CN101678013B - 哌啶/哌嗪衍生物 - Google Patents
哌啶/哌嗪衍生物 Download PDFInfo
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- CN101678013B CN101678013B CN200880018624.9A CN200880018624A CN101678013B CN 101678013 B CN101678013 B CN 101678013B CN 200880018624 A CN200880018624 A CN 200880018624A CN 101678013 B CN101678013 B CN 101678013B
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- phenyl
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- 150000003053 piperidines Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 267
- -1 adamantanyl Chemical group 0.000 claims abstract description 129
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- 108050004099 Diacylglycerol O-acyltransferase 1 Proteins 0.000 claims abstract description 96
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 63
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 49
- 239000003814 drug Substances 0.000 claims abstract description 45
- 239000001257 hydrogen Substances 0.000 claims abstract description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 40
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 36
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 125000003118 aryl group Chemical group 0.000 claims description 120
- 125000001424 substituent group Chemical group 0.000 claims description 118
- 150000003839 salts Chemical class 0.000 claims description 72
- 229910052736 halogen Inorganic materials 0.000 claims description 68
- 150000002367 halogens Chemical class 0.000 claims description 67
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 58
- 229910052717 sulfur Inorganic materials 0.000 claims description 55
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 54
- 201000010099 disease Diseases 0.000 claims description 53
- 229910052757 nitrogen Inorganic materials 0.000 claims description 48
- 229910052760 oxygen Inorganic materials 0.000 claims description 45
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 33
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 32
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
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- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
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- 125000004193 piperazinyl group Chemical class 0.000 claims description 3
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- 125000001475 halogen functional group Chemical group 0.000 claims 2
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
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- 101000927974 Homo sapiens Diacylglycerol O-acyltransferase 1 Proteins 0.000 description 32
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- 239000003054 catalyst Substances 0.000 description 32
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
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- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 23
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Abstract
