:硫酸)的硝酸钾)反应约2~16小时。然后,采用还原剂如:氯化锡,铁,锌或氢气/适宜催化剂,加或不加酸催化剂(如盐酸),在约0~100℃下,将前述所得式ⅩⅣ硝基化合物还原2-16小时,得到相应的式ⅩⅤ5-氨基喹啉或5-氨基异喹啉。
按下述方法可以制得下述式ⅩⅦ化合物,式中,R15是-SR14,并连接于喹啉或异喹啉的6位,并且,式中R14是(C1-6)烷基、(C5-7)环烷基,苯基(C1-4)烷基,苯基,取代苯基,杂芳基,或取代杂芳基。式中R5是-Cl,并且该R5连接在喹啉或异喹啉的6-位的式ⅩⅣ化合物与式中R14定义如前的式R14SH和碱(如:NaH)反应,或者该式ⅪⅤ化合物与式中R14定义如前的式R14SNa反应,反应溶剂为惰性溶剂(如:四氢呋喃),反应时间约为4~16小时,反应温度为约-10℃至室温。该反应得到式ⅩⅥ化合物,然后采用前文叙及的有关还原式ⅪⅤ化合物的方法,将式ⅩⅥ化合物转化为相应的式ⅩⅦ5-氨基喹啉或异喹啉。
用式R1N=C=Q化合物处理式R17R18NH化合物得到相应的式Ⅰ脲(Q=O)或硫脲(Q=S)。式R1N=C=Q化合物的制备方法是文献已知方法,“有机官能团的制备,第一卷”,第12章,Academic Press,New York(1968)中综述了几种方法。“有机官能团的制备,第二卷,第6章,Academic Press,New York(1971)中综述了通过氨与异氰酸酯和硫代异氰酸酯反应,制备脲和硫脲的方法。
由式R1NH2化合物与1~6当量的适宜试剂(如:光气,氯甲酸三氯甲酯或碳酸二(三氯甲基)酯反应,可制得式R1N=C=O化合物。该反应一般在下述惰性溶剂中进行:醚,芳烃或氯烃溶剂,例如,二噁烷,二异丙醚,苯,甲苯,二氯甲烷或氯仿。该反应可以在碱(如:叔胺,例如,吡啶,三乙胺,或喹啉)存在下进行。反应温度为约0~120℃,优选20~100℃。优选式R1NH2杂环胺与1~2当量的氯甲酸三氯甲酯在回流二氯甲烷中反应约18小时。
式R1N=C=Q化合物与式R17R18NH化合物反应形成式Ⅰ化合物的反应在下述惰性、无水溶剂中进行:氯仿、苯,二甲基甲酰胺,二噁烷或四氢呋喃,反应温度约为20~100℃,反应时间约为3~30小时,优选在二甲基甲酰胺中,于约80℃反应约16小时。采用本领域周知的方法之变通方法(参见:Vogel′s Textbook of Practical Organic Chemistry,Longman Inc.,New York,pp.769-782和pp.717-718(5th ed.1989),Organic Funetional Group Prepartions,Vol.2,Academic Press,New York,pp.401-405(2nd ed.1983)),可以制得式NHR17R18胺。EP0399422Al,EP0415123A2和EP0439059A2中描述了有关制备式NHR17R18胺的方法的其他实施例。
例如,采用标准方法;用碱金属氨基化物处理式Ar-CH2-CN物。然后加入式R20Ⅰ化合物,形成式Ar
CN化合物,然后将后者还原为式Ar-
-CH2-NH2胺,由此可以制得式中R19是氢,R20是任选取代芳基(C1-6)烷基或任选卤代(C1-12)烷基的式R17R18NH化合物。
氨基化物的碱金属部分可以例举:锂,钠,钾优选锂。最优选的氨基化物是二异丙基氨基锂。
腈的还原反应可采用甲硼烷,例如,使用它与四氢呋喃的配合物,或者采用在阮尼镍存在下的氢化反应来进行。
除特别指明外,在上述任何反应中,压力并不严格。上述反应的优选温度已在已知处指明。一般来说,各反应的优选温度是可能形成该产物的最低温度。采用薄层层析监测反应,可以确定具体反应的优选温度。
在制备实施例A至R中描述了用于制备本发明化合物的某些新的中间体的制备方法。
新的式Ⅰ化合物及其药学上适用的盐可用作为酰基辅酶A-胆固醇酰基转移酶(ACAT)的抑制剂。因此,本发明化合物可抑制哺乳动物中胆固醇的肠吸收,并可以用于治疗哺乳动物(包括人)的高血清胆固醇症。这里所述的“处理”意指既可预防又可减轻高血清胆固醇。可以通过各种常规的给药途径(包括口服给药、非经胃肠道给药和局部给药)给需要治疗的病体服用本发明的化合物。一般来讲,口服或非经胃肠道给予本发明化合物的剂量为需治疗的病体每天0.5~30mg/Kg体重,最好0.8~5mg/Kg体重。因此,对于体重为约70Kg的成人,常用的剂量为每天35~约2000mg。但是,根据需要治疗病体的情况和应用的化合物活性,在剂量方面进行一些改变也是必然会发生的。无论怎样对各个病体来讲,根据服药的个体确定合适的剂量。
式Ⅰ化合物或其药学上适用的盐可以按单次剂量或多次剂量单独服用,或者与药用载体一起服用。合适的药用载体包括惰性固体稀释剂或填充剂、无菌水溶液和各种有机溶剂。生成的药用组合物可以容易地以多种剂型(如片剂、粉剂、锭剂、糖浆剂、注射溶液剂等)服用。如果需要,上述药用组合物可以含有另外的成分如调味剂、粘合剂、赋形剂等。因此,对于口服给药来说,含有各种赋形剂(如柠檬酸钠、碳酸钙和磷酸钙)的片剂还可以含有各种崩解剂(如淀粉、藻酸和某些复合的硅酸盐)以及粘合剂(如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯树胶)。此外,润滑剂(如硬脂酸镁、硫酸月桂酯钠和滑石)通常用于制备片剂。同样类型的固体组合物还可以作填充剂用于软明胶胶囊和硬明胶胶囊。胶囊剂较好的填充剂包括乳糖和高分子量的聚乙二醇。如果希望将水混悬液或酏剂用于口服给药,那么可以将基本的有效成分与各种甜味或调味剂、着色物质或染料(如果需要,还应有乳化剂或混悬剂)以及稀释剂(如水、乙醇、聚乙二醇、甘油及它们的混合液)一起配制。
对于非经胃肠道给药,可以应用式Ⅰ化合物或其药学上适用的盐在芝麻油或花生油、丙二醇水溶液或在无菌水溶液中的溶液剂。如果需要,应适当地将上述水溶液剂缓冲,并且首先用足量的盐水或葡萄糖使液体稀释剂等渗。所述溶液剂尤其适用于经静脉注射、肌内注射、皮下注射和腹膜内注射给药。在这方面,应用的无菌水介质可由熟悉本技术领域的专业人员通过一般的技术容易地得到。
可以通过许多一般的生物学或药理学试验测定本发明化合物作为ACAT抑制剂的作用。例如,用下面的方法测定式Ⅰ化合物抑制ACAT的活性。按照Bilheimer,J.T,Meth Enzymol,111,P.286~293(1985)所述并经较小改进的方法,以喂混合平衡饲料的Sprague-Dawley品系大白鼠中分离出的微粒体进行ACAT试验。从大白鼠肝脏得到的微粒体通过差速离心,并在应用之前用试验缓冲液冲洗。试验混合物含有25μl BSA(40mg/ml)、30μl大白鼠肝脏微粒体溶液(100μg微粒体蛋白)、20μl试验缓冲液(0.1M K2PO4,1.0mM还原谷胱甘肽,pH7.4)、20μg胆固醇的(100μl0.6%Teition WR-1339的试验缓冲溶液和5μl试验化合物溶于100%DMSO的溶液(总体积为180μl)。将试验混合物于37℃温育30min。加入20μl14℃-Oleoyl-CoA(1000 μm,)2,000dpm/nmol)起动反应并于37℃进行15分钟。加入1ml ETOH使反应停止。将脂质萃取到4ml己烷中。3ml等份试样在氮气下干燥,再次悬浮到100μl氯仿中。将50μl氯仿溶液点在经加热活化的TLC薄板上,并用己烷∶乙醚∶乙酸(85∶15∶1,V∶V∶V)展开。在Berthold LB2842Linear TLC分析仪上定量加入胆甾烯酯的放射性。以DMSO对照试验为基准,计算抑制ACAT的活性。
式Ⅰ化合物抑制肠吸收胆固醇的作用可以按Melchoir和Harwell(J.Lipid.Res.,26,306~315(1985))所述的方法测定。
本发明列举以下实例。但是应该认识到,本发明不受这些实例具体说明的限制。熔点未经校正,以氘氯仿(CDCl3)或D6-二甲基亚砜(DMSO-D6)的溶液进行质子核磁共振谱(1H NMR)和13C核磁共振谱(13C NMR)的测定,并且峰的位置以百万分率(ppm)表示,以四甲基硅烷作内标。峰的形状用以下缩写表示:s,单峰;d,二重峰;t,三重峰;g,四重峰;hx,六重峰;h,七重峰;m,多重峰;b,宽峰;vb,很宽的峰;c,复杂峰。
制备实施例A
5-碘-1,1-二氟戊烷
将5-溴-1,1-二氟戊烷(2.65g,14.2mmol)和碘化钠(10.63g,70.8mmol)在丙酮(150ml)中的溶液在氮气流下回流过夜。然后将反应混合物过滤,常压下浓缩滤液,将残留物溶解在二氯甲烷(50ml)中,用水(2×30ml)和盐水(30ml)洗涤溶液,干燥(Na2SO4),室温下减压浓缩。减压蒸馏粗产物,得到微黄色液体状标题化合物(2.24g,收率93%),
制备实施例B
2-(2-氯苯并[b]噻吩-3-基)-7,7-二氟庚腈充氮,冷却(-70℃)下,将二异丙基氨基锂的环己烷溶液(5.13mmol,3.42ml1.5M的溶液)滴加到(2-氯苯并[b]噻吩-3-基)乙腈(1.06g,5.13mmol)的四氢呋喃(10ml)溶液中。将所得溶液在-70℃搅拌20分钟,然后在-70℃下慢慢地加入5-碘-1,1-二氟戊烷(1.2g,5.13mmol)在四氢呋喃(5ml)中的溶液。将反应混合物在-70℃搅拌1小时,然后慢慢地使之温热至室温,并在该温度下放置过夜。在该反应液中加入水(60ml),所得混合物用乙酸乙酯(3×70ml)提取。合并乙酸乙酯提取液,用盐水(80ml)洗涤,干燥(Na2SO4),减压浓缩。粗产物(2.1g)经硅胶(200g)柱层析纯化,先用4∶1己烷/二氯甲烷,再用7∶3己烷/二氯甲烷洗脱,得到油状标题化合物(950mg,收率:59%)。
1H NMR(300 MHz,CDCl3)δ1.4-1.7(c,4H),1.7-2.05(c,3H),2.2(c,1H),4.3(t,1H),5.6,5.78,5.98(3t,total 1H),7.42(m,2H),7.75(d,1H),7.95(d,1H).
按类似的方法,合成了下述腈。
制备实施例C
2-(萘-1-基)-7,7-二氟庚腈,收率:75%。
1H NMR(300 MHz,CDCl3)δ1.44-1.72(c,4H),1.72-1.94(c,2H),2.07(m,2H),4.57(t,1H),5.6,5.8,5.99(3t,total 1H),7.44-7.64(m,3H),7.69(d,1H),7.9(m,3H).
制备实施例D
2-(2,5-二甲基苯基)-6-苯基己腈,收率:86%。
1H NMR(300 MHz,CDCl3)δ1.48-2.0(c,6H),2.28(s,3H),2.34(s,3H),2.63(t,2H),3.89(q,1H),7.06(m,2H),7.12-7.32(m,6H)
制备实施例E
2-(2-氯苯并[b]噻吩-3-基)-7,7-二氟庚胺
在室温,通氮下,将甲硼烷-四氢呋喃配合物在四氢呋喃中的溶液(6.07mmol,6.07ml1.0M溶液)滴加到(2-氯苯并[b]噻吩-3-基)-7,7-二氟庚腈(950mg,3.03mmol)在四氢呋喃(15ml)中的溶液中,将该反应物在室温下放置过夜。然后加入盐酸水溶液(5ml 3N)溶液,反应混合物回流30分钟,然后减压下除去四氢呋喃。用水(10ml)稀释所得水相,用乙酸乙酯(3×30ml)提取,合并乙酸乙酯提取液,用盐水(40ml)提取,干燥(Na2SO4),减压浓缩。残余物(930mg)经硅胶(100g)柱层析纯化,用9∶1乙酸乙酯/甲醇洗脱,得到油状标题化合物(632mg,收率:66%)。
以类似的方法,合成了下述胺类:
制备实施例F
[2-(2-氯苯并[b]噻吩-3-基)-5-甲基己胺,收率:67%,
1H NMR(300 MHz,CDCl3)δ0.79,0.80,0.81,0.83(2d,6H),0.92-1.08(m,1H),1.1-1.28(m,1H),1.5(h,1H),1.66(b,2H),1.78(m,1H),1.94(c,1H),3.09(m,1H),3.18-3.37(c,2H),7.32(c,2H),7.71(c,1H),7.79(c,1H).
制备实施例G
5-甲基-2-(5-甲基苯并[b]噻吩-3-基)己胺,收率:53%,
1H NMR(300 MHz,CDCl3)δ0.84(d,6H),1.18(c,2H),1.52(h,1H),1.75(bq,2H),2.02(b,2H),2.49(s,3H),3.0(d,2H),3.12(p,1H),7.1(s,1H),7.17(d,1H),7.59(s,1H),7.73(d,1H).
制备实施例H
2-(苯并[b]噻吩-3-基)庚胺,收率:65%,
1H NMR(300 MHz,CDCl3)δ0.83(t,3H),1.25(c,6H),1.76(c,2H),2.05(b,2H),3.03(c,2H),3.19(p,1H),7.14(s,1H),7.36(c,2H),7.81(m,1H),7.87(m,1H).