本发明涉及式(I)的DGAT抑制剂,包括其任何立体化学异构形式、N-氧化物、可药用盐或溶剂化物,其中A代表CH或N;虚线在A代表碳原子时表示一个任选的键;X代表-O-C(=O)-,-C(=O)-C(=O)-,-NRx-C(=O)-,-Z-C(=O)-,-Z-NRx-C(=O)-,-C(=O)-Z-,-NRx-C(=O)-Z-,-C(=S)-,-NRx-C(=S)-,-Z-C(=S)-,-Z-NRx-C(=S)-,-C(=S)-Z-,-NRx-C(=S)-Z-;Z代表选自C1-6链烷二基、C2-6链烯二基或C2-6链炔二基的二价基团,其中该C1-6链烷二基、C2-6链烯二基或C2-6链炔二基均可任选地被取代,并且连接在C1-6链烷二基中同一碳原子上的两个氢原子可以任选地被C1-6链烷二基代替;Y代表-C(=O)-NRx-或-NRx-C(=O)-;R1代表金刚烷基,C3-6环烷基,芳基1或Het1;R2代表C3-6环烷基,苯基,萘基,2,3-二氢-1,4-苯并二氧杂环己烯基,1,3-苯并二氧杂环戊烯基,2,3-二氢苯并呋喃基,或含1或2个N原子的6元芳族杂环,其中该C3-6环烷基、苯基、萘基、2,3-二氢-1,4-苯并二氧杂环己烯基、1,3-苯并二氧杂环戊烯基或杂环可任选地被取代;R7代表氢,卤素,C1-4烷基,被羟基取代的C1-4烷基;条件是以下化合物(A),(B)被排除在外。本发明还涉及制备此类化合物的方法,含有该化合物的药物组合物,以及该化合物作为药物和DGAT抑制剂的用途。
Description
技术领域
本发明涉及DGAT抑制剂,特别是DGAT1抑制剂,在制造通过升高一种或多种饱感激素(特别是GLP-1)的水平预防或治疗疾病的药物方面的应用。本发明还涉及具有DGAT抑制活性,特别是DGAT1抑制活性的哌啶/哌嗪衍生物。本发明另外还涉及它们的制备方法和含有它们的药物组合物。本发明还涉及所述化合物在制造用于预防或治疗由DGAT,特别是DGAT1介导的疾病的药物中的应用。
背景技术
甘油三酯代表着真核生物中储存的能量的主要形式。甘油三酯代谢的失调或不平衡与肥胖、胰岛素抗性综合症和II型糖尿病的发病机制及风险增高有关(见,Lewis等,Endocrine Reviews(2002)23:201和Malloyand Kane,Adv.Intern.Med.(2001)47:111)。另外,高甘油三酯血症常常是癌症治疗的不良后果(见,Bast等,Cancer Medicine,第5版,(2000)B.C.Decker,Hamilton,Ontario,CA)。
在甘油三酯的合成中,一种关键的酶是酰基辅酶A:二酰甘油酰基转移酶,或DGAT。DGAT是一种微粒体酶,它广泛表达在哺乳动物组织中,并对1,2-二酰基甘油(DAG)和脂酰辅酶A在内质网连接形成甘油三酯(TG)起催化作用(Chen和Farese的评述,Trends Cardiovasc.Med.(2000)10:188和Farese等,Curr.Opin.Lipidol.(2000)11:229)。最初认为,在甘油三酯合成的两条主要途径-甘油磷酸酯途径和单酰甘油途径中,二酰基甘油经酰化形成甘油三酯这一最后步骤的催化反应只由DGAT控制。因为甘油三酯被认为对于生存是必不可少的,而且它们的合成被想象成经由单一的机制进行,所以对于通过抑制DGAT的活性抑制甘油三酯合成作为大量研究。
编码鼠DGAT1和相关的人同源物ARGP1(人DGAT1)和ARGP2(人ACAT2)的基因现在已被克隆和鉴定(Cases等,Proc.Natl.Acad.Sci.(1998)95:13018;Oelkers等,J.Biol.Chem.(1998)273:26765)。编码鼠DGAT1的基因已被用来产生DGAT剔除的小鼠以便更好地阐明DGAT基因的功能。
出乎意料的是,不能表达功能性DGAT1酶的小鼠(Dgat 1-/-小鼠)可以生存并且仍能合成甘油三酯,表明有多种催化机制对甘油三酯的合成起作用(Smith等,Nature Genetics(2000)25:87)。还鉴定了催化甘油三酯合成的其它的酶,例如DGAT2和二酰甘油转酰基酶(Cases等,J.Biol.Chem.(2001)276:38870)。对小鼠的基因剔除研究揭示了DGAT2在哺乳动物甘油三酯合成中起十分重要的作用,并且是生存所必需的。DGAT2缺陷小鼠的脂肪减少,并在出生后不久死亡,显然是由于用于能量代谢的基质减少以及皮肤中通透屏障功能受损(Farese等,J.Biol.Chem.(2004)279:11767)。
有意义的是,Dgat 1-/-小鼠对于饮食诱发的肥胖具有抗性并保持清瘦。即使喂食高脂饮食(21%脂肪),Dgat 1-/-小鼠仍保持与喂食正规饮食(4%脂肪)的小鼠相近的体重,且体内甘油三酯总水平较低。Dgat1-/-小鼠的抗肥胖性不是由于热量摄入减少,而是能量消耗增大和对胰岛素及瘦蛋白的抗性降低的结果(Smith等,Nature Genetics(2000)25:87;Chen和Farese,Trends Cardiovasc.Med(2000)10:188;及Chen等,J.Clin.Invest.(2002)109:1049)。另外,Dgat 1-/-小鼠的甘油三酯吸收率降低(Buhman等,J.Biol.Chem.(2002)277:25474)。除了甘油三酯代谢改善以外,Dgat 1-/-小鼠还改善了葡萄糖代谢,在摄入葡萄糖之后,与野生型小鼠相比,葡萄糖和胰岛素水平较低(Chen和Farese,FrendsCardiovasc.Med.(2000)10:188)。
关于多种酶对于由二酰基甘油合成甘油三酯起催化作用的发现是有意义的,因为它展示了通过调节这一生化反应的一种催化机制在个体中以最小的不良副作用达到治疗效果的可能性。抑制二酰基甘油向甘油三酯转化(例如通过特异地抑制DGAT1的活性)的化合物,在降低甘油三酯的体浓度和吸收,以便治疗性地对抗由于在肥胖、胰岛素抗性综合症和II型糖尿病、充血性心力衰竭和动脉粥样硬化中以及癌症治疗引起的甘油三酯代谢异常造成的致病作用方面会有用处。
由于全世界社会内肥胖、II型糖尿病、心脏病和癌症的日益增加的流行,发展有效治疗和预防这些疾病的新治疗方法已是紧迫的需要。因此,有兴趣研发能够有效和特异地抑制DGAT,特别是DGAT1的催化活性的化合物。
我们现在出乎意料地发现,本发明的化合物具有DGAT抑制活性,特别是DGAT1抑制活性,因此能用来预防或治疗与DGAT有关或由其介导的疾病,例如肥胖、II型糖尿病、心脏病和癌症。本发明化合物与先有技术化合物在结构、药理活性、药理效力和/或药理型式方面不同。
我们还出乎意料地发现,DGAT抑制剂能用来升高一种或多种饱感激素,特别是胰高血糖素样肽-1(GLP-1)的水平,因此DGAT抑制剂,特别是DGAT1抑制剂,还能用来预防或治疗会从饱感激素(特别是GLP-1)的升高受益的疾病。胰高血糖素样肽1(GLP-1)是一种肠激素,它通常在高血糖症期间刺激胰岛素分泌,抑制高血糖素分泌,刺激(前)胰岛素生物合成,和减缓胃排空及胃酸分泌。GLP-1是在摄入脂肪和蛋白质后由小肠和大肠中的L细胞分泌的。除其它的适应症外,已经提出GLP-1作为控制II型非胰岛素依赖性糖尿病和相关的代谢障碍(例如肥胖)的可能的治疗剂。
于是,由于这一发现,能够从GLP-1水平增高受益的疾病可以用小分子(与大分子如蛋白质或蛋白质样化合物,例如GLP-1类似物相比)治疗。
背景先有技术
WO 2006/034441公开了杂环衍生物及其作为硬脂酰辅酶A脱饱和酶抑制剂(SCD-1抑制剂)的应用。