制备实施例I
2-(苯并[b]噻吩-3-基)-6-甲基庚胺,收率:66%,
1H NMR(300 MHz,CDCl3)δ0.78,0.80,0.81,0.82(2d,6H),1.1-1.44(c,4H),1.47(h,1H),1.74(q,2H),2.06(b,2H),3.04(c,2H),3.19(p,1H),7.14(s,1H),7.36(c,2H),7.84(m,2H).
制备实施例J
2-(5-甲基苯并[b]噻吩-3-基)-6,6,6-三氟己胺,收率:51%,
1H NMR(300 MHz,CDCl3)δ1.54(m,2H),1.69(b,2H),1.86(c,2H),2.06(m,2H),2.49(s,3H),3.03(d,2H),3.16(p,1H),7.12(s,1H),7.19(d,1H),7.57(s,1H),7.75(d,1H).
制备实施例K
2-(2-氯苯并[b]噻吩-3-基)-6,6,6-三氟己胺,收率:60%,
1H NMR(300 MHz,CDCl3)δ1.35-1.7(c,4H),1.89(c,1H),2.05(c,3H),3.09(q,1H),3.2-3.4(c,m,2H),7.34(m,2H),7.75(m,2H).
制备实施例L
2-(2-氯苯并[b]噻吩-3-基)庚胺,收率:68%,
1H NMR(300 MHz,CDCl3)δ0.81(t,3H),1.2(c,6H),1.65(b,2H),1.78(c,1H),1.95(c,1H),3.07(q,1H),3.16-3.38(c,m,2H),7.32(c,2H),7.72(m,1H),7.8(m,1H).
制备实施例M
2-(5-氯苯并[b]噻吩-3-基)庚胺,收率:60%,
1H NMR(300 MHz,CDCl3)δ0.84(t,3H),1.26(c,6H),1.65-1.9(c,4H),3.0(d,2H),3.1(p,1H),7.19(s,1H),7.29,7.30,7.32,7.33(q,1H),7.77(m,2H).
制备实施例N
2-(5-甲基苯并[b]噻吩-3-基)庚胺,收率:63%,
1H NMR(300 MHz,CDCl3)δ0.84(t,3H),1.26(c,6H),1.76(c,2H),1.84(b,2H),2.49(s,3H),3.0(d,2H),3.13(p,1H),7.1(s,1H),7.18(d,1H),7.6(s,1H),7.74(d,1H).
制备实施例O
2-(5-氯苯并[b]噻吩-3-基)-6,6,6-三氟己胺,收率:33%,
1H NMR(300 MHz,CDCl3)δ1.43-2.0(c,6H),2.08(m,2H),3.02(c,2H),3.12(m,1H),7.22(s,1H),7.31,7.32,7.34,7.35(q,1H),7.75,7.76,7.77,7.8(q,2H).
制备实施例P
2-(5-氯苯并[b]噻吩-3-基)-6-甲基庚胺,收率:69%,
1H NMR(300 MHz,CDCl3)δ0.79,0.81,0.82,0.83(2d,6H),1.1-1.33(c,4H),1.47(h,1H),1.62-1.93(c,4H),3.01(d,2H),3.11(p,1H),7.2(s,1H),7.29,7.30,7.32,7.33(q,1H),7.76,7.77,7.78,7.784(q,2H).
制备实施例Q
2-(萘-1-基)-7,7-二氟庚胺
将2-(萘-1-基)-7,7-二氟庚腈(413mg,1.51mmol),阮尼镍(413mg)和氨(0.9g)在甲醇(20ml)中的混合物在340kpa(50psi)的氢气压下,于室温下氢化过夜。将该混合物过滤,将滤液减压浓缩。残余物在乙酸乙酯(50ml)和水(40ml)之间分配,用盐水(30ml)洗涤乙酸乙酯提取液,干燥(Na2SO4),减压浓缩。残余物(400mg)经硅胶(100g)柱层析纯化,用85∶15乙酸乙酯/甲醇洗脱,得到油状标题化合物(321mg,收率:77%)。1H NMR(300 MHz,CDCl3)δ1.35(c,6H),1.78(c,4H),3.08(c,2H),3.61(c,1H),5.52,5.71,5.9(3t,total 1H),7.37(d,1H),7.5(m,3H),7.75(d,1H),7.88(d,1H),8.16(d,1H).
以类似的方法合成了下述化合物:
制备实施例R
2-(2,5-二甲基苯基)-6-苯基己胺,收率:74%,
1H NMR(300 MHz,CDCl3)δ1.15-1.44(c,4H),1.5-1.75(c,4H),2.29(s,3H),2.32(s,3H),2.55(m,2H),2.9(c,3H),6.91,6.94,6.95(t,2H),7.05(d,1H),7.14(m,3H),7.29(t,2H).
实施例1
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(4-异丙基苄基)脲
将2-(4-异丙基苄基氨基)-2,3-二氢化茚(159mg,0.6mmol)和异氰酸2,4-二(甲硫基)-6-甲基吡啶-3-基酯(136mg,0.6mmol)在3ml二甲基甲酰胺中的溶液于80℃,在氮气流下加热过夜。将反应混合物冷却到室温,用50ml乙酸乙酯稀释,用3×50ml水洗涤,然后用50ml盐水洗涤,干燥(Na2SO4),过滤,减压浓缩,固体残余物(265mg)经硅胶(150g)柱层析纯化,用7∶3己烷/乙酸乙酯洗脱,得到白色固体状标题化合物(195mg,收率:66%)。
1H NMR(300 MHz,CDCl3)δ1.25(d,6H),2.36(s,3H),2.45(s,3H),2.47(s,3H),2.91(h,1H),3.06(dd,2H),3.31(dd,2H),4.57(s,2H),5.39(p,1H),5.57(s,1H),6.59(s,1H),7.15(c,4H),7.22-7.35(m,4H).
按类似的方法,合成了实施例2-18的1-和2,3-二氢化茚-2-基脲衍生物。
实施例2
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,5-二甲基苄基)-N′-(2,3-二氢化茚-2-基)脲;收率:66%,
1H NMR(300 MHz,CDCl3)δ2.15(s,3H),2.37(s,3H),2.39(s,3H),2.45(s,3H),2.47(s,3H),2.99(dd,2H),3.29(dd,2H),4.47(s,2H),5.48(s) and 5.50(m)(total 2H),6.58(s,1H),7.04(m,2H),7.15(c,5H),7.43(s,1H).
实施例3
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,4-二甲基苄基)-N′-(2,3-二氢化茚-2-基)脲;收率:66%,
1H NMR(300 MHz,CDCl3)δ2.17(s,3H),2.33(s,3H),2.37(s,3H),2.45(s,3H),2.48(s,3H),2.99(dd,2H),3.26(dd,2H),4.48(s,2H),5.44(m) and 5.49(s)(total 2H),6.58(s,1H),6.99(s,1H),7.14(c,5H),7.47(d,1H).
实施例4
N-[4,6-二(甲硫基)-6-甲基嘧啶-5-基]-N′-(2,3-二氢化茚-2-基)-N′-(4-异丙基苄基)脲;收率:62%,
1H NMR(300 MHz,CDCl3)δ1.25(d,6H),2.46(s,6H),2.56(s,3H),2.92(h,1H),3.04(dd,2H),3.31(dd,2H),4.55(s,2H),5.41(m) and 5.46(s)(total 2H),7.16(c,4H),7.23-7.34(m,4H).
实施例5
N-[4,6-二(甲硫基)-2-甲基嘧啶-5-基]-N′-(2,4-二甲基苄基)-N′-(2,3-二氢化茚-2-基)脲;收率:70%,
1H NMR(300 MHz,CDCl3)δ2.17(s,3H),2.33(s,3H),2.47(s,6H),2.56(s,3H),2.99(dd,2H),3.28(dd,2H),4.46(s,2H),5.41(s) and 5.44(m)(total 2H),6.99(m,1H),7.14(c,5H),7.44(d,1H).
实施例6
N-(2,5-二甲基苄基)-N-(2,3-二氢化茚-2-基)-N′-(6-甲硫基喹啉-5-基)脲;收率:19%,
1H NMR(300 MHz,CDCl3)δ2.20(s,3H),2.45(s,6H),3.06(dd,2H),3.34(dd,2H),4.60(s,2H),5.54(p,1H),6.20(s,1H),7.07(m,2H),7.16(c,4H),7.38(q,1H),7.46(s,1H),7.60(d,1H),7.96(d,1H),8.07(d,1H),8.82(m,1H).
实施例7
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2-氯苄基)-N′-(2,3-二氢化茚-2-基)脲;收率:17%
1H NMR(300 MHz,CDCl3)δ2.38(s,3H),2.45(s,3H),2.48(s,3H),3.02(dd,2H),3.26(dd,2H),4.67(s,2H),5.37(p,1H),5.51(s,1H),6.59(s,1H),7.14(c,4H),7.25(c,1H),7.38(c,2H),7.64(d,1H).
实施例8
N-[4,6-二(甲硫基)-2-甲基嘧啶-5-基]-N′-(2,3-二氢化茚-2-基)脲;收率:69%,
1H NMR(300 MHz,CDCl3)δ2.15(s,3H),2.39(s,3H),2.47(s,6H),2.57(s,3H),2.98(dd,2H),3.29(dd,2H),4.45(s,2H),5.40(s,1H),5.50(p,1H),7.06(m,2H),7.14(m,4H),7.38(s,1H).
实施例9
N-[4,6-二(甲硫基)-2-甲基嘧啶-5-基]-N′-(2,3-二氢化茚-2-基)-N′-[4-(3-甲基丁基)苄基]脲;收率:71%,
1H NMR(300 MHz,CDCl3)δ0.93(d,6H),1.45-1.69(c,3H),2.47(s,6H),2.57(s) and 2.61(m)(total 5H),3.03(dd,2H),3.31(dd,2H),4.55(s,2H),5.40(m) and 5.46(m)(total 2H),7.10-7.33(c,8H).
实施例10
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-[4-(3-甲基丁基)苄基]脲;收率:58%
1H NMR(300 MHz,CDCl3)δ0.92(d,6H),1.44-1.68(c,3H),2.36(s,3H),2.44(s,3H),2.46(s,3H),2.60(m,2H),3.04(dd,2H),3.30(dd,2H),4.56(s,2H),5.39(p,1H),5.54(s,1H),6.58(s,1H),7.10-7.34(c,8H).
实施例11
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(萘-1-基甲基)脲;收率:25%,
1H NMR(300 MHz,CDCl3)δ2.1(c,1H),2.32-2.54[total 10H,including 2.4(s,3H),2.46(s,3H),2.51(s,3H),2.83(c,2H),4.69(d,1H),5.26(d,1H),5.5(b,1H),6.06(vb,1H),6.6(s,1H),7.15-7.39(c,4H),7.5(c,3H),7.72-8.0(c,4H).
实施例12
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(萘-2-基甲基)脲;收率:32%,
1H NMR(300 MHz,CDCl3)δ2.1(c,1H),2.33-2.55[total 10H,including 2.37(s,3H),2.47(s,3H),2.49(s,3H),2.88(c,2H),4.5(d,1H),4.8(d,1H),5.6(b,1H),6.08(vb,1H),6.6(s,1H),7.22(c,3H),7.47-7.54(c,4H),7.83(c,3H),7.93(s,1H).
实施例13
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-1-基)-N′-(4-叔丁基苄基)脲;收率:23%,
1H NMR(300 MHz,CDCl3)δ1.32(s,9H),2.1(c,1H),2.36-2.55[total 10H,including 2.38(s,3H),2.46(s,3H),2.48(s,3H),2.9(c,2H),4.29(d,1H),4.6(d,1H),5.52(b,1H),6.05(vb,1H),6.6(s,1H),7.22(c,4H),7.32(d,2H),7.39(d,2H).
实施例14
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-1-基)-N′-(4-苯基苄基)脲;收率:28%,
1H NMR(300 MHz,CDCl3)δ2.1(c,1H),2.38-2.58[total 10H,including 2.39(s,3H),2.47(s,3H),2.5(s,3H),2.9(c,2H),4.4(d,1H),4.7(d,1H),5.54(b,1H),6.02(vb,1H),6.61(s,1H),7.24(c,4H),7.31-7.52(c,5H),7.6(c,4H).
实施例15
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(萘-1-基甲基)脲;收率:20%,
1H NMR(300 MHz,CDCl3)δ2.4(s,3H),2.48(s,3H),2.53(s,3H),3.07(dd,2H),3.33(dd,2H),5.1(s,2H),5.5(m) and 5.57(s)(total 2H),6.6(s,1H),7.12(c,4H),7.48-7.64(c,3H),7.76-7.97(c,4H).
实施例16
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(萘-2-基甲基)脲;收率:20%,
1H NMR(300 MHz,CDCl3)δ2.37(s,3H),2.48(s,6H),3.1(dd,2H),3.34(dd,2H),4.78(s,2H),5.47(p,1H),5.68(s,1H),6.6(s,1H),7.15(c,4H),7.38-7.58(c,3H),7.87(c,3H),7.95(s,1H).
实施例17
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(2,4,6-三甲基苄基)脲;收率:13%,
1H NMR(300 MHz,CDCl3)δ2.27(s,3H),2.38(s,3H),2.4(s,6H),2.46(s,3H),2.5(s,3H),3.07(dd,2H),3.55(dd,2H),4.16(m,1H),4.77(s,2H),5.41(s,1H),6.6(s,1H),6.88(s,2H),7.12(c,4H).
实施例18
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢苄基)-N′-(2,3-二氢化茚-2-基)脲;收率:27%,
1H NMR(300 MHz,CDCl3)δ2.41(s,3H),2.49(s,3H),2.52(s,3H),3.0(dd,2H),3.28(dd,2H),4.68(s,2H),5.32(q,1H),5.54(s,1H),6.63(s,1H),7.16(c,4H),7.34(t,1H),7.45(d,1H),7.55(d,1H).
实施例19
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-环庚基-N′-(4-苯基苄基)脲;收率:33%
1H NMR(300 MHz,CDCl3)δ1.28,1.32(2t,6H),1.4-1.8(C,10H),2.02(c,2H),2.42(s,3H),2.86(q,2H),3.09(q,2H),4.37(c,1H),4.62(s,2H),5.54(s,1H),6.62(s,1H),7.34(t,1H),7.44(t,2H),7.51(d,2H),7.6(m,4H).
实施例20
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-环庚基-N′-(芴-4-基甲基)脲;收率:40%
1H NMR(300 MHz,CDCl3)δ1.22,1.24,1.26,1.27,1.3(2t,6H),1.4-1.8(c,10H),2.02(c,2H),2.41(s,3H),2.84(q,2H),3.06(q,2H),3.91(s,2H),4.42(c,1H),4.65(s,2H),5.55(s,1H),6.6(s,1H),7.25-7.44(m,3H),7.54(d,1H),7.68(s,1H),7.78(d,2H).
实施例21
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-环庚基-N′-(萘-2-基甲基)脲;收率:31%
1H NMR(300 MHz,CDCl3)δ1.2,1.22,1.27,1.3(2t,6H),1.4-1.8(c,10H),2.04(c,2H),2.4(s,3H),2.82(q,2H),3.04(q,2H),4.47(c,1H),4.73(s,2H),5.6(s,1H),6.59(s,1H),7.48(c,3H),7.85(m,3H),7.99(s,1H).
实施例22
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-庚基-N′-(萘-2-基甲基)脲;收率:33%
1H NMR(300 MHz,CDCl3)δ0.86(t,3H),1.2-1.42(c,14H),1.72(c,2H),2.43(s,3H),2.88(q,2H),3.11(q,2H),3.44(t,2H),4.79(s,2H),5.73(s,1H),6.65(s,1H),7.48(m,3H),7.85(m,4H).
实施例23
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-庚基-N′-(2,4,6-三甲基苄基)脲;收率:34%
1H NMR(300 MHz,CDCl3)δ0.86(t,3H),1.23(c,8H),1.3,1.32,1.33,1.35,1.36,1.38(2t,6H),1.65(c,2H),2.27(s,3H),2.36(s,6H),2.46(s,3H),2.91(q,2H),3.05(t,2H),3.15(q,2H),4.71(s,2H),5.7(s,1H),6.68(s,1H),6.87(s,2H).
实施例24
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-环庚基-N′-(4-苯基苄基)脲,收率:17%,
1H NMR(300 MHz,CDCl3)δ1.4-1.77(c,10H),2.02(c,2H),2.36(s,3H),2.45(s,3H),2.46(s,3H),4.38(c,1H),4.62(s,2H),5.51(s,1H),6.58(s,1H),7.34(t,1H),7.4-7.54(m,4H),7.61(t,4H).
实施例25
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-环庚基-N′-(芴-2-基甲基)脲,收率:9%,
1H NMR(300 MHz,CDCl3)δ1.4-1.8(c,10H),2.02(c,2H),2.35(s,3H),2.43(s,3H),2.44(s,3H),3.91(s,2H),4.42(c,1H),4.66(s,1H),5.52(s,1H),6.57(s,1H),7.24-7.45(m,3H),7.55(d,1H),7.67(s,1H),7.79(d,2H).
实施例26
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-(4-异丙基苄基)-N′-(1,2,3,4-四氢-萘-2-基)脲;收率:13%,
1H NMR(300 MHz,CDCl3)δ1.25,1.26,1.27,1.29,1.31,1.34,1.36(2t and d,12H),1.88(m,1H),2.13(c,1H),2.42(s,3H),2.8-3.02(m and q,6H),3.02-3.18(c and q,3H),4.61(s,2H),4.78(c,1H),5.62(s,1H),6.63(s,1H),7.08(s,4H),7.26(d,2H),7.4(d,2H).
实施例27
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-庚基-N′-(3-甲基苯并[b]噻吩-2-基甲基)脲;收率:35%,
1H NMR(300 MHz,CDCl3)δ0.87(t,3H),1.29-1.9[c including 2t(1.26,1.28,1.29,1.31,1.32),total 14H],1.75(c,2H),2.42(s,3H),2.45(s,3H),2.88(q,2H),3.11(q,2H),3.36(t,2H),4.86(s,2H),5.77(s,1H),6.67(s,1H),7.28-7.4(m,2H),7.66(d,1H),7.79(d,1H).
实施例28
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-(1,2,3,4-四氢萘-2-基)-N′-(2,4,6-三甲基苄基)脲;收率:26%,
1H NMR(300 MHz,CDCl3)δ1.32,1.36(2t,6H),2.06(c,1H),2.15-2.35[c and s(2.25),total 4H],2.42(s,6H),2.44(s,3H),2.6-2.96(c,5H),3.14(q,2H),3.42(m,1H),3.73(c,1H),4.74(s,2H),5.75(s,1H),6.66(s,1H),6.84(s,2H),7.06(c,4H).
实施例29
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-环庚基-N′-(萘-2-基甲基)脲,收率:18%,
1H NMR(300 MHz,CDCl3)δ1.49-1.74(c,10H),2.04(c,2H),2.33(s,3H),2.43(s,6H),4.45(c,1H),4.74(s,2H),5.57(s,1H),6.56(s,1H),7.48(c,3H),7.85(c,3H),7.97(s,1H).
实施例30
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(4-异丙基苄基)脲;收率:17%,
1H NMR(300 MHz,CDCl3)δ1.26(d)and 1.29,1.34(2t)(total 12H),2.42(s,3H),2.82-2.98(m,3H),3.0-3.14(m,4H),3.31(dd,2H),4.57(s,2H),5.41(p,1H),5.58(s,1H),6.63(s,1H),7.15(c,4H),7.25(d,2H),7.33(d,2H).
实施例31
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-(2,4-二甲基苄基)-N′-(2,3-二氢化茚-2-基)脲;收率:43%
1H NMR(300 MHz,CDCl3)δ1.31,1.35(2t,6H),2.18(s,3H),2.33(s,3H),2.43(s,3H),2.89(q,2H),3.0(dd,2H),3.11(q,2H),3.29(dd,2H),4.49(s,2H),5.44(p,1H),5.52(s,1H),6.63(s,1H),6.99(s,1H),7.1-7.2(c,5H),7.49(d,1H).
实施例32
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(4-异丙基苄基)-N′-(6,7,8,9-四氢-5H-苯并环庚烯-7-基)脲;收率:39%,
1H NMR(300 MHz,CDCl3)δ1.24(d,6H),1.45-1.6(m,2H),2.22(c,2H),2.36(s,3H),2.46(s,3H),2.7-2.96(m,6H),4.45(s,2H),4.72(c,1H),5.52(s,1H),6.59(s,1H),7.1(m,4H),7.23(d,2H),7.31(d,2H).
实施例33
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(2,4,6-三甲基苄基)脲;收率:27%,
1H NMR(300 MHz,CDCl3)δ1.3,1.34(2t,6H),2.27(s,3H),2.4(s,6H),2.41(s,3H),2.88(q,2H),2.98-3.18(m,4H),3.57(dd,2H),4.16(p,1H),4.77(s,2H),5.43(s,1H),6.62(s,1H),6.87(s,2H),7.11(c,4H).
实施例34
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2,2-二苯基乙基]脲
将2,2-二苯基乙胺(148mg,0.75mmol)和异氰酸2,4-二(甲硫基)-6-甲基吡啶-3-基酯(170mg,0.75mmol)在15ml二氯甲烷中的溶液在氮气氛下回流过夜,然后将该反应混合物冷至室温,减压浓缩。残留固体经硅胶(200g)柱层析纯化,用8∶2二氯甲烷/乙酸乙酯洗脱,得到白色固体状标题化合物(111mg,收率:35%)。
1H NMR(300 MHz,CDCl3)δ2.29(s,3H),2.46(s,3H),2.50(s,3H),3.82(q,2H),4.18(t,1H),6.53(s,1H),7.12-7.28(c,12H).
按照实施例34的方法,制得了实施例35-37的(2,2-二苯基乙基)脲衍生物。
实施例35
N-(2,2-二苯基乙基)-N′-(6-甲硫基喹啉-5-基)脲;收率:63%,
1H NMR(300 MHz,CDCl3)δ2.27(s,3H),3.62(bd,2H),3.98(t,1H),6.39(b,1H),6.88-7.08(c,10H),7.54(q,1H),7.62(d,1H),7.95(s,1H),8.27(d,1H),8.39(d,1H),8.64(m,1H).
实施例36
N-[4,6-二(甲硫基)-6-甲基嘧啶-5-基]-N′-(2,2-二苯基乙基)脲;收率:80%,
1H NMR(CDCl3)δ2.42(s,6H),2.60(s,3H),3.82(bm,2H),4.19(t,1H),4.50(b,1H),5.07(b,1H),7.09-7.27(c,10H).
实施例37
N-[4,6-二(甲硫基)嘧啶-5-基]-N′-(2,2-二苯基乙基)脲;收率:49%,
1H NMR(300 MHz,CDCl3)δ2.43(s,3H),3.84(q,2H),4.20(t,1H),4.43(c,1H),5.46(s,1H),7.12-7.31(c,10H),8.59(s,1H).
实施例38
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(1-苯基环戊基)甲基]脲
将(1-苯基环戊基)甲胺(140mg,0.8mmol)和异氰酸2,4-二(甲硫基)-6-甲基吡啶-3-基酯(180mg,0.8mmol)在3ml二甲基甲酰胺中的溶液在充氮,80℃下加热过夜,将该反应混合物冷却至室温,用70ml乙酸乙酯稀释。所得溶液用3×60ml水,和60ml盐水洗涤,干燥(Na2SO4),过滤,减压浓缩,残余物经硅胶(200g)柱层析纯化,用1∶1乙酸乙酯/己烷洗脱,得到白色固体状标题化合物(90mg,收率:28%)。
1H NMR(300 MHz,CDCl3)δ1.6-1.9(c,6H),2.03(c,2H),2.35(s,3H),2.49(s,3H),2.51(s,3H),3.27(d,2H),4.07(b,1H),5.38(b,1H),6.55(s,1H),7.12(c,5H).
按照实施例38的方法,制得了实施例39-46的脲衍生物。
实施例39
N-(6-甲硫基喹啉-5-基)-N′-[(1-苯基环戊基)甲基]脲;收率:31%
1H NMR(300 MHz,CDCl3)δ1.59-1.96(c,8H),2.50(s,3H),3.25(d,2H),3.91(b,1H),5.96(bs,1H),6.81(c,2H),6.95(c,3H),7.41(q,1H),7.57(d,1H),8.05(d,1H),8.22(d,1H),8.86(m,1H).
实施例40
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[{1-(4-甲基苯基)环戊基}甲基]脲;收率:24%,
1H NMR(300 MHz,CDCl3)δ1.6-1.9(c,6H),2.0(c,2H),2.27(s,3H),2.35(s,3H),2.49(s,3H),2.51(s,3H),3.24(d,2H),4.06(b,1H),5.36(b,1H),6.51(s,1H),6.98(q,4H).
实施例41
N-[{1-(4-甲基苯基)环戊基}甲基]-N′-(6-甲硫基喹啉-5-基)脲;收率:28%,
1H NMR(300 MHz,CDCl3)δ1.6-1.98(c,8H),2.19(s,3H),2.52(s,3H),3.25(d,2H),3.98(b,1H),5.95(b,1H),6.74(q,4H),7.43(q,1H),7.60(d,1H),8.11(d,1H),8.24(d,1H),8.87(m,1H).
实施例42
N-[6-甲基硫喹啉-5-基]-N′-[{1-(苯基环己基)甲基]脲;收率:37%,
1H NMR(300 MHz,CDCl3)δ1.18-1.62(c,8H),1.96(c,2H),2.51(s,3H),3.25(d,2H),3.86(b,1H),5.99(b,1H),6.97(c,5H),7.43(q,1H),7.58(d,1H),8.09(d,1H),8.23(d,1H),8.85(m,1H).
实施例43
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(1-苯基环己基)甲基]脲;收率:42%,
1H NMR(300 MHz,CDCl3)δ1.22-1.72(c,8H),2.08(c,2H),2.35(s,3H),2.50(s,3H),2.51(s,3H),3.25(d,2H),3.95(b,1H),5.38(b,1H),6.51(s,1H),7.05-7.25(c,5H).
实施例44
N-(6-甲硫基喹啉-5-基)-N′-[{1-(4-甲基苯基)环己基}甲基]脲;收率:42%,
1H NMR(300 MHz,CDCl3)δ1.15-1.6(c,8H),1.93(c,2H),2.18(s,3H),2.51(s,3H),3.22(d,2H),3.81(b,1H),5.94(b,1H),6.77(b,4H),7.41(q,1H),7.59(d,1H),8.07(d,1H),8.21(d,1H),8.86(m,1H).
实施例45
N-[4,6-二(甲硫基)-2-甲基嘧啶-5-基]-N′-[{1-(4-甲基苯基)环己基}甲基]脲;收率:42%
1H NMR(300 MHz,CDCl3)δ1.23-1.68(c,8H),2.06(c,2H),2.30(s,3H),2.47(s,6H),2.62(s,3H),3.23(d,2H),3.89(b,1H),5.27(b,1H),7.04(q,4H).
实施例46
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[{1-(4-甲基苯基)环己基}甲基]脲;收率:24%
1H NMR(300 MHz,CDCl3)δ1.2-1.7(c,8H),2.06(c,2H),2.28(s,3H),2.35(s,3H),2.50(s,3H),2.52(s,3H),3.22(d,2H),3.95(b,1H),5.38(b,1H),6.56(s,1H),7.03(q,4H).