WO 2006/086445涉及SCD-1抑制剂和另一种药物治疗有害的体重增长的联合疗法。
WO 2006/004200和JP 2007131584涉及具有DGAT抑制活性的尿素和氨基衍生物。
WO 2004/047755涉及具有DGAT抑制活性的稠合双环含氮杂环化合物。
WO 2005/072740涉及一种具有DGAT抑制活性的化合物的抑制食欲作用。
发明的描述
本发明涉及DGAT抑制剂在制造用于预防或治疗,特别是用于治疗,能够由于一种或多种饱感激素(特别是GLP-1)的水平升高而受益的疾病的药物方面的应用。
本发明还涉及下式化合物
包括其任何立体化学异构形式,N-氧化物,可药用的盐或溶剂化物,其中
A代表CH或N;
虚线在A是碳原子的情况下代表一个任选存在的键;
X代表-O-C(=O)-,-C(=O)-C(=O)-,-NRx-C(=O)-,-Z-C(=O)-,-Z-NRx-C(=O)-,-C(=O)-Z-,-NRx-C(=O)-Z-,-C(=S)-,-NRx-C(=S)-,-Z-C(=S)-,-Z-NRx-C(=S)-,-C(=S)-Z-,-NRx-C(=S)-Z-;
Z代表选自C1-6链烷二基,C2-6链烯二基或C2-6链炔二基的一个二价基团,其中所述的C1-6链烷二基、C2-6链烯二基或C2-6链炔二基均可任选地被羟基或氨基取代;并且连接在C1-6链烷二基的同一碳原子上的两个氢原子可以任选地被C1-6链烷二基代替;
Rx代表氢或C1-4烷基;
Y代表-C(=O)-NRx-或-NRx-C(=O)-;
R1代表金刚烷基,C3-6环烷基;芳基1或Het1;
R2代表C3-6环烷基,苯基,萘基,2,3-二氢-1,4-苯并二氧杂环己烯基,1,3-苯并二氧杂环戊烯基,2,3-二氢苯并呋喃基或含有1或2个N原子的6元芳族杂环,其中该C3-6环烷基、苯基、萘基、2,3-二氢-1,4-苯并二氧杂不己烯基、1,3-苯并二氧杂环戊烯基或含1或2个N原子的6元芳族杂环可以任选地被至少一个取代基,特别是被1、2、3、4或5个取代基取代,各取代基独立地选自以下基团:羟基,羧基,卤素,任选被羟基取代的C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,其中C1-6烷基可任选地被芳基取代的C1-6烷氧羰基,氰基,C1-6烷基羰基,硝基,氨基,一或二(C1-4烷基)氨基,C1-4烷基羰基氨基,-S(=O)p-C1-4烷基,R4R3N-C(=O)-,R4R3N-C1-6烷基,C3-6环烷基,C3-6环烷基C1-4烷基,C3-6环烷基-C(=O)-,芳基,芳氧基,芳基C1-4烷基,芳基-C(=O)-C1-4烷基,芳基-C(=O)-,Het,HetC1-4烷基,Het-C(=O)-C1-4烷基,Het-C(=O)-,Het-O-;
R3代表氢,任选被羟基或C1-4烷氧基取代的C1-4烷基,R6R5N-C1-4烷基,C1-4烷氧基,Het,Het-C1-4烷基,芳基,R6R5N-C(=O)-C1-4烷基;
R4代表氢或C1-4烷基;
R5代表氢,C1-4烷基,C1-4烷基羰基;
R6代表氢或C1-4烷基;或者
R5和R6可以与它们连接的氮原子合起来形成一个饱和单环5、6或7元杂环,它可以另外含有一个或多个各自独立选自O、S、S(=O)p或N的杂原子,并且该杂环可以任选地被C1-4烷基取代;
R7代表氢,卤素,C1-4烷基,被羟基取代的C1-4烷基;
芳基代表苯基或被至少一个取代基,特别是1、2、3、4或5个取代基取代的苯基,各取代基独立地选自以下基团:羟基,羧基,卤素,任选被C1-4烷氧基、氨基或者一或二(C1-4烷基)氨基取代的C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,C1-6烷氧羰基,氰基,氨基羰基,一或二(C1-4烷基)氨基羰基,C1-6烷基羰基,硝基,氨基,一或二(C1-4烷基)氨基,-S(=O)p-C1-4烷基;
芳基1代表苯基、萘基或芴基,该苯基、萘基或芴基均可任选地被至少一个取代基,特别是1、2、3、4或5个取代基取代,各取代基独立地选自:羟基,氧,羧基,卤素,任选被羧基、C1-4烷氧羰基或芳基-C(=O)-取代的C1-6烷基,任选被芳基或芳基-C(=O)-取代的羟基C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,其中的C1-6烷基可任选地被芳基取代的C1-6烷氧羰基,氰基,氨基羰基,一或二(C1-4烷基)氨基羰基,C1-6烷基羰基,硝基,氨基,一或二(C1-6烷基)氨基,R4R3N-C1-6烷基,C3-6环烷基-NRx-,芳基-NRx-,Het-NRx-,C3-6环烷基C1-4烷基-NRx-,芳基C1-4烷基-NRx-,HetC1-4烷基-NRx-,-S(=O)p-C1-4烷基,C3-6环烷基,C3-6环烷基C1-4烷基,C3-6环烷基-C(=O)-,芳基,芳氧基,芳基C1-4烷基,芳基-C(=O)-C1-4烷基,芳基-C(=O)-,Het,HetC1-4烷基,Het-C(=O)-C1-4烷基,Het-C(=O)-,Het-O-;
Het代表一个含有至少一个独立选自O、S、S(=O)p或N的杂原子的单环非芳族或芳族杂环,或是一个含至少一个独立选自O、S、S(=O)p或N的杂原子的双环或三环非芳族或芳族杂环,该单环杂环或者双环或三环杂环任选地被至少一个取代基,特别是1、2、3、4或5个取代基取代,各取代基独立地选自:羟基,氧,羧基,卤素,任选被C1-4烷氧基、氨基或者一或二(C1-4烷基)氨基取代的C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,C1-6烷氧羰基,氰基,氨基羰基,一或二(C1-4烷基)氨基羰基,C1-6烷基羰基,硝基,氨基,一或二(C1-4烷基)氨基,-S(=O)p-C1-4烷基;
Het1代表一个含有至少一个独立选自O、S、S(=O)p或N的杂原子的单环非芳族或芳族杂环,或是一个含至少一个独立选自O、S、S(=O)p或N的杂原子的双环或三环非芳族或芳族杂环,该单环杂环或者双环或三环杂环任选地被至少一个取代基,特别是1、2、3、4或5个取代基取代,各取代基独立地选自:羟基,氧,羧基,卤素,任选被芳基-C(=O)-取代的C1-6烷基,任选被芳基或芳基-C(=O)-取代的羟基C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,其中的C1-6烷基可任选地被芳基取代的C1-6烷氧羰基,氰基,氨基羰基,一或二(C1-4烷基)氨基羰基,C1-6烷基羰基,硝基,氨基,一或二(C1-6烷基)氨基,R4R3N-C1-6烷基,C3-6环烷基-NRx-,芳基-NRx-,Het-NRx-,C3-6环烷基C1-4烷基-NRx-,芳基C1-4烷基-NRx-,HetC1-4烷基-NRx-,-S(=O)p-C1-4烷基,C3-6环烷基,C3-6环烷基C1-4烷基;C3-6环烷基-C(=O)-,芳基,芳氧基,芳基C1-4烷基,芳基-C(=O)-C1-4烷基,芳基-C(=O)-,Het,HetC1-4烷基,Het-C(=O)-C1-4烷基,Het-C(=O)-,Het-O-;
p代表1或2;
条件是,以下化合物不包括在内:
本发明还涉及式(I”’)化合物在制造用于预防或治疗由DGAT介导的疾病的药物中的应用,特别是,本发明涉及式(I”’)化合物在制造用于预防或治疗能够从抑制DGAT中受益的疾病,特别是用于治疗能够从抑制DGAT、尤其是DGAT1受益的疾病的药物中的应用,其中该式(I”’)化合物是下式化合物
包括其任何立体化学异构形式,N-氧化物,可药用的盐或溶剂化物,其中
A代表CH或N;
虚线在A是碳原子的情况下代表一个任选存在的键;
X代表-O-C(=O)-,-C(=O)-C(=O)-,-NRx-C(=O)-,-Z-C(=O)-,-Z-NRx-C(=O)-,-C(=O)-Z-,-NRx-C(=O)-Z-,-C(=S)-,-S(=O)P-,-NRx-C(=S)-,-Z-C(=S)-,-Z-NRx-C(=S)-,-C(=S)-Z-,-NRx-C(=S)-Z-;
Z代表选自C1-6链烷二基,C2-6链烯二基或C2-6链炔二基的一个二价基团,其中所述的C1-6链烷二基、C2-6链烯二基或C2-6链炔二基均可任选地被羟基或氨基取代;并且连接在C1-6链烷二基的同一碳原子上的两个氢原子可以任选地被C1-6链烷二基代替;
Rx代表氢或C1-4烷基;
Y代表-C(=O)-NRx-或-NRx-C(=O)-;
R1代表金刚烷基,C3-6环烷基;芳基1或Het1;
R2代表氢、C1-6烷基、C2-6烯基、C3-6环烷基,苯基,萘基,2,3-二氢-1,4-苯并二氧杂环己烯基,1,3-苯并二氧杂环戊烯基,2,3-二氢苯并呋喃基或含有1或2个N原子的6元芳族杂环,其中该C3-6环烷基、苯基、萘基、2,3-二氢-1,4-苯并二氧杂不己烯基、1,3-苯并二氧杂环戊烯基或含1或2个N原子的6元芳族杂环可以任选地被至少一个取代基,特别是被1、2、3、4或5个取代基取代,各取代基独立地选自以下基团:羟基,羧基,卤素,任选被羟基取代的C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,其中C1-6烷基可任选地被芳基取代的C1-6烷氧羰基,氰基,C1-6烷基羰基,硝基,氨基,一或二(C1-4烷基)氨基,C1-4烷基羰基氨基,-S(=O)p-C1-4烷基,R4R3N-C(=O)-,R4R3N-C1-6烷基,C3-6环烷基,C3-6环烷基C1-4烷基,C3-6环烷基-C(=O)-,芳基,芳氧基,芳基C1-4烷基,芳基-C(=O)-C1-4烷基,芳基-C(=O)-,Het,HetC1-4烷基,Het-C(=O)-C1-4烷基,Het-C(=O)-,Het-O-;
R3代表氢,任选被羟基或C1-4烷氧基取代的C1-4烷基,R6R5N-C1-4烷基,C1-4烷氧基,Het,Het-C1-4烷基,芳基,R6R5N-C(=O)-C1-4烷基;
R4代表氢或C1-4烷基;
R5代表氢,C1-4烷基,C1-4烷基羰基;
R6代表氢或C1-4烷基;或者
R5和R6可以与它们连接的氮原子合起来形成一个饱和单环5、6或7元杂环,它可以另外含有一个或多个各自独立选自O、S、S(=O)p或N的杂原子,并且该杂环可以任选地被C1-4烷基取代;
R7代表氢,卤素,C1-4烷基,被羟基取代的C1-4烷基;
芳基代表苯基或被至少一个取代基,特别是1、2、3、4或5个取代基取代的苯基,各取代基独立地选自以下基团:羟基,羧基,卤素,任选被C1-4烷氧基、氨基或者一或二(C1-4烷基)氨基取代的C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,C1-6烷氧羰基,氰基,氨基羰基,一或二(C1-4烷基)氨基羰基,C1-6烷基羰基,硝基,氨基,一或二(C1-4烷基)氨基,-S(=O)p-C1-4烷基;
芳基1代表苯基、萘基或芴基,该苯基、萘基或芴基均可任选地被至少一个取代基,特别是1、2、3、4或5个取代基取代,各取代基独立地选自:羟基,氧,羧基,卤素,任选被羧基、C1-4烷氧羰基或芳基-C(=O)-取代的C1-6烷基,任选被芳基或芳基-C(=O)-取代的羟基C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,其中的C1-6烷基可任选地被芳基取代的C1-6烷氧羰基,氰基,氨基羰基,一或二(C1-4烷基)氨基羰基,C1-6烷基羰基,硝基,氨基,一或二(C1-6烷基)氨基,R4R3N-C1-6烷基,C3-6环烷基-NRx-,芳基-NRx-,Het-NRx-,C3-6环烷基C1-4烷基-NRx-,芳基C1-4烷基-NRx-,HetC1-4烷基-NRx-,-S(=O)p-C1-4烷基,C3-6环烷基,C3-6环烷基C1-4烷基,C3-6环烷基-C(=O)-,芳基,芳氧基,芳基C1-4烷基,芳基-C(=O)-C1-4烷基,芳基-C(=O)-,Het,HetC1-4烷基,Het-C(=O)-C1-4烷基,Het-C(=O)-,Het-O-;
Het代表一个含有至少一个独立选自O、S、S(=O)p或N的杂原子的单环非芳族或芳族杂环,或是一个含至少一个独立选自O、S、S(=O)p或N的杂原子的双环或三环非芳族或芳族杂环,该单环杂环或者双环或三环杂环任选地被至少一个取代基,特别是1、2、3、4或5个取代基取代,各取代基独立地选自:羟基,氧,羧基,卤素,任选被C1-4烷氧基、氨基或者一或二(C1-4烷基)氨基取代的C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,C1-6烷氧羰基,氰基,氨基羰基,一或二(C1-4烷基)氨基羰基,C1-6烷基羰基,硝基,氨基,一或二(C1-4烷基)氨基,-S(=O)p-C1-4烷基;
Het1代表一个含有至少一个独立选自O、S、S(=O)p或N的杂原子的单环非芳族或芳族杂环,或是一个含至少一个独立选自O、S、S(=O)p或N的杂原子的双环或三环非芳族或芳族杂环,该单环杂环或者双环或三环杂环任选地被至少一个取代基,特别是1、2、3、4或5个取代基取代,各取代基独立地选自:羟基,氧,羧基,卤素,任选被芳基-C(=O)-取代的C1-6烷基,任选被芳基或芳基-C(=O)-取代的羟基C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,其中的C1-6烷基可任选地被芳基取代的C1-6烷氧羰基,氰基,氨基羰基,一或二(C1-4烷基)氨基羰基,C1-6烷基羰基,硝基,氨基,一或二(C1-6烷基)氨基,R4R3N-C1-6烷基,C3-6环烷基-NRx-,芳基-NRx-,Het-NRx-,C3-6环烷基C1-4烷基-NRx-,芳基C1-4烷基-NRx-,HetC1-4烷基-NRx-,-S(=O)p-C1-4烷基,C3-6环烷基,C3-6环烷基C1-4烷基;C3-6环烷基-C(=O)-,芳基,芳氧基,芳基C1-4烷基,芳基-C(=O)-C1-4烷基,芳基-C(=O)-,Het,HetC1-4烷基,Het-C(=O)-C1-4烷基,Het-C(=O)-,Het-O-;
p代表1或2。
本发明还涉及式(I)化合物对于制造用于预防或治疗由DGAT介导的疾病的药物的应用,特别是,本发明涉及式(I)化合物对于制造用于预防或治疗能够从抑制DGAT中受益的疾病,特别是用于治疗能够从抑制DGAT,尤其是抑制DGAT1中受益的疾病的药物的应用。