实施例47
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-乙基-2-苯基)丁基]脲;
将2-乙基-2-苯基丁胺(106mg,0.6mmol)和异氰酸2,4-二(甲硫基)-6-甲基吡啶-3-基酯(136mg,0.6mmol)在3ml二甲基甲酰胺中的溶液于80℃,氮气流下加热过夜,将该反应混合物冷却至室温,并用50ml乙酸乙酯稀释,所得溶液依次用3×25ml水,25ml盐水洗涤,干燥(Na2SO4),过滤,减压浓缩,残余物经硅胶(125g)层析,用65∶35己烷/乙酸乙酯洗脱,得到白色固体状标题化合物(67mg,收率:28%)。
1H NMR(300 MHz,CDCl3)δ0.74(t,6H),1.57-1.8(c,4H),2.33(s,3H),2.47(s,3H),2.48(s,3H),3.41(d,2H),3.95(b,1H),5.36(b,1H),6.52(s,1H),7.05-7.27(c,5H).
按照实施例47的方法,制得了实施例48-55的脲衍生物。
实施例48
N-[2,4-二(异丙硫基)-6-甲基吡啶-3-基]-N′-[(2-乙基-2-苯基)丁基]脲,收率:35%,
1H NMR(300 MHz,CDCl3)δ0.72(t,6H),1.29(d,6H),1.33(d,6H),1.57-1.8(c,4H),2.45(s,3H),3.39(d and m,3H),3.93(m and b,2H),5.28(b,1H),6.58(s,1H),7.04-7.2(c,5H).
实施例49
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-乙基-2-{2-甲基苯基}丁基]脲;收率:33%,
1H NMR(300 MHz,CDCl3)δ0.74(t,6H),1.67(m,4H),2.28(s,3H),2.33(s,3H),2.47(s,3H),2.49(s,3H),3.4(d,2H),3.97(b,1H),5.35(b,1H),6.53(s,1H),6.94(t,1H),6.98(s,2H),7.08(t,1H).
实施例50
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-苯基-2-丙基)戊基]脲;收率:88%,
1H NMR(300 MHz,CDCl3)δ0.85(t,6H),0.88-1.3(c,4H),1.59(c,4H),2.32(s,3H),2.47(s,3H),2.49(s,3H),3.4(d,2H),3.96(b,1H),5.33(b,1H),6.52(s,1H),7.05-7.24(c,5H).
实施例51
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2-甲基苯基}-2-丙基)戊基]脲;收率:43%,
1H NMR(300 MHz,CDCl3)δ0.84(t,6H),0.96-1.3(c,4H),1.58(c,4H),2.27(s,3H),2.32(s,3H),2.46(s,3H),2.47(s,3H),3.39(d,2H),3.96(b,1H),5.3(s,1H),6.52(s,1H),6.93(t,1H),6.97(s,2H),7.06(t,1H).
实施例52
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2-甲基苯基}-2-丁基)己基]脲;收率:57%,
1H NMR(300 MHz,CDCl3)δ0.84(t,6H),0.94-1.33(c,8H),1.59(c,4H),2.27(s,3H),2.32(s,3H),2.46(s,3H),2.48(s,3H),3.4(d,2H),3.96(b,1H),5.29(s,1H),6.53(s,1H),6.93(c,3H),7.07(t,1H).
实施例53
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2,5-二甲氧基苯基}-2-丙基)戊基]脲;收率:30%,
1H NMR(300 MHz,CDCl3)δ0.83(t,6H),0.94-1.3(c,4H),1.5-1.8(c,4H),2.33(s,3H),2.45(s,3H),2.48(s,3H),3.6(d,2H),3.68(s,3H),3.74(s,3H),4.11(b,1h),5.38(b,1H),6.5(s,1H),6.64(s and m,total 3H).
实施例54
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2,3-二甲氧基苯基}-2-丙基)戊基]脲;收率:45%,
1H NMR(300 MHz,CDCl3)δ0.83(t,6H),0.98-1.25(c,4H),1.67(c,4H),2.32(s,3H),2.44(s,3H),2.47(s,3H),3.59(d,2H),3.78(s,3H),3.82(s,3H),4.08(b,1H),5.33(b,1H),6.51(s,1H),6.66(d,1H),6.77(d,1H),6.84(t,1H).
实施例55
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2,5-二甲基苯基}-2-丙基)戊基]脲;收率:30%,
1H NMR(300 MHz,CDCl3)δ0.83(t,6H),1.08(m,4H),1.65(c,4H),2.22(s,3H),2.32(s,3H),2.38(s,3H),2.45(s,3H),2.46(s,3H),3.57(d,2H),4.04(b,1H),5.37(b,1H),6.49(s,1H),6.85(c,3H).
实施例56
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2-甲基苯基)乙基]脲
将2-(2-甲基苯基)己胺(153mg,0.8mmol)和异氰酸2,4-二(甲硫基)-6-甲基吡啶-3-基酯(180mg,0.8mmol)在3ml二甲基甲酰胺中的溶液在80℃,充氮下加热过夜。将反应混合物冷却至室温,用60ml乙酸乙酯稀释,所得溶液依次用3×50ml水,50ml盐水洗涤,干燥(Na2SO4),过滤,减压浓缩,残余物经硅胶(200g)层析,用7∶3己烷/乙酸乙酯洗脱,得到白色固体状标题化合物(110mg,收率:33%)。
1H NMR(300 MHz,CDCl3)δ0.80(t,3H),1.06-1.32(c,4H),1.46-1.74(c,2H),2.23(s,3H),2.30(s,3H),2.43(s,3H),2.48(s,3H),3.03-3.26(c,2H),3.51(p,1H),4.21(b,1H),5.33(b,1H),6.52(s,1H),7.01-7.11(c,4H).
按照实施例56的方法,制得了实施例57-82的脲衍生物。
实施例57
N-[2-(2-甲基苯基)己基]-N′-[6-甲硫基喹啉-5-基]脲;收率:28%,
1H NMR(300 MHz,CDCl3)δ0.80(t,3H),0.98-1.28(c,4H),1.4-1.65(c,2H),2.08(s,3H),2.48(s,3H),2.96-3.27(c,2H),3.51(p,1H),4.10(b,1H),5.94(b,1H),6.87-7.02(c,4H),7.36(q,1H),7.57(d,1H),8.06(d,1H),8.14(d,1H),8.82(m,1H).
实施例58
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(4-甲基苯基)庚基]脲;收率:24%,
1H NMR(300 MHz,CDCl3)δ0.80(t,3H),1.07-1.28(c,6H),1.45-1.7(c,2H),2.28(s,3H),2.32(s,3H),2.45(s,3H),2.48(s,3H),2.65(c,1H),3.10(c,1H),3.56(p,1H),4.21(b,1H),5.35(b,1H),6.54(s,1H),6.98(q,4H).
实施例59
N-[2-(4-甲基苯基)庚基]-N′-[6-甲硫基喹啉-5-基]脲;收率:30%,
1H NMR(300 MHz,CDCl3)δ0.79(t,3H),1.02-1.26(c,6H),1.46-1.62(c,2H),2.23(s,3H),2.48(s,3H),2.57(c,1H),3.10(c,1H),3.56(p,1H),4.11(b,1H),5.96(s,1H),6.81(q,4H),7.34(q,1H),7.57(d,1H),8.04(d,1H),8.13(d,1H),8.82(m,1H).
实施例60
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3-甲基苯基)庚基]脲;收率:26%,
1H NMR(300 MHz,CDCl3)δ0.82(t,3H),1.06-1.32(c,6H),1.45-1.72(c,2H),2.28(s,3H),2.34(s,3H),2.48(s,3H),2.50(s,3H),2.67(c,1H),3.14(m,1H),3.57(p,1H),4.31(b,1H),5.47(b,1H),6.56(s,1H),6.87(d,1H),6.89(s,1H),6.96(d,1H),7.09(t,1H).
实施例61
N-[2-(3-甲基苯基)庚基]-N′-[6-甲硫基喹啉-5-基]脲;收率:24%,
1H NMR(300 MHz,CDCl3)δ0.8(t,3H),1.0-1.3(c,6H),1.37-1.64(c,2H),2.19(s,3H),2.48(s,3H),2.59(c,1H),3.14(m,1H),3.57(p,1H),4.23(b,1H),6.11(b,1H),6.7(d,1H),6.72(s,1H),6.88(d,1H),6.97(t,1H),7.35(q,1H),7.56(d,1H),8.04(d,1H),8.14(d,1H),8.81(m,1H).
实施例62
N-[2-(3-甲基苯基)庚基]-N′-[6-甲氧基喹啉-5-基]脲;收率:53%,
1H NMR(300 MHz,CDCl3)δ0.8(t,3H),1.04-1.28(c,6H),1.38-1.63(c,2H),2.21(s,3H),2.6(m,1H),3.13(m,1H),3.59(m,1H),3.9(s,3H),4.22(b,1H),5.98(b,1H),6.71(d,1H),6.73(s,1H),6.91(d,1H),7.01(t,1H),7.31(q,1H),7.46(d,1H),8.07(d,1H),8.18(d,1H),8.77(m,1H).
实施例63
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)己基]脲;收率:32%
1H NMR(300 MHz,CDCl3)δ0.82(t,3H),1.04-1.32(c,4H),1.45-1.74(c,2H),2.18(s,3H),2.23(s,3H),2.31(s,3H),2.45(s,3H),2.49(s,3H),3.04(m,1H),3.2(m,1H),3.53(p,1H),4.2(b,1H),5.34(b,1H),6.53(s,1H),6.84(d,1H),6.93(d,1H).
实施例64
N-[2-(2,5-二甲基苯基)己基]-N′-[6-甲硫基喹啉-5-基]脲;收率:33%,
1H NMR(300 MHz,CDCl3+DMSO-d6)δ0.76(t,3H),1.0-1.26(c,4H),1.35-1.65(c,2H),2.1(s,3H),2.17(s,3H),2.44(s,3H),3.0(c,1H),3.15(m,1H),3.56(p,1H),4.96(b,1H),6.74-6.92[total 4H,including 6.78(d,1H),6.81(s,1H),6.87(d,1H and b)],7.34(q,1H),7.56(d,1H),8.02(d,1H),8.16(d,1H),8.76(m,1H).
实施例65
N-[2-(2,5-二甲基苯基)己基]-N′-[6-甲氧基喹啉-5-基]脲;收率:37%,
1H NMR(300 MHz,CDCl3+DMSO-d6)δ0.76(t,3H),1.0-1.28(c,4H),1.35-1.64(c,2H),2.07(s,3H),2.17(s,3H),3.0(c,1H),3.11(m,1H),3.57(p,1H),3.86(s,3H),4.71(b,1H),6.46(b,1H),6.77(s,1H),6.78(d,1H),6.86(d,1H),7.28(q,1H),7.42(d,1H),8.0(d,1H),8.16(d,1H),8.71(m,1H).
实施例66
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)庚基]脲;收率:28%
1H NMR(300 MHz,CDCl3)δ0.82(t,3H),1.08-1.3(c,6H),1.43-1.74(c,2H),2.19(s,3H),2.23(s,3H),2.33(s,3H),2.48(s,3H),2.53(s,3H),3.04(c,1H),3.21(m,1H),3.51(p,1H),4.35(b,1H),5.0(b,1H),6.56(s,1H),6.84(d,1H),6.86(d,1H),6.93(d,1H).
实施例67
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,4-二甲基苯基)己基]脲;收率:68%
1H NMR(300 MHz,CDCl3)δ0.81(t,3H),1.05-1.31(c,4H),1.42-1.75(c,2H),2.2(s,3H),2.26(s,3H),2.32(s,3H),2.46(s,3H),2.52(s,3H),3.04(c,1H),3.18(m,1H),3.49(p,1H),4.3(b,1H),5.46(b,1H),6.55(s,1H),6.86(s,1H),6.89(d,1H),6.95(d,1H).
实施例68
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3-甲基苯基)己基]脲;收率:60%
1H NMR(300 MHz,CDCl3)δ0.81(t,3H),1.05-1.33(c,4H),1.45-1.75(c,2H),2.28(s,3H),2.34(s,3H),2.49(s,3H),2.51(s,3H),2.67(m,1H),3.15(m,1H),3.57(p,1H),4.34(b,1H),5.48(b,1H),6.57(s,1H),6.88(d,1H),6.89(s,1H),6.96(d,1H),7.1(t,1H).
实施例69
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,4-二甲基苯基)庚基]脲;收率:59%
1H NMR(300 MHz,CDCl3)δ0.81(t,3H),1.08-1.28(c,6H),1.42-1.72(c,2H),2.19(s,3H),2.26(s,3H),2.32(s,3H),2.45(s,3H),2.51(s,3H),3.04(c,1H),3.18(m,1H),3.49(p,1H),4.24(b,1H),5.38(b,1H),6.55(s,1H),6.86(s,1H),6.89(d,1H),6.95(d,1H).
实施例70
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(萘-1-基)庚基]脲;收率:50%
1H NMR(300 MHz,CDCl3)δ0.79(t,3H),1.14-1.34(c,6H),1.56-1.92(c,2H),2.14(s,3H),2.38(s,3H),2.44(s,3H),3.48(m,1H),3.6(p,1H),3.73(c,1H),4.26(b,1H),5.37(b,1H),6.39(s,1H),7.28(d,1H),7.36(t,1H),7.47(c,2H),7.67(d,1H),7.82(c,1H),8.13(c,1H).
实施例71
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(萘-2-基)己基]脲;收率:36%
1H NMR(300 MHz,CDCl3)δ0.8(t,3H),1.06-1.35(c,4H),1.55-1.81(c,2H),2.07(s,3H),2.37(s,3H),2.4(s,3H),2.9(c,1H),3.24(m,1H),3.66(p,1H),4.25(b,1H),5.39(b,1H),6.34(s,1H),7.25(m,1H),7.4-7.51(c,3H),7.68-7.87(c,3H).
实施例72
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(萘-1-基)己基]脲;收率:36%
1H NMR(300 MHz,CDCl3)δ0.79(t,3H),1.1-1.34(c,4H),1.56-1.92(c,2H),2.13(s,3H),2.37(s,3H),2.44(s,3H),3.47(m,1H),3.6(p,1H),3.73(c,1H),4.28(b,1H),5.36(b,1H),6.4(s,1H),7.28(d,1H),7.35(t,1H),7.46(c,2H),7.66(d,1H),7.82(c,1H),8.12(c,1H).