本发明还涉及式(I)或(I”’)化合物在制造用于预防或治疗能够从一种或多种饱感激素(特别是GLP-1)的水平提高受益的疾病的药物方面的应用,特别是,本发明涉及式(I)或式(I”’)化合物在制造用于治疗能够从GLP-1的水平升高中受益的疾病的药物方面的应用。
在上文和下文使用时,作为基团或基团的一部分使用的C0-3烷基定义为具有0(此时代表一个直接键)至3个碳原子的直链或支链饱和烃基,例如甲基、乙基、丙基、1-甲基乙基;作为基团或基团的一部分的C1-2烷基定义为有1或2个碳原子的直链或支链饱和烃基,例如甲基、乙基;作为基团或基团的一部分的C1-4烷基定义为有1-4个碳原子的直链或支链饱和烃基,例如甲基、乙基、丙基、1-甲基乙基、丁基;作为基团或基团的一部分的C1-5烷基定义为有1至5个碳原子的直链或支链饱和烃基,例如对于C1-4烷基定义的基团和戊基、2-甲基丁基等;作为基团或基团的一部分的C1-6烷基定义为有1至6个碳原子的直链或支链饱和烃基,例如对C1-4烷基和C1-5烷基定义的基团和己基、2-甲基戊基等;C1-6链烷二基定义为有1至6个碳原子的直链或支链饱和的二价烃基,例如亚甲基,1,2-乙二基或1,2-亚乙基,1,3-丙二基或1,3-亚丙基,1,4-丁二基或1,4-亚丁基,1,5-戊二基等;作为基团或基团的一部分的C2-6烯基定义为有2至6个碳原子和一个双键的直链或支链烃基,例如乙烯基、丙烯基、丁烯基、戊烯基、己烯基、3-甲基丁烯基等;C2-6链烯二基定义为有2至6个碳原子和一个双键的直链或支链二价烃基,例如1,2-乙烯二基,1,3-丙烯二基,1,4-丁烯二基,1,5-戊烯二基等;作为基团或基团的一部分的C2-6链炔二基定义为有2至6个碳原子和一个三键的直链或支链二价烃基,例如1,2-乙炔二基、1,3-丙炔二基、1,4-丁炔二基、1,5-戊炔二基等;C3-6环烷基是对环丙基、环丁基、环戊基和环己基的通称。
术语卤素是氟、氯、溴和碘的通称。在上文或下文使用时,作为基团或基团的一部分的多卤代C1-6烷基定义为被一个或多个,例如2、3、4或5个卤原子取代的C1-6烷基,例如被一个或多个氟原子取代的甲基,如,二氟甲基或三氟甲基,1,1-二氟乙基,1,1-二氟-2,2,2-三氟乙基等。如果在多卤代C1-6烷基的定义内有一个以上的卤原子连接在C1-6烷基上,则它们可以相同或不同。
如前文中使用的,术语(=O)在与碳原子连接时形成一个羰基部分,当与硫原子连接时形成一个亚砜部分,当两个所述基团与一个硫原子连接时,形成一个磺酰基部分。氧基意味着=O。
上文定义的基团Het或Het1可以是任选取代的单环非芳族或芳族杂环,含有至少一个,特别是1、2或3个独立选自O、S、S(=O)p或N的杂原子;或者是任选取代的双环或三环非芳族或芳族杂环,含有至少一个,特别是1、2、3、4或5个独立选自O、S、S(=O)p或N的杂原子。这种未取代的单环杂环的实例包括,但不限于,非芳族(完全饱和或部分饱和的)或芳族的4、5、6或7元单环杂环,例如,氮杂环丁基、四氢呋喃基、吡咯烷基、二氧杂环戊烷基、咪唑烷基、噻唑烷基、四氢噻吩基、二氢噁唑基、异噻唑烷基、异噁唑烷基、噁二唑烷基、三唑烷基、噻二唑烷基、吡唑烷基、哌啶基、六氢嘧啶基、六氢吡嗪基、二氧杂环己烷基、吗啉基、二硫杂环己烷基、硫代吗啉基、哌嗪基、三硫杂环己烷基、六氢二氮杂基、吡咯啉基、咪唑啉基、吡唑啉基、吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡唑基、三唑基、噻二唑基、噁二唑基、四唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、吡喃基等。此类未取代的双环或三环杂环包括,但不限于,非芳族(完全饱和的或部分饱和的)或芳族的8-17元双环或三环杂环,例如,十氢喹啉基、八氢吲哚基、2,3-二氢苯并呋喃基、1,3-苯并二氧杂环戊烯基、2,3-二氢-1,4-苯并二氧杂环己烯基、二氢吲哚基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、异苯并噻吩基、吲嗪基、吲哚基、异吲哚基、苯并噁唑基、苯并咪唑基、吲唑基、苯并异噁唑基、苯并异噻性基、苯并吡唑基、苯并噁二唑基、苯并噻二唑基、苯并三唑基、嘌呤基、喹啉基、异喹啉基、噌啉基、喹嗪基、酞嗪基、喹喔啉基、喹唑啉基、1,5-二氮杂萘基、蝶啶基、苯并吡喃基、吡咯并吡啶基、噻吩并吡啶基、呋喃并吡啶基、异噻唑并吡啶基、噻唑并吡啶基、异噁唑并吡啶基、噁唑并吡啶基、吡唑并吡啶基、咪唑并吡啶基、吡咯并吡嗪基、噻吩并吡嗪基、呋喃并吡嗪基、异噻唑并吡嗪基、噻唑并吡嗪基、异噁唑并吡嗪基、噁唑并吡嗪基、吡唑并吡嗪基、咪唑并吡嗪基、吡咯并嘧啶基、噻吩并嘧啶基、呋喃并嘧啶基、异噻唑并嘧啶基、噻唑并嘧啶基、异噁唑并嘧啶基、噁唑并嘧啶基、吡唑并嘧啶基、咪唑并嘧啶基、吡咯并哒嗪基、噻吩并哒嗪基、呋喃并哒嗪基、异噻唑并哒嗪基、噻唑并哒嗪基、异噁唑并哒嗪基、噁唑并哒嗪基、吡唑并哒嗪基、咪唑并哒嗪基、噁二唑并吡啶基、噻二唑并吡啶基、三唑并吡啶基、噁二唑并吡嗪基、噻二唑并吡嗪基、三唑并吡嗪基、噁二唑并嘧啶基、噻二唑并嘧啶基、三唑并嘧啶基、噁二唑并哒嗪基、噻二唑并哒嗪基、三唑并哒嗪基、咪唑并噁唑基、咪唑并噻唑基、咪唑并咪唑基、咪唑并吡唑基、异噁唑并三嗪基、异噻唑并三嗪基、吡唑并三嗪基、噁唑并三嗪基、噻唑并三嗪基、咪唑并三嗪基、噁二唑并三嗪基、噻二唑并三嗪基、三唑并三嗪基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。对于Het杂环,任选存在的取代基是羟基,氧基,羧基,卤素,任选被C1-4烷氧基、氨基或者一或二(C1-4烷基)氨基取代的C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,C1-6烷氧羰基,氰基,氨基羰基,一或二(C1-4烷基)氨基羰基,C1-6烷基羰基,硝基,氨基,一或二(C1-4烷基)氨基,-S(=O)p-C1-4烷基。对于Het1取代基,任选存在的取代基是羟基,氧基,羧基,卤素,任选被芳基-C(=O)-取代的C1-6烷基,任选被芳基或芳基-C(=O)-取代的羟基C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,其中C1-6烷基可任选被芳基取代的C1-6烷氧羰基,氰基,氨基羰基,一或二(C1-4烷基)氨基羰基,C1-6烷基羰基,硝基,氨基,一或二(C1-6烷基)氨基,R4R3N-C1-6烷基,C3-6环烷基-NRx-,芳基-NRx-,Het-NRx-,C3-6环烷基C1-4烷基-NRx-,芳基C1-4烷基NRx-,HetC1-4烷基-NRx-,-S(=O)p-C1-4烷基,C3-6环烷基,C3-6环烷基C1-4烷基,C3-6环烷基-C(=O)-,芳基,芳氧基,芳基C1-4烷基,芳基-C(=O)-C1-4烷基,芳基-C(=O)-,Het,HetC1-4烷基,Het-C(=O)-C1-4烷基,Het-C(=O)-;Het-O-。
在R2的定义中含1或2个N原子的6元芳族杂环的实例是吡啶基、嘧啶基、哒嗪基、吡嗪基。
当任何变量在任何结构成分(例如芳基,Het)中出现一次以上时,每次的定义都是独立的。
术语Het或Het1意味着包括该杂环的所有可能的异构形式,例如,吡咯基包括1H-吡咯基和2H-吡咯基。
被例如术语芳基、芳基1、Het、Het1或R3涵盖的碳环或杂环,如果没有另外指定,均可通过任何合适的环碳原子或杂原子与式(I)分子的其余部分连接。例如,当杂环是咪唑基时,它可以是1-咪唑基、2-咪唑基、4-咪唑基等;或者当碳环是萘基时,它可以是1-萘基、2-萘基等。
由取代基画出的进入环系统中的直线表示该键可以连接到任何合适的环原子上。
当X被定为例如-NRx-C(=O)-时,意味着NRx的氮连接到R2取代基上,而C(=O)的碳原子与环的氮连接。于是,在X的该定义中,二价基团的左部分是与R2取代基连接,而X定义中的二价基团的右部分与环连接。
一些式(I)化合物还可以其互变异构形式存在。这些形式未在以上的化学式中明确示出,但都确定要包括在本发明的范围之内。
在上文或下文中使用时,取代基均可从许多定义中各自独立地选择,例如对于R3和R4,所有化学上可能的组合都在计划之内。
对于治疗应用,式(I)化合物的盐是其中的反离子是药学上可接受的那些盐。然而,非药用的酸或碱的盐也可以找到用途,例如用于可药用的化合物的制备或纯化。所有的盐,不管是可药用的或者不是,均被包括在本发明的范围之内。
上文或下文提到的可药用的盐意味着包括式(I)化合物能够形成的治疗活性的无毒性酸加成盐形式。它们可以方便地通过用合适的酸处理该碱形式得到,酸的实例有无机酸,例如,氢卤酸(例如盐酸、氢溴酸等)、硫酸、硝酸、磷酸等;或者有机酸,例如乙酸、丙酸、羟基乙酸、2-羟基丙酸、2-氧代丙酸、草酸、丙二酸、丁二酸、马来酸、富马酸、苹果酸、酒石酸、2-羟基-1,2,3-丙三羧酸、甲磺酸、乙磺酸、苯磺酸、4-甲基苯磺酸、环己烷磺酸、2-羟基苯甲酸、4-氨基-2-羟基苯甲酸等。反过来,通过用碱处理,可以将盐形式转化成游离碱形式。
含酸性质子的式(I)化合物可以通过用合适的有机和无机碱处理,转化成其治疗活性的无毒性金属或胺加成盐形式。上文或下文提到的可药用的盐意味着还包括式(I)化合物能够形成的有治疗活性的无毒性金属盐或胺加成盐(碱加成盐形式)。合适的碱加成盐形式包括,例如,铵盐,碱和碱土金属盐(例如锂、钠、钾、镁、钙盐等),与有机碱形成的盐,例如,脂族和芳族的伯胺、仲胺以及叔胺的盐,如甲胺、乙胺、丙胺、异丙胺、四种丁胺异构体、二甲胺、二乙胺、二乙醇胺、二丙胺、二异丙胺、二正丁基胺、吡咯烷、哌啶、吗啉、三甲胺、三乙胺、三丙胺、奎宁环、吡啶、喹啉和异喹啉、苯、苄星(N,N’-二苄基乙二胺)、N-甲基-D-还原葡糖胺、2-氨基-2-(羟甲基)-1,3-丙二醇、海巴明的盐,以及与氨基酸如精氨酸、赖氨酸等的盐。
反过来,通过用酸处理,该盐形式可以转化成游离酸形式。
术语“盐”还包括式(I)化合物能够形成的季铵盐(季胺),这是通过式(I)化合物的碱性氮与合适的季铵化剂,例如任选取代的C1-6烷基卤化物、芳香卤化物、C1-6烷基羰基卤化物、芳基羰基卤化物或芳基C1-6烷基卤化物,如甲基碘或苄基碘,进行反应得到的。也可以使用具有良好的离去基团的其它反应物,例如三氟甲磺酸C1-6烷基酯,甲磺酸C1-6烷基酯和对甲苯磺酸C1-6烷基酯。季胺具有一个带正电的氮原子。可药用的反离子包括氯、溴、碘、三氟乙酸根、乙酸根、三氟甲磺酸根、硫酸根、磺酸根。所选择的反离子可以利用离子交换树脂引入。
术语“溶剂化物”包括式(I)化合物能够形成的水合物和溶剂加成形式,及它们的盐。这些形式的实例是例如水化物、醇化物等。
本发明化合物的N-氧化物形式意味着包括其中一个或几个叔氮原子被氧化成所谓的N-氧化物的式(I)化合物。
应当理解,一些式(I)化合物和其N-氧化物、盐和溶剂化物可以包含一个或多个手性中心,并以立体化学异构形式存在。
上文或下文使用的术语“立体化学异构形式”定义了式(I)化合物及其N-氧化物、盐或溶剂化物可以具有的所有可能的立体异构形式。除非另外说明或指出,化合物的化学名称代表所有可能的立体化学异构形式的混合物,该混合物包括基础分子结构的所有非对映体和对映体,以及式(I)化合物及其N-氧化物、盐或溶剂化物的各个异构形式,基本上不含,即,其它异构体的含量小于10%,优选小于5%,特别是小于2%,最好是小于1%。因此,当式(I)化合物被指定例如为(E)型时,意味着该化合物基本上不含(Z)型异构体。
特别是,立体异构源中心可以有R-或S-构型;二价环形(部分)饱和基团上的取代基可以是顺式或反式构型。含双键的化合物在该双键处可以具有E(反侧)或Z(同侧)型立体化学结构。术语顺式、反式、R、S、E和Z是本领域技术人员所熟知的。
式(I)化合物的立体化学异构形式显示要被包括在本发明的范围之内。
按照CAS命名规则,当一个分子中存在两个绝对构型已知的立体异构源中心时,对最低位次的手性中心(参考中心)用描述符R或S表示(根据Cahn-Ingold-Prelog排序规则)。第二个立体异构源中心的构型用相对描述符[R*,R*]或[R*,S*]表示,其中第一个R*总是指定为参考中心,[R*,R*]表示这些中心具有相同的手性,而[R*,S*]表示中心的手性不同。例如,如果分子中位次最低的手性中心具有S构型,而第二个中心是R,则立体描述符应指定为S-[R*,S*]。如果使用“α”和“β”:在环数最低的环系中的不对称碳原子上的位次最优先的取代基的位置总是任意地处在由该环系决定的平均平面的“α”位。在该环系的其它不对称碳原子上的最优先的取代基的位置,相对于参考原子上的最优先取代基的位置,如果是在由环系决定的平均平面的同侧,则命令为“α”,如果是在该环系决定的平均平面的另一侧,则命名不“β”。
式(I)化合物可以合成为对映体的外消旋混合物的形式,它可以按照本领域已知的拆解方法彼此分离。式(I)的外消旋化合物可以通过与合适的手性酸反应,转化成相应的非对映异构的盐形式。该非对映异构的盐形式随后利用例如选择性结晶或分级结晶进行分离,用碱从其中释放出对映体。另一种分离式(I)化合物对映异构形式的方法涉及用于相固定相进行液相层析。所述的纯立体化学异构形式也可以由相应的纯立体化学异构形式的合适起始物衍生得到,条件是反应要立体专一性地进行。如果希望得到特定的立体异构体,最好是利用立体专一性的制备方法合成该化合物。这些方法最好是使用对映异构纯的起始物。
下文每当使用术语“式(I)化合物”或其任何亚族时,均意味着还包括它们的N-氧化物形式,盐,立体化学异构形式及溶剂化物。特别重要的是立体化学上纯的式(I)化合物。
本发明的第一实施方案是具有以下化学式的式(I)化合物
包括其任何立体化学异构形式,N-氧化物,可药用的盐或溶剂化物,其中
A代表CH或N;
虚线在A代表碳原子的情形代表一个任选存在的键;
X代表-NRx-C(=O)-;-Z-C(=O)-;-Z-NRx-C(=O)-;-C(=O)-Z-;-NRx-C(=O)-Z-;-C(=S)-;-NRx-C(=S)-;-Z-C(=S)-;-Z-NRx-C(=S)-;-C(=S)-Z-;-NRx-C(=S)-Z-;
Z代表选自C1-6链烷二基、C2-6链烯二基或C2-6链炔二基的一个二价基团,其中该C1-6链烷二基、C2-6链烯二基或C2-6链炔二基均可任选地被羟基取代;
Rx代表氢或C1-4烷基;
Y代表-C(=O)-NRx-或-NRx-C(=O)-;