实施例73
N-(6-甲硫基喹啉-5-基)-N′-[2-(萘-1-基)己基]脲;收率:34%,
1H NMR(300 MHz,CDCl3)δ0.78(t,3H),1.1-1.3(c,4H),1.56-1.82(c,2H),2.35(s,3H),3.44(c,1H),3.7(c,2H),4.21(b,1H),5.98(s,1H),7.08(c,2H),7.22(t,1H),7.42(c,3H),7.6(d,1H),7.8(d,1H),7.9(d,1H),7.94(d,1H),8.03(d,1H),8.7(m,1H).
实施例74
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,3-二甲氧基苯基)庚基]脲;收率:29%
1H NMR(300 MHz,CDCl3)δ0.81(t,3H),1.1-1.3(c,6H),1.45-1.77(c,2H),2.33(s,3H),2.48(s,3H),2.53(s,3H),3.12-3.35(c,2H),3.45(p,1H),3.69(s,3H),3.84(s,3H),4.54(b,1H),5.52(b,1H),6.59(s,1H),6.7(d,1H),6.73(d,1H),6.95(t,1H).
实施例75
N-[2-(2,3-二甲氧基苯基)庚基]-N′-(6-甲硫基喹啉-5-基)脲;收率:31%,
1H NMR(300 MHz,CDCl3)δ0.81(t,3H),1.05-1.3(c,6H),1.42-1.65(c,2H),2.49(s,3H),3.12(c,1H),3.27(c,1H),3.46(m,1H),3.53(s,3H),3.8(s,3H),4.44(b,1H),6.04(b,1H),6.56(d,1H),6.66(d,1H),6.85(t,1H),7.37(q,1H),7.61(d,1H),8.08(d,1H),8.17(d,1H),8.82(m,1H).
实施例76
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3-甲基苯基)辛基]脲;收率:47%
1H NMR(300 MHz,CDCl3)δ0.83(t,3H),1.19(b,8H),1.46-1.72(c,2H),2.27(s,3H),2.33(s,3H),2.46(s,3H),2.48(s,3H),2.66(c,1H),3.13(c,1H),3.58(p,1H),4.23(b,1H),5.35(s,1H),6.55(s,1H),6.87(d) and 6.88(s)(total 2H),6.96(d,1H),7.09(t,1H).
实施例77
N-[2-(3-甲基苯基)辛基]-N′-(6-甲氧基喹啉-5-基)脲;收率:54%,
1H NMR(300 MHz,CDCl3)δ0.83(t,3H),1.18(b,8H),1.53(c,2H),2.22(s,3H),2.61(m,1H),3.14(m,1H),3.6(p,1H),3.91(s,3H),4.24(b,1H),5.99(s,1H),6.72(d) and 6.73(s)(total 2H),6.92(d,1H),7.01(t,1H),7.33(q,1H),7.47(d,1H),8.09(d,1H),8.19(d,1H),8.77(q,1H).
实施例78
N-[2-(3-甲基苯基)辛基]-N′-(6-甲硫基喹啉-5-基)脲;收率:25%,
1H NMR(300 MHz,CDCl3)δ0.83(t,3H),1.17(b,8H),1.52(c,2H),2.2(s,3H),2.49(s,3H),2.6(m,1H),3.15(m,1H),3.58(p,1H),4.21(b,1H),6.05(s,1H),6.71(d) and 6.73(s)(total 2H),6.89(d,1H),6.99(t,1H),7.37(q,1H),7.58(d,1H),8.07(d,1H),8.17(d,1H),8.82(t,1H).
实施例79
N-[2-(萘-1-基)庚基]-N′-(6-甲氧基喹啉-5-基)脲;收率:58%,
1H NMR(300 MHz,CDCl3)δ0.81(t,3H),1.19(b,6H),1.7(b,2H),3.41(c,1H),3.72(c) and 3.75(s)(total 5H),4.21(b,1H),5.88(s,1H),7.02(q,1H),7.13(d,1H),7.25(t,1H),7.33(d,1H),7.45(m,2H),7.63(d,1H),7.83(d,1H),7.92(d,1H),7.98(d,1H),8.04(d,1H),8.65(m,1H).
实施例80
N-[2-(萘-1-基)庚基]-N′-(6-甲硫基喹啉-5-基)脲;收率:47%,
1H NMR(300 MHz,CDCl3)δ0.81(t,3H),1.17(b,6H),1.7(b,2H),2.35(s,3H),3.44(c,1H),3.6-3.78(c,2H),4.22(b,1H),5.97(s,1H),7.06(q,1H),7.12(d,1H),7.23(t,1H),7.43(m,3H),7.6(d,1H),7.81(d,1H),7.9(d,1H),7.96(d,1H),8.03(d,1H),8.69(m,1H).
实施例81
N-[2-(2,4-二甲基苯基)庚基]-N′-(6-甲硫基喹啉-5-基)脲;收率:41%,
1H NMR(300 MHz,CDCl3)δ0.79(t,3H),1.14(b,6H),1.48(c,2H),2.0(s,3H),2.2(s,3H),2.47(s,3H),2.95(c,1H),3.15(m,1H),3.5(p,1H),4.06(b,1H),5.91(s,1H),6.71(s,1H),6.75(s,2H),7.32(q,1H),7.55(d,1H),8.03(d,1H),8.03(d,1H),8.11(d,1H),8.82(q,1H).
实施例82
N-[2-(2,4-二甲基苯基)庚基]-N′-(6-甲氧基喹啉-5-基)脲;收率:57%,
1H NMR(300 MHz,CDCl3)δ0.8(t,3H),1.16(b,6H),1.49(c,2H),2.02(s,3H),2.23(s,3H),2.97(c,1H),3.13(m,1H),3.55(p,1H),3.9(s,3H),4.14(b,1H),5.89(s,1H),6.75(s,1H),6.78(s,2H),7.28(q,1H),7.44(d,1H),8.04(d,1H),8.14(d,1H),8.77(q,1H).
实施例83
N-[2,4-二(甲基)-6-甲基吡啶-3-基]-N′-[2-(3,4,5-三甲氧基苯基)庚基]脲;收率45%,
1H NMR(300 MHz,CDCl3)δ0.83(t,3H),1.23(b,6H),1.4-1.7(c,2H),2.3(s,3H),2.45(s,3H),2.48(s,3H),2.64(c,1H),3.12(m,1H),3.57(q,1H),3.79(s,6H),3.82(s,3H),4.23(b,1H),5.39(b,1H),6.27(s,2H),6.54(s,1H).
实施例84
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基-4-甲氧基苯基)庚基]脲;收率:35%,
1H NMR(300 MHz,CDCl3)δ0.82(t,3H),1.19(b,6H),1.5(c,1H),1.63(c,1H),2.11(s,3H),2.2(s,3H),2.34(s,3H),2.49(s,3H),2.54(s,3H),2.98(c,1H),3.18(m,1H),3.49(p,1H),3.79(s,3H),4.2(b,1H),5.35(b,1H),6.5(s,1H),6.58(s,1H),6.79(s,1H).
实施例85
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲氧基苯基)庚基]脲,收率:40%,
1H NMR(300 MHz,CDCl3)δ0.82(t,3H),1.2(b,6H),1.63(b,2H),2.34(s,3H),2.46(s,3H),2.51(s,3H),3.15(c,1H),3.26-3.5(c,2H),3.62(s,3H),3.73(s,3H),4.48(b,1H),5.54(b,1H),6.58(s,1H),6.61-6.71(c,3H).
实施例86
N-[2-(2,5-二甲氧基苯基)庚基]-N′-(6-甲硫基喹啉-5-基)脲,收率;30%,
1H NMR(300 MHz,CDCl3)δ0.81(t,3H),1.17(b,6H),1.54(b,2H),2.49(s,3H),3.08(c,1H),3.24-3.4(mincluding s at 3.38,total 4H),3.45(p,1H),3.72(s,3H),4.42(b,1H),6.05(b,1H),6.49(d,1H),6.52-6.61(c,2H),7.35(q,1H),7.61(d,1H),8.09(d,1H),8.14(d,1H),8.81(m,1H).
实施例87
N-[2-(2,5-二甲氧基苯基)庚基]-N′-(6-甲氧基喹啉-5-基)脲,收率:39%,
1H NMR(300 MHz,CDCl3)δ0.81(t,3H),1.18(b,6H),1.55(b,2H),3.09(c,1H),3.27(m,1H),3.37(s,3H),3.49(p,1H),3.72(s,3H),3.9(s,3H),4.45(b,1H),5.98(b,1H),6.51(d,1H),6.55-6.63(c,2H),7.31(q,1H),7.48(d,1H),8.09(d,1H),8.17(d,1H),8.77(q,1H).
实施例88
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3,5-二甲氧基苯基)庚基]脲,收率:45%,
1H NMR(300 MHz,CDCl3)δ0.82(t,3H),1.2(b,6H),1.44-1.68(c,2H),2.33(s,3H),2.44(s,3H),2.47(s,3H),2.65(c,1H),3.11(m,1H),3.58(p,1H),3.74(s,6H),4.22(b,1H),5.34(s,1H),6.24(s and c,3H),6.54(s,1H).
实施例89
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲氧基苯基)辛基]脲,收率:50%,
1H NMR(300 MHz,CDCl3)δ0.83(t,3H),1.2(b,8H),1.64(b,2H),2.33(s,3H),2.45(s,3H),2.5(s,3H),3.15(c,1H),3.27-3.5(c,2H),3.61(s,3H),3.73(s,3H),4.43(b,1H),5.47(b,1H),6.57(s,1H),6.6-6.71(c,3H).
实施例90
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3-甲基苯基)-6,6,6-三氟己基]脲,收率:34%,
1H NMR(300 MHz,CDCl3)δ1.42(c,2H),1.55-1.82(c,2H),2.0(c,2H),2.28(s,3H),2.34(s,3H),2.47(s,3H),2.48(s,3H),2.68(c,1H),3.17(m,1H),3.56(p,1H),4.28(b,1H),5.39(s,1H),6.56(s,1H),6.88(d) and 6.89(s)(total 2H),6.98(d,1H),7.12(t,1H).
实施例91
N-[2-(3-甲基苯基)庚基]-N′-(6-戊硫基喹啉-5-基)脲,收率:53%,
1H NMR(300 MHz,CDCl3)δ0.81(t,3H),0.9(t,3H),1.04-1.7(c,14H),2.2(s,3H),2.59(c,1H),2.93(t,2H),3.14(m,1H),3.59(p,1H),4.15(b,1H),6.11(s,1H),6.69(d) and 6.71(s)(total 2H),6.89(d,1H),6.99(t,1H),7.33(q,1H),7.62(d,1H),7.98(d,1H),8.13(d,1H),8.82(q,1H).
实施例92
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-{2-(5-氯苯并[b]噻吩-3-基)庚基}脲,收率:36%,
1H NMR(300 MHz,CDCl3)δ0.82(t,3H),1.22(b,6H),1.63(b,2H),2.23(s,3H),2.4(s,3H),2.46(s,3H),3.21(m,1H),3.51(c,2H),4.32(b,1H),5.44(b,1H),6.48(s,1H),7.13(s,1H),7.29(c,1H),7.72(d,1H),7.41(s,1H).
实施例93
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3,5-二甲基苯基)庚基]脲,收率:34%,
1H NMR(300 MHz,CDCl3)δ0.82(t,3H),1.21(b,6H),1.57(b,2H),2.23(s,6H),2.33(s,3H),2.46(s,3H),2.48(s,3H),2.61(c,1H),3.13(m,1H),3.56(p,1H),4.21(b,1H),5.33(s,1H),6.55(s,1H),6.67(s,2H),6.78(s,1H).
实施例94
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)辛基]脲,收率:35%,
1H NMR(300 MHz,CDCl3)δ0.84(t,3H),1.19(b,8H),1.6(b,2H),2.18(s,3H),2.23(s,3H),2.31(s,3H),2.45(s,3H),2.49(s,3H),3.04(c,1H),3.2(m,1H),3.52(p,1H),4.22(b,1H),5.37(b,1H),6.54(s,1H),6.84(d)and 6.85(s),(total 2H),6.92(d,1H).
实施例95
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[5-甲基-2-{3-甲基苯基}己基]脲,收率:44%,
1H NMR(300 MHz,CDCl3)δ0.79,0.8,0.81,0.82(2d,6H),0.92-1.18(c,2H),1.38-1.74(c,3H),2.28(s,3H),2.33(s,3H),2.46(s,3H),2.48(s,3H),2.63(c,1H),3.14(m,1H),3.58(p,1H),4.22(b,1H),5.36(s,1H),6.55(s,1H),6.87(d)and 6.88(s)(total 2H),6.96(d,1H),7.09(t,1H).
实施例96
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-{2,5-二甲基苯基}-4-苯基丁基]脲,收率:33%,
1H NMR(300 MHz,CDCl3)δ1.8-1.96(m,1H),1.99-2.14(m)and 2.11(s)(total 4H),2.24(s,3H),2.3(s,3H),2.4-2.54(m,8H)including 2.44(s,3H)and 2.49(s,3H),3.08(c,1H),3.3(m,1H),3.49(p,1H),4.25(b,1H),5.37(s,1H),6.54(s,1H),6.87(d)and(6.9(s)(total 2H),6.95(d,1H),7.08(d)and 7.09(s)(total 2H),7.14(m,1H),7.23(m,2H).
实施例97
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)-5-苯基戊基]脲,收率:19%,
1H NMR(300 MHz,CDCl3)δ1.4-1.8(c,4H),2.17(s,3H),2.22(s,3H),2.3(s,3H),2.43(s,3H),2.48(s,3H),2.53(c,2H),3.08(c,1H),3.2(m,1H),3.52(p,1H),4.22(b,1H),5.36(s,1H),6.52(s,1H),6.81(s)and 6.83(d)(total 2H),6.91(d,1H),7.08(d,2H),7.13(m,1H),7.23(m,2H).