R1代表C3-6环烷基,芳基1或Het1;
R2代表C3-6环烷基,苯基,萘基,2,3-二氢-1,4-苯并二氧杂环己烯基,1,3-苯并二氧杂环戊烯基,其中该C3-6环烷基、苯基、萘基、2,3-二氢-1,4-苯并二氧杂环己烯基、1,3-苯并二氧杂环戊烯基可以任选地被至少一个取代基,特别是1、2、3、4或5个取代基取代,各取代基独立地选自以下基团:羟基,羧基,卤素、任选被羟基取代的C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,其中的C1-6烷基可任选地被芳基取代的C1-6烷氧羰基,氰基,C1-6烷基羰基,硝基,氨基,一或二(C1-4烷基)氨基,-S(=O)p-C1-4烷基,R4R3N-C(=O)-,R4R3N-C1-6烷基,C3-6环烷基,C3-6环烷基C1-4烷基,C3-6环烷基-C(=O)-,芳基,芳氧基,芳基C1-4烷基,芳基-C(=O)-,Het,HetC1-4烷基,Het-C(=O)-,Het-O-;
R3代表氢,任选被羟基或C1-4烷氧基取代的C1-4烷基,R6R5N-C1-4烷基,C1-4烷氧基,Het,芳基,R6R5N-C(=O)-C1-4烷基;
R4代表氢或C1-4烷基;
R5代表氢,C1-4烷基,C1-4烷基羰基;
R6代表氢或C1-4烷基;或者
R5和R6可以与它们连接的氮原子合起来形成一个饱和单环5、6或7元杂环,该杂环可另外含有选自O、S、S(=O)p或N的一个或多个杂原子,并可任选地被C1-4烷基取代;
芳基代表苯基或被至少一个取代基,特别是1、2、3、4或5个取代基取代的苯基,各取代基独立地选自以下基团:羟基,羧基,卤素,任选被C1-4烷氧基、氨基或者一或二(C1-4烷基)氨基取代的C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,C1-6烷氧羰基,氰基,氨基羰基,一或二(C1-4烷基)氨基羰基,C1-6烷基羰基,硝基,氨基,一或二(C1-4烷基)氨基,-S(=O)p-C1-4烷基;
芳基1代表苯基、萘基或芴基,该苯基、萘基或芴基任选地被至少一个取代基,特别是1、2、3、4或5个取代基取代,各取代基独立地选自以下基团:羟基,氧,羧基,卤素,任选被芳基-C(=O)-取代的C1-6烷基,任选被芳基或芳基-C(=O)-取代的羟基C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,C1-6烷氧羰基(其中C1-6烷基可任选地被芳基取代),氰基,氨基羰基,一或二(C1-4烷基)氨基羰基,C1-6烷基羰基,硝基,氨基,一或二(C1-6烷基)氨基,C3-6环烷基-NRx-,芳基-NRx-,Het-NRx-,C3-6环烷基C1-4烷基-NRx-,芳基C1-4烷基-NRx-,HetC1-4烷基-NRx-,-S(=O)p-C1-4烷基,C3-6环烷基,C3-6环烷基C1-4烷基,C3-6环烷基-C(=O)-,芳基,芳氧基,芳基C1-4烷基,芳基-C(=O)-,Het,HetC1-4烷基,Het-C(=O)-,Het-O-;
Het代表含至少一个选自O、S、S(=O)p或N的杂原子的单环非芳族或芳族杂环,或含至少一个选自O、S、S(=O)p或N的杂原子的双环或三环非芳族或芳族杂环;所述的单环杂环或双环或三环杂环任选地被至少一个取代基,特别是1、2、3、4或5个取代基取代,各取代基独立地选自以下基团:羟基,氧基,羧基,卤素,任选被C1-4烷氧基、氨基或者一或二(C1-4烷基)氨基取代的C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,C1-6烷氧羰基,氰基,氨基羰基,一或二(C1-4烷基)氨基羰基,C1-6烷基羰基,硝基,氨基,一或二(C1-4烷基)氨基,-S(=O)p-C1-4烷基;
Het1代表含至少一个选自O、S、S(=O)p或N的杂原子的单环非芳族或芳族杂环,或是含至少一个选自O、S、S(=O)p或N的杂原子的双环或三环非芳族或芳族杂环;所述的单环杂环或者双环或三环杂环任选地被至少一个,特别是1、2、3、4或5个取代基取代,各取代基独立地选自以下基团:羟基,氧,羧基,卤素,任选被芳基-C(=O)-取代的C1-6烷基,任选被芳基或芳基-C(=O)-取代的羟基C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,C1-6烷氧羰基(其中C1-6烷基可任选地被芳基取代),氰基,氨基羰基,一或二(C1-4烷基)氨基羰基,C1-6烷基羰基,硝基,氨基,一或二(C1-6烷基)氨基,C3-6环烷基-NRx-,芳基-NRx-,Het-NRx-,C3-6环烷基C1-4烷基-NRx-,芳基C1-4烷基-NRx-,HetC1-4烷基-NRx-,-S(=O)p-C1-4烷基,C3-6环烷基,C3-6环烷基C1-4烷基,C3-6环烷基-C(=O)-,芳基,芳氧基,芳基C1-4烷基,芳基-C(=O)-,Het,HetC1-4烷基,Het-C(=O)-,Het-O-;
p代表1或2;
条件是,不包括以下化合物
本发明的第二实施方案是上文作为实施方案提到的那些式(I)化合物或其任何可能的亚族,其中X代表-O-C(=O)-,-NRx-C(=O)-,-Z-C(=O)-,-Z-NRx-C(=O)-,-C(=O)-Z-,-NRx-C(=O)-Z-,-NRx-C(=S)-;特别是其中X代表-NRx-C(=O)-,-Z-C(=O)-,-Z-NRx-C(=O)-,-C(=O)-Z-,-NRx-C(=O)-Z-,-NRx-C(=S)-;尤其是其中X代表-NRx-C(=O)-,-Z-C(=O)-,-Z-NRx-C(=O)-;更特别是X代表-NRx-C(=O)-或-Z-NRx-C(=O)-;或者X代表-NRx-C(=O)-或-Z-C(=O)-。或者X代表-O-C(=O)-;-C(=O)-C(=O)-;-NRx-C(=O)-;-Z-C(=O)-;-Z-NRx-C(=O)-;-C(=S)-;-NRx-C(=S)-;-Z-C(=S)-;-Z-NRx-C(=S)-。
本发明的第三实施方案是上文作为实施方案叙述的那些式(I)化合物或其任何可能的亚族,其中A代表N。
本发明的第四实施方案是上文作为实施方案叙述的那些式(I)化合物或其任何可能的亚族,其中A代表CH,特别是其中A代表CH,并且虚线不代表一个键。
本发明的第五实施方案是上文作为实施方案叙述的那些式(I)化合物或其任何可能的亚族,其中R1代表芳基1或Het1,特别是任选取代的苯基,任选取代的芴基或者任选取代的含至少一个独立选自O、S、S(=O)p或N(特别是S或N)的杂原子的单环非芳族或芳族杂环;尤其是苯基或芴基,该苯基或芴基任选地被一个或二个取代基取代,该取代基独立地选自氧基、羧基、卤素、任选被羧基或C1-4烷氧羰基取代的C1-6烷基、C1-6烷氧基、C1-6烷氧羰基、氨基、芳基、Het或多卤代C1-6烷基;或者是一个4、5或6元非芳族或芳族杂环,例如氮杂环丁基、噻唑烷基、噻唑基、吡咯烷基、哌啶基,所述的5或6元杂环任选地被一或二个取代基取代,该取代基独立地选自羟基、氧基、C1-6烷基、C1-6烷氧羰基、芳基或Het。