实施例98
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(萘-1-基)-6-甲基庚基]脲,收率:59%,
1H NMR(300 MHz,CDCl3)δ0.76(t,6H),1.06-1.34(c,m,4H),1.43(h,1H),1.75(c,2H),2.13(s,3H),2.37(s,3H),2.43(s,3H),3.48(m,1H),3.56-3.82(c,2H),4.21(c,1H),5.28(s,1H),6.37(s,1H),7.28(m,1H),7.36(t,1H),7.46(m,2H),7.67(d,1H),7.83(m,1H),8.13(m,1H).
实施例99
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(萘-1-基)-6-甲基庚基]脲,收率:31%,
1H NMR(300 MHz,CDCl3)δ0.74,0.76,0.79(2d,6H),1.06-1.32(m,c,10H),1.42(h,1H),1.78(c,2H),2.42(s,3H),2.68(q,2H),3.02(q,2H),3.53(m,2H),3.72(c,1H),4.20(c,1H),5.27(s,1H),6.42(s,1H),7.28(m,1H),7.34(t,1H),7.46(m,2H),7.67(d,1H),7.81(m,1H),8.12(m,1H).
实施例100
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)-6-甲基庚基]脲,收率:38%,
1H NMR(300 MHz,CDCl3)δ0.77,0.79,0.81(2d,6H),1.04-1.72[c,mincluding 2t(1.29,1.31,6H),total 13H],2.18(s,3H),2.22(s,3H),2.46(s,3H),2.81(q,2H),2.98-3.25[mincluding q(3.08,2H),total 4H],3.53(p,1H),4.2(c,1H),5.32(s,1H),6.56(s,1H),6.84(d,1H),6.92(d,1H),7.26(s,1H).
实施例101
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(萘-1-基)庚基]脲,收率:15%,
1H NMR(300 MHz,CDCl3)δ0.79(t,3H),1.23(m,c,12H),1.65-1.94(c,2H),2.42(s,3H),2.68(q,2H),3.02(q,2H),3.54(c,2H),3.72(c,1H),4.22(c,1H),5.28(s,1H),6.42(s,1H),7.32(m,2H),7.45(m,2H),7.67(d,1H),7.82(m,1H),8.11(m,1H).
实施例102
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)-6-苯基己基]脲,收率:57%,
1H NMR(300 MHz,CDCl3)δ1.14-1.36[cincluding 2t(1.28,1.3,6H),total 10H],1.48-1.8(m,c,4H),2.17(s,3H),2.23(s,3H),2.46(s,3H),2.52(t,2H),2.81(q,2H),2.29-3.13[c and q(3.07,2H)total 3H],3.2(m,1H),3.52(p,1H),4.21(c,1H),5.33(s,1H),6.56(s,1H),6.93(d,1H),7.13(m,3H),7.24(m,3H).
实施例103
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)庚基]脲,收率:48%,
1H NMR(300 MHz,CDCl3)δ0.82(t,3H),1.2(c,6H),1.29,1.31(2t,6H),1.47-1.72(c,2H),2.17(s,3H),2.23(s,3H),2.46(s,3H),2.82(q,2H),2.98-3.13[c including q(3.08),total 3H],3.19(m,1H),3.53(p,1H),4.18(b,1H),5.29(s,1H),6.56(s,1H),6.84(d)and 6.85(s),total 2H,6.92(d,1H).
实施例104
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,4,6-三甲基苯基)辛基]脲,收率:27%,
1H NMR(300 MHz,CDCl3)δ0.83(t,3H),1.2(c,8H),1.7(c,2H),2.16(s,3H),2.22(s,3H),2.28(s,3H),2.3(s,3H),2.42(s,3H),2.48(s,3H),3.28(c,2H),3.68(m,1H),4.14(b,1H),5.29(s,1H),6.48(s,1H),6.66(s,1H),6.69(s,1H).
实施例105
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)-6,6,6-三氟己基]脲,收率:20%,
1H NMR(300 MHz,CDCl3)δ1.29,1.32(2t,6H),1.43(c,2H),1.63(c,1H),1.78(c,1H),2.0(c,2H),2.2(s,3H),2.24(s,3H),2.46(s,3H),2.84(q,2H),3.0-3.15[c including t(3.09)total 3H],3.22(m,1H),3.49(p,1H),4.25(b,1H),5.34(s,1H),6.58(s,1H),6.86(d,2H),6.95(d,1H).
实施例106
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(5-甲基苯并[b]噻吩-3-基)庚基]脲,收率:10%,
1H NMR(300 MHz,CDCl3)δ0.82(c,3H),1.24(c,6H),1.74(c,2H),2.2(s,3H),2.4(s,3H),2.46(s,6H),3.25(m,1H),3.5(t,2H),4.28(b,1H),5.37(s,1H),6.45(s,1H),6.99(s,1H),7.15(d,1H),7.55(s,1H),7.71(d,1H).
实施例107
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2-氯苯并[b]噻吩-3-基)庚基]脲,收率:32%,
1H NMR(300 MHz,CDCl3)δ0.79(c,3H),1.2(c,6H),1.79(c,1H),1.91(c,1H),2.23(s,3H),2.37(s,3H),2.46(s,3H),3.4-3.59(c,2H),3.79(c,1H),4.27(b,1H),5.36(s,1H),6.47(s,1H),7.3(m,2H),7.67(m,1H),7.76(c,1H).
实施例108
N-[2-(2,5-二甲基苯基)庚基]-N′-[6-甲硫基喹啉-5-基]脲,收率:33%,
1H NMR(300 MHz,CDCl3)δ0.82(t,3H),1.16(c,6H),1.5(c,2H),2.0(s,3H),2.13(s,3H),2.47(s,3H),2.96(m,1H),3.16(m,1H),3.55(p,1H),4.09(b,1H),5.97(s,1H),6.7(s,1H),6.77(q,2H),7.34(q,1H),7.56(d,1H),8.03(d,1H),8.2(d,1H),8.82(q,1H).
实施例109
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)-6-甲基庚基]脲,收率:35%,
1H NMR(300 MHz,CDCl3)δ0.77,0.79,0.81(2d,6H),1.04-1.7(c,7H),2.18(s,3H),2.23(s,3H),2.31(s,3H),2.44(s,3H),2.48(s,3H),3.04(c,1H),3.19(m,1H),3.53(p,1H),4.2(b,1H),5.33(s,1H),6.53(s,1H),6.84(d and s,2H),6.92(d,1H).
实施例110
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)-5-苯基戊基]脲,收率:37%,
1H NMR(300 MHz,CDCl3)δ1.26,1.29,1.31,1.33(2t,6H),1.41-1.82(c,4H),2.17(s,3H),2.22(s,3H),2.46(s,3H),2.54(c,2H),2.81(q,2H),3.0-3.24[c and including q(3.08),total 4H],3.52(p,1H),4.2(b,1H),5.31(s,1H),6.56(s,1H),6.82,6.85(s and d,2H),6.91(d,1H),7.08(d,2H),7.15(d,1H),7.23(t,2H).
实施例111
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)辛基]脲,收率:26%,
1H NMR(300 MHz,CDCl3)δ0.83(t,3H),1.19(c,8H),1.27,1.29,1.32,1.34(2t,6H),1.54(c,1H),1.67(c,1H),2.18(s,3H),2.23(s,3H),2.46(s,3H),2.82(q,2H),2.98-3.14[c including t(3.08)total 3H],3.19(m,1H),3.53(p,1H),4.2(b,1H),5.31(s,1H),6.56(s,1H),6.83,6.85(s and d,2H),6.92(d,1H).
实施例112
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)-5-甲基己基]脲,收率:39%,
1H NMR(300 MHz,CDCl3)δ0.79,0.80,0.81,0.82(2d,6H),0.92-1.18(c,2H),1.27,1.29,1.31,1.34(2t,6H),1.4-1.75(c,3H),2.17(s,3H),2.23(s,3H),2.46(s,3H),2.82(q,2H),2.93-3.13[c including t(3.08),total 3H],3.2(m,1H),3.53(p,1H),4.2(b,1H),5.3(s,1H),6.56(s,1H),6.83,6.85(d and s,2H),6.92(d,1H).
实施例113
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2-氯苯并[b]噻吩-3-基)-6-甲基庚基]脲,收率:19%,
1H NMR(300 MHz,CDCl3)δ0.73,0.75,0.76,0.78(2d,6H),1.01-1.42[c and 2t(1.22,1.23,1.24,1.25,1.26,1.27,1.28),total 10H],1.41(h,1H),1.79(c,1H),1.92(c,1H),2.44(s,3H),2.74(c,2H),3.02(q,2H),3.48(c,2H),3.8(c,1H),4.26(b,1H),5.3(s,1H),6.5(s,1H),7.29(m,2H),7.66(m,1H),7.77(c,1H).
实施例114
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2-氯苯并[b]噻吩-3-基)-5-甲基己基]脲,收率:35%,
1H NMR(300 MHz,CDCl3)δ0.75-1.3[c including 2d(0.77,0.78,0.79,0.80,6H),and 2t(1.22,1.23,1.24,1.25,1.26,1.27,1.28,6H),total 14H],1.47(h,1H),1.75-1.2(c,2H),2.44(s,3H),2.75(c,2H),3.02(q,2H),3.46(c,2H),3.8(c,1H),4.27(b,1H),5.3(s,1H),6.5(s,1H),7.3(m,2H),7.66(m,1H),7.77(c,1H).
实施例115
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(5,6,7,8-四氢萘-1-基)庚基]脲,收率:36%,
1H NMR(300 MHz,CDCl3)δ0.82(t,3H),1.2(c,6H),1.29,1.31,1.34(2t,6H),1.45-1.82(c,6H),2.46(s,3H),2.7(c,4H),2.83(q,2H),3.03-3.28(c including q(3.08),total 4H),3.46(p,1H),4.23(b,1H),5.3(s,1H),6.58(s,1H),6.85,6.88,6.91(2d,2H),6.98(t,1H).
实施例116
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(3,5-二甲基苯基)庚基]脲,收率:20%,
1H NMR(300 MHz,CDCl3)δ0.82(t,3H),1.21(c,6H),1.28,1.30,1.32,1.35(2t,6H),1.6(c,2H),2.33(s,6H),2.45(s,3H),2.61(c,1H),2.84(q,2H),3.05-3.2[c and q(3.1),total 3H],3.56(p,1H),4.2(b,1H),5.3(s,1H),6.59(s,1H),6.67(s,2H),6.78(s,1H).
实施例117
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2-氯苯并[b]噻吩-3-基)庚基]脲,收率:51%,
1H NMR(300 MHz,CDCl3)δ0.79(t,3H),1.04-1.32[c including 2t(1.22,1.23,1.24,1.25,1.26,1.27,1.28),total 12H],1.81,(c,1H),1.94(c,1H),2.44(s,3H),2.76(c,2H),3.02(q,2H),3.48(c,2H),3.8(c,1H),4.27(b,1H),5.3(s,1H),6.5(s,1H),7.3(m,2H),7.66(m,1H),7.78(c,1H).
实施例118
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(3,5-二甲基苯基)辛基]脲,收率:19%,
1H NMR(300 MHz,CDCl3)δ0.83(t,3H),1.2(c,8H),1.27,1.30,1.32,1.35(2t,6H),1.45-1.72(c,2H),2.22(s,6H),2.45(s,3H),2.6(c,1H),2.84(q,2H),3.05-3.2[c and q(3.1),total 3H],3.56(h,1H),4.23(b,1H),5.35(s,1H),6.58(s,1H),6.67(s,2H),6.77(s,1H).
实施例119
N-[2,4-二(乙硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基-4-甲氧基苯基)庚基]脲,收率:50%,
1H NMR(300 MHz,CDCl3)δ0.82(t,3H),1.2(c,6H),1.26,1.29,1.31,1.34(2t,6H),1.44-1.72(c,2H),2.09(s,3H),2.18(s,3H),2.46(s,3H),2.82(q,2H),2.96(c,1H),3.01-3.2[c including q(3.07),total 3H],3.48(p,1H),3.78(s,3H),4.18(b,1H),5.29(s,1H),6.48(s,1H),6.56(s,1H),6.77(s,1H).
实施例120
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(5-甲基苯并[b]噻吩-3-基)庚基]脲,收率:10%,
1H NMR(300 MHz,CDCl3)δ0.82(t,3H),1.23(c,6H),1.73(c,2H),2.2(s,3H),2.41(s,3H),2.46(s,6H),3.25(p,1H),3.5(t,2H),4.28(b,1H),5.35(s,1H),6.45(s,1H),6.99(s,1H),7.15(d,1H),7.55(s,1H),7.7(d,1H).
实施例121
N-[2-(2-氯苯并[b]噻吩-3-基)-5-甲基己基]-N′-(2,6-二异丙基苯基)脲,收率:43%,
1H NMR(300 MHz,CDCl3)δ0.72-1.31(c,20H),1.46(h,1H),1.78(c,1H),1.82(c,1H),3.06(c,2H),3.44(c,2H),3.76(c,1H),4.01(b,1H),5.52(s,1H),7.06(c,2H),7.26(c,3H),7.64(c,1H),7.71(c,1H).
实施例122
N-(2,6-二异丙基苯基)-N′-[2-(5-甲基苯并[b]噻吩-3-基)-5-甲基己基]脲,收率:44%,
1H NMR(300 MHz,CDCl3)δ0.76-1.3[m,c including d(0.79,0.81),total 21H],1.46(h,1H),1.68(c,2H),2.45(s,3H),3.08(c)and 3.17(m),(total 2H),3.47(c,2H),4.08(b,1H),5.57(s,1H),6.86(s,1H),7.05(s,1H),7.07(s,1H),7.14(d,1H),7.22(d,1H),7.51(s,1H),7.67(d,1H).
实施例123
N-[2-(苯并[b]噻吩-3-基)庚基]-N′-(2,6-二异丙基苯基)脲,收率:41%,
1H NMR(300 MHz,CDCl3)δ0.76-1.31-(c,20H),1.68(c,2H),1.95(c,1H),3.05(c,2H),3.25(p,1H),3.49(c,2H),4.1(b,1H),5.72(s,1H),6.92(s,1H),7.06(s,1H),7.08(s,1H),7.21-7.38(c,3H),7.74(m,1H),7.8(m,1H).
实施例124
N-[2-(苯并[b]噻吩-3-基)-6-甲基庚基]-N′-(2,6-二异丙基苯基)脲,收率:58%,
1H NMR(300 MHz,CDCl3)δ0.74-1.48[m,c including 2d(0.76,0.77,0.78,0.80)total 22H],1.67(m,2H),1.8(c,1H),3.07(c,2H),3.25(p,1H),3.48(c,2H),4.1(b,1H),5.68(s,1H),6.92(s,1H),7.06(s,1H),7.08(s,1H),7.2-7.4(c,3H),7.74(m,1H),7.8(m,1H).
实施例125
N-[2-(2-氯苯并[b]噻吩-3-基)-6-甲基庚基]-N′-(2,6-二异丙基苯基)脲,收率:70%,
1H NMR(300 MHz,CDCl3)δ0.7-1.3[c and 2d(0,73,0.75,0.76,0.78),total 22H],1.4(h,1H),1.73(c,1H),1.91(c,1H),3.06(c,2H),3.44(c,2H),3.76(c,1H),4.02(b,1H),5.54(s,1H),7.06(c,2H),7.2-7.32(c,3H),7.64(m,1H),7.71(c,1H).
实施例126
N-(2,6-二异丙基苯基)-N′-[2-(5-甲基苯并[b]噻吩-3-基)-6,6,6-三氟己基]脲,收率:70%,
1H NMR(300 MHz,CDCl3)δ0.8-1.3(c,12H),1.51(m,2H),1.78(m,2H),2.0(m,2H),2.46(s,3H),3.07(c,2H),3.25(p,1H),3.48(m,2H),4.11(b,1H),5.6(s,1H),6.92(s,1H),7.07(d,2H),7.16(d,1H),7.24(d,1H),7.52(s,1H),7.69(d,1H).
实施例127
N-[2-(2-氯苯并[b]噻吩-3-基)-6,6,6-三氟己基]-N′-(2,6-二异丙基苯基)脲,收率:46%,
1H NMR(300 MHz,CDCl3)δ0.78-1.27(c,12H),1.42(c,2H),1.85(c,1H),2.02(c,3H),3.08(c,2H),3.47(c,2H),3.79(c,1H),4.08(b,1H),5.58(s,1H),7.07(d,2H),7.2-7.35(c,3H),7.7(c,2H).
实施例128
N-(2,6-二异丙基苯基)-N′-[2-(萘-2-基)-6,6,6-三氟己基]脲,收率:67%,
1H NMR(300 MHz,CDCl3)δ0.63-1.14(c,12H),1.45(m,2H),1.68-2.08(c,4H),2.9(c,1H),3.09(c,1H),3.4(c,1H),3.6(c,1H),3.79(c,1H),4.07(b,1H),5.67(s,1H),7.02(d,2H),7.2(m,2H),7.34(t,1H),7.47(m,2H),7.68(d,1H),7.82(m,1H),8.06(c,1H).
实施例129
N-[7,7-二氟-2-(萘-1-基)庚基]-N′-(2,6-二异丙基苯基)脲,收率:58%,
1H NMR(300 MHz,CDCl3)δ0.63-1.46(c,16H),1.57-1.9(c,4H),2.92(c,1H),3.08(c,1H),3.39(m,1H),3.59(c,1H),3.75(c,1H),4.03(b,1H),5.57(s,1H),5.48,5.67,5.86(3t,total 1H),7.0(d,1H),7.18(t,2H),7.32(t,1H),7.44(m,2H),7.65(d,1H),7.8(m,1H),8.05(m,1H).
实施例130
N-[7,7-二氟-2-(2-氯苯并[b]噻吩-3-基)庚基]-N′-(2,6-二异丙基苯基)脲,收率:73%,
1H NMR(300 MHz,CDCl3)δ0.73-1.5(c,16H),1.56-1.85(c,3H),1.96(c,1H),3.07(c,2H),3.47(c,2H),3.77(c,1H),4.05(b,1H),5.59(s,1H),5.50,5.69,5.88(3t,total 1H),7.06(d,2H),7.2-7.35(c,3H),7.62-7.77(c,2H).
实施例131
N-[2-(5-氯苯并[b]噻吩-3-基)庚基]-N′-(2,6-二异丙基苯基)脲,收率:59%,
1H NMR(300 MHz,CDCl3)δ0.77-1.46(c,21H),1.65(m,2H),3.01-3.24(m,3H),3.46(m,2H),4.04(b,1H),5.6(s,1H),7.02(s,1H),7.08(c,2H),7.26(m,2H),7.71(m,2H).
实施例132
N-[2-(2-氯苯并[b]噻吩-3-基)庚基]-N′-(2,6-二异丙基苯基)脲,收率:60%,
1H NMR(300 MHz,CDCl3)δ0.74-1.42(c,21H),1.75(c,1H),1.92(c,1H),3.07(c,2H),3.45(c,2H),3.76(c,1H),4.02(b,1H),5.74(s,1H),7.06(c,2H),7.2-7.34(m,3H),7.65(m,1H),7.7(c,1H).
实施例133
N-[2-(5-氯苯并[b]噻吩-3-基)-6,6,6-三氟己基]-N′-(2,6-二异丙基苯基)脲,收率:72%,
1H NMR(300 MHz,CDCl3)δ0.82-1.32(c,12H),1.5(m,2H),1.76(c,2H),2.0(c,2H),3.07(c,2H),3.23(p,1H),3.48(c,2H),4.11(b,1H),5.68(s,1H),7.07,7.09(d and s,3H),7.21-7.34(m,2H),7.72,7.75(d and s,2H).
实施例134
N-(2,6-(二异丙基苯基)-N′-[2-(5-甲基苯并[b]噻吩-3-基)庚基]脲,收率:50%,
1H NMR(300 MHz,CDCl3)δ0.76-1.32(c,21H),1.67(c,2H),2.45(s,3H),3.08(c,2H),3.2(p,1H),3.47(t,2H),4.06(b,1H),5.6(s,1H),6.86(s,1H),7.07(d,2H),7.14(d,1H),7.22(d,1H),7.52(s,1H),7.67(d,1H).
实施例135
N-[2-(5-氯苯并[b]噻吩-3-基)-6-甲基庚基]-N′-(2,6-二异丙基苯基)脲,收率:49%,
1H NMR(300 MHz,CDCl3)δ0.75-1.8[c including 2d(0.76,0.78,0.79,0.80),total 23H),2.26(m,2H),3.07(p,2H),3.18(p,1H),3.47(c,2H),4.06(b,1H),5.65(s,1H),7.03(s,1H),7.08(c,2H),7.2-7.3(m,2H),7.71(m,2H).
实施例136
N-(2,6-二异丙基苯基)-N′-[2-(2,5-二甲基苯基)-6,6,6-三氟己基]脲,收率:37%,
1H NMR(300 MHz,CDCl3)δ0.9-1.76(c,16H),1.98(m,2H),2.08(s,3H),2.19(s,3H),2.95-3.21(c,4H),3.52(p,1H),3.97(b,1H),5.6(b,1H),6.74(s,1H),6.83(d,1H),6.9(d,1H),7.11(d,2H),7.28(t,1H).
实施例137
N-[7,7-二氟-2-(2,5-二甲基苯基)庚基]-N′-(2,6-二异丙基苯基)脲,收率:65%,
1H NMR(300 MHz,CDCl3)δ0.92-1.82(c,20H),2.06(s,3H),2.18(s,3H),2.98(c,1H),3.12(c,3H),3.51(p,1H),3.95(b,1H),5.61(s,1H),5.52,5.71,5.9(3t,total 1H),6.74(s,1H),6.81(d,1H),6.89(d,1H),7.1(d,2H),7.27(t,1H).
实施例138
N-(2,6-二异丙基苯基)-N′-[2-(萘-1-基)庚基]脲,收率:61%,
1H NMR(300 MHz,CDCl3)δ0.78(t,3H),0.9-1.3(m and c,18H),1.72(c,2H),2.85-3.16(c,2H),3.41(m,1H),3.58(c,1H),3.72(c,1H),4.02(b,1H),5.49(s,1H),7.01(d,2H),7.18(m,2H),7.31(t,1H),7.44(m,2H),7.65(d,1H),7.8(m,1H),8.07(m,1H).
实施例139
N-(2,6-二异丙基苯基)-N′-[6-甲基-2-(萘-1-基)庚基]脲,收率:59%,
1H NMR(300 MHz,CDCl3)δ0.74(t,6H),0.91-1.29(m and c,18H),1.4(h,1H),1.7(c,2H),2.84-3.16(c,2H),3.41(m,1H),3.51-3.8(c,2H),4.02(c,1H),5.51(s,1H),7.0(d,2H),7.19(m,2H),7.31(t,1H),7.44(m,2H),7.66(d,1H),8.07(m,1H).
Claims (10)
1、式Ⅰ化合物或其可药用盐:
式中Q是氧或硫,
R17-(CH2)n-(CR19R20)z(CH2)r-ArⅩⅩⅩⅧ,其中n是0或1至3的整数,z是0或1;r是0或1至4的整数,
R19和R20独立地选自氢、任选卤化的(C1-12)烷基,任选取代的芳基(C1-5)烷基,(C3-8)环烷基-(C1-5)烷基和Ar;或者R19及R20与和它们相连接的碳原子形成(C4-7)环烷基环或苯稠合的(C5-7)环烷基或杂烷基环;其前提是R19和R20不能同时为氢;
Ar选自下述基团之一:
式中U是J,直接键-CH=CH-或-CH2-CH2-;
z,n和r的限定同前,X是3至10的整数,而W是0或1至X-1的整数。
R21,R22及各R23独立地选自:任选卤代的(C1-6)烷基,任选地卤代(C1-6)烷氧基,任选地卤代的(C1-6)烷硫基,苯基和卤素;其中,在所说烷基,烷氧基和烷硫基中的烷基可以是直链烷基,或者,如果其中含有3个或多个碳原子,则该烷基可以是支链的、环状的,或者是环状和支链或直链残基的组合;
或者R21和R22一起形成下式基团:
-J(CH2)t-J-或-(CH2)q-
其中J是氧或硫;
t是1至3的整数;
q是3至5的整数;
k是J-或-CH=CH-;
L是-(CH2)u或-(CH2)vJ-;
u是3至5的整数;
v是2、3或4;
R18是氢,任选取代的(C1-8)烷基,任选取代的(C3-8)环烷基,或任选取代的芳基(C1-4)烷基,其前提是如果式ⅩⅩⅩⅧ中n,z或r中的任一个不是O,R18是氢;
R1选自下述基团之一:
式中m是0或1至4的整数,Y是0或1。
R6和R15各自独立地选自下述基团:卤素,(C1-6)烷基,任选卤代的(C1-6)烷基,任选地卤化(C1-6)烷氧基,任选地卤化(C1-6)烷硫基,(C3-7)环烷硫基,苯基(C1-6)烷硫基,取代的苯硫基,杂芳硫基,杂芳氧基,(C1-6)烷基亚硫酰基,(C1-6)烷基磺酰基,(C5-7)环烷基亚硫酰基,(C5-7)环烷基磺酰基,苯基(C1-6)烷基亚硫酰基,苯基(C1-6)烷基磺酰基,取代的苯基亚硫酰基,取代的苯基磺酰基,杂芳亚硫酰基,杂芳磺酰基,和NR10R11,其中R10和R11相同或不同,并且选自氢,(C1-6)烷基,苯基,取代苯基,(C1-6)酰基,芳酰基,和取代的芳酰基,其中所说取代苯基和取代芳酰基由一个或多个独立地选自下述基团的取代基取代:(C1-6)烷基,(C1-6)烷氧基,(C1-6)烷硫基,卤素和三氟甲基,或者R10和R11与它们相连接的氮原子一起形成哌啶,吡咯烷或吗啉环;并且
B,D,E和G选自氮和碳,其前提是,B,D和E中的一个或多个是氮,其另一前提是,当G为氮时,基团ⅩⅥ以嘧啶环4或5位连接在式Ⅰ的氮上(4和5-位标为a和b),其中所有的所说氮原子都可被氧化;
或者R1是
其中R7,R8和R9可以相同或不同,各自独立地选自:任选卤代(C1-6)烷氧基,任选卤代(C1-6)烷硫基,任选卤代(C1-6)烷基和卤素;其前提是,当R1是式ⅩⅩⅦ基团是,Ar是式ⅩⅩⅫ,ⅩⅩⅩⅢ或ⅩⅩⅩⅤ基团,并且,当Ar是ⅩⅩⅫ时,R19或R20不是烷基和卤代(C1-12)烷基,其前提是R19和R20不能同时为氢,并且在式ⅩⅩⅩⅧ中的r是0。
2、按照权利要求1的化合物,其中R1是式ⅩⅩⅣ基团,式中E是碳,B或D是氮。
3、按照权利要求1的化合物,其中,R1是式ⅩⅩⅥ基团,式中,G是碳。
4、按照权利要求1的化合物,其中,R1是式ⅩⅩⅥ基团,式中,G是氮。
5、按照权利要求2的化合物,其中,R1是
并且,R15选自:任选取代的(C1-8)烷基,任选取代的(C1-8)烷氧基,任选取代的(C1-8)烷硫基,优选烷硫基;R17选自:苯稠合的(C5-8)环烷基和任选取代的(C1-8)烷基,其中,所说取代基选自:苯基,苯并[b]噻吩基,联苯基,芴基,萘基,卤素和(C3-12)环烷基,其中,所说苯基,萘基,环烷基,联苯基,芴基和苯并[b]噻吩基任选地由选自下述的取代基取代:任选卤代的(C1-6)烷基,任选卤代的(C1-6)烷氧基,任选卤代的(C1-6)烷硫基和卤素,R18选自:氢,任选卤代的(C1-8)烷(C1-6)烷硫基和卤素,R18选自:氢,任选卤代的(C1-8)烷基(3-12)环烷基或任选取代的芳基(C1-6)烷基,其中,所说芳基任选地由选自下述的取代基取代:任选卤代的(C1-6)烷基,任选卤代的(C1-6)烷氧基,任选卤代的(C1-6)烷硫基和卤素。
6、按照权利要求3或权利要求4的化合物,其中,R1是
并且,每个R6独立地选自:(C1-8)烷基和(C1-8)烷硫基,R17选自苯稠合的(C5-8)环烷基和任选取代的(C1-8)烷基,其中,所说取代基选自:苯基,联苯基,芴基,苯并[b]噻吩基,萘基,卤素和(C3-12)环烷基,其中,所说苯基,萘基,环烷基,联苯基,芴基和苯并[b]噻吩基任选地由下述取代基取代,所说取代基选自:任选卤代的(C1-6)烷氧基,任选卤代(C1-6)烷基,任选卤代(C1-6)烷硫基和卤素,R18选自:氢,任选卤代(C1-8)烷基,(C3-12)环烷基或任选取代的芳基(C1-6)烷基,其中,所说芳基任选地由选自下述的取代基取代:任选卤代的(C1-6)烷基,任选卤代的(C1-6)烷氧基,任选卤代的(C1-6)烷硫基和卤素,其前提是:如果R1是式ⅩⅩⅥA,在6-位的R6优选为氢或烷基并且在4-和2-位的每个R6优选为烷硫基,并且,如果R1是式ⅩⅩⅥB,在2-位的R6优选是氢或烷基,在4-位和6-位的每个R6优选为烷硫基。
7、按照权利要求1的化合物,所说的化合物选自:
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(4-异丙基苄基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,5-二甲基苄基)-N′-(2,3-二氢化茚-2-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,4-二甲基苄基)-N′-(2,3-二氢化茚-2-基)脲;
N-[4,6-二(甲硫基)-2-甲基吡啶-5-基]-N′-(2,3-二氢化茚-2-基)-N′-(4-异丙基苄基)脲;
N-[4,6-二(甲硫基)-2-甲基嘧啶-5-基]-N′-(2,4-二甲基苄基)-N′-(2,3-二氢化茚-2-基)脲;
N-(2,5-二甲基苄基)-N′-(2,3-二氢化茚-2-基)-N′-(6-甲硫基喹啉-5-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2-氯苄基)-N′-(2,3-二氢化茚-2-基)脲;
N-[4,6-二(甲硫基)-2-甲基嘧啶-5-基]-N′-(2,5-二甲基苄基)-N′-(2,3-二氢化茚-2-基)脲;
N-[4,6-二(甲硫基)-2-甲基嘧啶-5-基]-N′-(2,3-二氢化茚-2-基)-N′-[4-(3-甲基丁基)苄基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-[4-(3-甲基丁基)苄基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-1-基)-N′-(萘-1-基甲基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-1-基)-N′-(萘-2-基甲基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-1-基)-N′-(4-叔丁基苄基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-1-基)-N′-(4-苯基苄基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(萘-1-基甲基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(萘-2-基甲基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氢化茚-2-基)-N′-(2,4,6-三甲基苄基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-(2,3-二氯苄基)-N′-(2,3-二氢化茚-2-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2,2-二苯基乙基]脲;
N-(2,2-二苯基乙基)-N′-(6-甲硫基喹啉-5-基)脲;
N-[4,6-二(甲硫基)-2-甲基嘧啶-5-基]-N′-(2,2-二苯基乙基)脲;
N-[4,6-二(甲硫基)嘧啶-5-基]-N′-(2,2-二苯基乙基)脲;
N-[2,4-二(甲硫基)-6-甲基嘧啶-3-基]-N′-[(1-苯基环戊基)甲基]脲;
N-(6-甲硫基喹啉-5-基)-N′-[(1-苯基环戊基)甲基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[{1-(4-甲基苯基)环戊基}甲基]脲;
N-[{1-(4-甲基苯基)环戊基}甲基]-N′-(6-甲硫基喹啉-5-基)脲;
N-(6-甲硫基喹啉-5-基)-N′-[(1-苯基环己基)甲基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(1-苯基环己基)甲基]脲;
N-[{1-(4-甲基苯基)环己基}甲基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[4,6-二(甲硫基)-2-甲基嘧啶-5-基]-N′-[{1-(4-甲基苯基)环己基}甲基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[{1-(4-甲基苯基)环己基}甲基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-乙基-2-苯基)丁基]脲;
N-[2,4-二(异丙硫基)-6-甲基吡啶-3-基]-N′-[(2-乙基-2-苯基)丁基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-乙基-2-{2-甲基苯基}丁基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-苯基-2-丙基)戊基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2-甲基苯基}-2-丙基)戊基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2-甲基苯基}-2-丁基)己基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2,5-二甲氧基苯基}-2-丙基)戊基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2,3-二甲氧基苯基}-2-丙基)戊基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2,5-二甲氧基苯基}-2-丙基)戊基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2-甲基苯基)己基]脲;
N-[2-(2-甲基苯基)己基]-N′-[6-甲硫基喹啉-5-基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(4-甲基苯基)庚基]脲;
N-[2-(4-甲基苯基)庚基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3-甲基苯基)庚基]脲;
N-[2-(3-甲基苯基)庚基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[2-(3-甲基苯基)庚基]-N′-(6-甲氧基喹啉-5-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-甲基苯基)己基]脲;
N-[2-(2,5-二甲基苯基)己基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[2-(2,5-二甲基苯基)己基]-N′-(6-甲氧基喹啉-5-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,4-二甲基苯基)己基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3-甲基苯基)己基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,4-二甲基苯基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(萘-1-基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(萘-2-基)己基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(萘-1-基)己基]脲;
N-(6-甲硫基喹啉-5-基)-N′-[2-(萘-1-基)己基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,3-二甲氧基苯基)庚基]脲;
N-[2-(2,3-二甲氧基苯基)庚基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3-甲基苯基)辛基]脲;
N-[2-(3-甲基苯基)辛基]-N′-(6-甲氧基喹啉-5-基)脲;
N-[2-(3-甲基苯基)辛基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[2-(萘-1-基)庚基]-N′-(6-甲氧基喹啉-5-基)脲;
N-[2-(萘-1-基)庚基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[2-(2,4-二甲基苯基)庚基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[2-(2,4-二甲基苯基)庚基]-N′-(6-甲氧基喹啉-5-基)脲;
N-[2,4-二(甲基)-6-甲基吡啶-3-基]-N′-[2-(3,4,5-三甲氧基苯基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基-4-甲氧基苯基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲氧基苯基)庚基]脲;
N-[2-(2,5-二甲氧基苯基)庚基]-N′-(6-甲硫基喹啉-5-基)脲;
N-[2-(2,5-二甲氧基苯基)庚基]-N′-(6-甲氧基喹啉-5-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3,5-二甲氧基苯基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲氧基苯基)辛基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-2-[2-(3-甲基苯基)-6,6,6-三氟己基]脲;
N-[2-(3-甲基苯基)庚基]-N′-(6-戊硫基喹啉-5-基)脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-{2-(5-氯苯并[b]噻吩-3-基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(3,5-二甲基苯基)庚基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)辛基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[5-甲基-2-{3-甲基苯基}己基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[(2-{2,5-二甲基苯基}-4-苯基丁基]脲;
N-[2,4-二(甲硫基)-6-甲基吡啶-3-基]-N′-[2-(2,5-二甲基苯基)-5-苯基戊基]脲;
N-(2,6-二异丙基苯基)-N′-[2-(萘-1-基)庚基]脲;
N-(2,6-二异丙基苯基)-N′-[6-甲基-2-(萘-1-基)庚基]脲。
8、按照权利要求1的化合物,包括至少一个选自氘和C-14的放射性同位素。
9、一种药用组合物,包括一种抑制ACAT有效量的权利要求1所述化合物和可药用的稀释剂和载体。
10、在人体或动物体内抑制ACAT的方法,包括所说人或动物服用抑制ACAT有效量的权利要求1所述化合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US89005092A | 1992-05-28 | 1992-05-28 | |
US890,050 | 1992-05-28 |
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Publication Number | Publication Date |
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CN1080919A true CN1080919A (zh) | 1994-01-19 |
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CN93106774A Pending CN1080919A (zh) | 1992-05-28 | 1993-05-27 | 作为酰基辅酶a-胆固醇酰基转移酶抑制剂的、新的n-芳基和n-杂芳基脲类衍生物 |
Country Status (23)
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US (1) | US6001860A (zh) |
EP (1) | EP0642498A1 (zh) |
JP (1) | JPH07503737A (zh) |
KR (1) | KR950701621A (zh) |
CN (1) | CN1080919A (zh) |
AU (1) | AU4028393A (zh) |
BG (1) | BG99188A (zh) |
BR (1) | BR9306421A (zh) |
CA (1) | CA2134359C (zh) |
FI (1) | FI932423A (zh) |
HR (1) | HRP930931A2 (zh) |
HU (1) | HUT64303A (zh) |
IL (1) | IL105756A0 (zh) |
IS (1) | IS4023A (zh) |
MA (1) | MA22896A1 (zh) |
MX (1) | MX9303100A (zh) |
OA (1) | OA10114A (zh) |
PL (1) | PL299082A1 (zh) |
RU (1) | RU94046149A (zh) |
SK (1) | SK142694A3 (zh) |
UY (1) | UY23589A1 (zh) |
WO (1) | WO1993024458A1 (zh) |
YU (1) | YU37193A (zh) |
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CN1051311C (zh) * | 1993-02-27 | 2000-04-12 | 日本农药株式会社 | N-杂芳基-n'-苯脲衍生物及其生产和应用 |
CN103172543A (zh) * | 2011-12-21 | 2013-06-26 | 中国科学院上海药物研究所 | 一种脲类化合物、制备方法及其用途 |
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JP2001521934A (ja) | 1997-11-03 | 2001-11-13 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド | 抗炎症薬としての芳香族ヘテロ環式化合物 |
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-
1993
- 1993-04-20 SK SK1426-94A patent/SK142694A3/sk unknown
- 1993-04-20 BR BR9306421A patent/BR9306421A/pt not_active Application Discontinuation
- 1993-04-20 WO PCT/US1993/003539 patent/WO1993024458A1/en not_active Application Discontinuation
- 1993-04-20 JP JP6500522A patent/JPH07503737A/ja active Pending
- 1993-04-20 AU AU40283/93A patent/AU4028393A/en not_active Abandoned
- 1993-04-20 US US08/343,557 patent/US6001860A/en not_active Expired - Fee Related
- 1993-04-20 RU RU94046149/04A patent/RU94046149A/ru unknown
- 1993-04-20 CA CA002134359A patent/CA2134359C/en not_active Expired - Fee Related
- 1993-04-20 KR KR1019940704262A patent/KR950701621A/ko not_active Application Discontinuation
- 1993-04-20 EP EP93909519A patent/EP0642498A1/en not_active Withdrawn
- 1993-05-20 IL IL105756A patent/IL105756A0/xx unknown
- 1993-05-24 IS IS4023A patent/IS4023A/is unknown
- 1993-05-26 PL PL93299082A patent/PL299082A1/xx unknown
- 1993-05-26 MX MX9303100A patent/MX9303100A/es unknown
- 1993-05-26 HR HR07/890,050A patent/HRP930931A2/hr not_active Application Discontinuation
- 1993-05-27 CN CN93106774A patent/CN1080919A/zh active Pending
- 1993-05-27 YU YU37193A patent/YU37193A/sh unknown
- 1993-05-27 FI FI932423A patent/FI932423A/fi not_active Application Discontinuation
- 1993-05-27 HU HU9301552A patent/HUT64303A/hu unknown
- 1993-05-27 MA MA23195A patent/MA22896A1/fr unknown
- 1993-05-28 UY UY23589A patent/UY23589A1/es unknown
-
1994
- 1994-11-17 BG BG99188A patent/BG99188A/bg unknown
- 1994-11-28 OA OA60588A patent/OA10114A/en unknown
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1051311C (zh) * | 1993-02-27 | 2000-04-12 | 日本农药株式会社 | N-杂芳基-n'-苯脲衍生物及其生产和应用 |
CN103172543A (zh) * | 2011-12-21 | 2013-06-26 | 中国科学院上海药物研究所 | 一种脲类化合物、制备方法及其用途 |
WO2013091285A1 (zh) * | 2011-12-21 | 2013-06-27 | 中国科学院上海药物研究所 | 一种脲类化合物、制备方法及其用途 |
CN103172543B (zh) * | 2011-12-21 | 2016-02-10 | 中国科学院上海药物研究所 | 一种脲类化合物、制备方法及其用途 |
Also Published As
Publication number | Publication date |
---|---|
JPH07503737A (ja) | 1995-04-20 |
OA10114A (en) | 1996-12-18 |
BG99188A (bg) | 1995-07-28 |
AU4028393A (en) | 1993-12-30 |
BR9306421A (pt) | 1998-09-15 |
SK142694A3 (en) | 1995-06-07 |
US6001860A (en) | 1999-12-14 |
FI932423A0 (fi) | 1993-05-27 |
RU94046149A (ru) | 1996-11-27 |
UY23589A1 (es) | 1993-11-15 |
YU37193A (sh) | 1997-07-31 |
FI932423A (fi) | 1993-11-29 |
MX9303100A (es) | 1994-06-30 |
IS4023A (is) | 1993-11-29 |
KR950701621A (ko) | 1995-04-28 |
WO1993024458A1 (en) | 1993-12-09 |
HUT64303A (en) | 1993-12-28 |
EP0642498A1 (en) | 1995-03-15 |
IL105756A0 (en) | 1993-09-22 |
CA2134359C (en) | 1997-07-01 |
MA22896A1 (fr) | 1993-12-31 |
PL299082A1 (en) | 1994-04-05 |
CA2134359A1 (en) | 1993-12-09 |
HRP930931A2 (en) | 1997-06-30 |
HU9301552D0 (en) | 1993-09-28 |
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