本发明的第六实施方案是上文作为实施方案叙述的那些式(I)化合物或其任何可能的亚族,其中R2代表C3-6环烷基,苯基,2,3-二氢-1,4-苯并二氧杂环己烯基,或一个含1或2个N原子的6元芳族杂环,例如吡啶基,其中该苯基或杂环可任选地被1-4个取代基取代,优选各取代基独立地选自卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氧羰基、硝基、氨基、一或二(C1-4烷基)氨基、芳氧基、R4R3N-C1-6烷基、Het-C(=O)-C1-4烷基。
本发明的第七实施方案是上文作为实施方案叙述的那些式(I)化合物或其任何可能的亚族,其中该式(I)化合物是式(I’)化合物
其中R3a和R3b彼此独立地代表氢,羟基,羧基,卤素,C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,C1-6烷氧羰基,氰基,氨基羰基,一或二(C1-4烷基)氨基羰基,C1-6烷基羰基,硝基,氨基,一或二(C1-4烷基)氨基,-S(=O)p-C1-4烷基;其中R3c代表氢,羟基,羧基,卤素,C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,C1-6烷氧羰基(其中C1-6烷基可任选地被芳基取代),氰基,C1-6烷基羰基,硝基,氨基,一或二(C1-4烷基)氨基,-S(=O)p-C1-4烷基,R4R3N-C(=O)-,R4R3N-C1-6烷基,C3-6环烷基,芳基,芳氧基,芳基C1-4烷基,芳基-C(=O)-C1-4烷基,芳基-C(=O)-,Het,HetC1-4烷基,Het-C(=O)=C1-4烷基,Het-C(=O)-,Het-O-。
本发明的第八实施方案是如上文作为实施方案叙述的那些式(I)化合物或其任何可能的亚族,其中该式(I)化合物是式(I”)化合物
其中R3a和R3b彼此独立地代表氢,羟基,羧基,卤素,C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,C1-6烷氧羰基,氰基,氨基羰基,一或二(C1-4烷基)氨基羰基,C1-6烷基羰基,硝基,氨基,一或二(C1-4烷基)氨基,-S(=O)p-C1-4烷基;其中R3c代表氢,羟基,羧基,卤素,C1-6烷基,多卤代C1-6烷基,任选被C1-4烷氧基取代的C1-6烷氧基,C1-6烷硫基,多卤代C1-6烷氧基,C1-6烷氧羰基(其中C1-6烷基可任选地被芳基取代),氰基,C1-6烷基羰基,硝基,氨基,一或二(C1-4烷基)氨基,-S(=O)p-C1-4烷基,R4R3N-C(=O)-,R4R3N-C1-6烷基,C3-6环烷基,芳基,芳氧基,芳基C1-4烷基,芳基-C(=O)-C1-4烷基,芳基-C(=O)-,Het,HetC1-4烷基,Het-C(=O)=C1-4烷基,Het-C(=O)-,Het-O-。
本发明的第九实施方案是如上文作为实施方案叙述的那些式(I)化合物或其任何可能的亚族,其中该式(I)化合物是式(I’)或(II”)化合物,并且其中R3a和R3b彼此独立地代表卤素、C1-6烷基或C1-6烷氧基,特别是卤素或C1-6烷基,尤其是R3a和R3b都代表卤素,特别是R3a和R3b都代表氯。
本发明的第十实施方案是如上文作为实施方案叙述的那些式(I)化合物或其任何可能的亚族,其中该式(I)化合物是式(I’)或式(I”)化合物,并且其中R3c代表氨基、一或二(C1-4烷基)氨基,R4R3N-C(=O)-,R4R3N-C1-6烷基,Het-C(=O)-或HetC1-4烷基;或者R3c代表氢。
本发明的第十一实施方案是如上文作为实施方案叙述的那些式(I)化合物或其任何可能的亚族,其中p代表2。
本发明的第十二实施方案是如上文作为实施方案叙述的那些式(I)化合物或其可能的任何亚族,其中Z代表C1-6链烷二基或C2-6链烯二基,特别是C1-6链烷二基,尤其是-CH2-。
本发明的第十三实施方案是如上文作为实施方案叙述的那些式(I)化合物或其可能的任何亚族,其中Rx代表氢。
本发明的第十四实施方案是如上文作为实施方案叙述的那些式(I)化合物或其可能的任何亚族,其中Y代表-NRx-C(=O)-。
本发明的第十五实施方案是如上文作为实施方案叙述的那些式(I)化合物或其可能的任何亚族,其中Y代表-C(=O)-NRx-。
本发明的第十六实施方案是如上文作为实施方案叙述的那些式(I)化合物或其可能的任何亚族,其中R7代表氢。
本发明的第十七实施方案是如上文作为实施方案叙述的那些式(I)化合物或其可能的任何亚族,其中R7代表卤素、C1-4烷基或被羟基取代的C1-4烷基,特别是代表卤素。
本发明的第十八实施方案是如上文作为实施方案叙述的那些式(I)化合物或其可能的任何亚族,其中芳基代表苯基或者被卤素、C1-6烷基、多卤代C1-6烷基或C1-6烷氧羰基取代的苯基。
本发明的第十九实施方案是如上文作为实施方案叙述的那些式(I)化合物或其可能的任何亚族,其中Het代表一个含至少一个独立选自O、S、S(=O)p或N的杂原子的单环非芳族或芳族杂环,或含至少一个独立选自O、S、S(=O)p或N(特别是N)的杂原子的双环非芳族或芳族杂环,该单环杂环或双环杂环任选地被一个或二个取代基取代,各取代基独立地选自氧基或C1-6烷基。
本发明的第二十实施方案是如上文作为实施方案叙述的那些式(I)化合物或其可能的任何亚族,其中施加一个或多个,最好是所有的以下限制:
a)X代表-NRx-C(=O)-,-Z-NRx-C(=O)-或-NRx-C(=S)-;
b)R1代表芳基1或Het1;
c)R2代表C3-6环烷基、苯基或2,3-二氢-1,4-苯并二氧杂环己烯基,其中苯基任选地被1-4个取代基取代,各取代基独立地选自卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氧羰基、硝基、氨基、一或二(C1-4烷基)氨基、芳氧基;
d)A代表N;
e)A代表CH;
f)Z代表C1-6链烷二基或C2-6链烯二基;
g)Rx代表氢;
h)芳基1代表苯基或芴基,该苯基或芴基任选地被卤素、C1-6烷基或多卤代C1-6烷基取代;
i)Het1代表一个4、5或6元非芳族或芳族杂环,例如氮杂环丁基、噻唑烷基、噻唑基、吡咯烷基、哌啶基,所述的5或6元杂环任选地被羟基、氧基、C1-6烷基、C1-6烷氧羰基、芳基或Het取代;
j)Y代表-NRx-C(=O)-;
k)R7代表氢。
本发明的二十一实施方案是如上文作为实施方案叙述的那些式(I)化合物或其任何可能的亚族,其中施加一个或多个、最好是所有的以下限制:
a)A代表CH;
b)A代表N;
c)虚线在A代表碳原子的情形代表一个键;
d)虚线在A代表碳原子的情形不代表一个键;
e)X代表-O-C(=O)-;-NRx-C(=O)-;-Z-C(=O)-;-Z-NRx-C(=O)-;-NRx-C(=S)-;
f)Z代表C1-6链烷二基;
g)Rx代表氢;
h)Y代表-C(=O)-NRx-或-NRx-C(=O)-;
i)R1代表芳基1或Het1;
j)R2代表C3-6环烷基,苯基,2,3-二氢-1,4-苯并二氧杂环己烯基,或是一个含1或2个N原子的6元芳族杂环,其中该C3-6环烷基、苯基、2,3-二氢-1,4-苯并二氧杂环己烯基或含1或2个N原子的6元芳族杂环可任选地被至少一个,特别是1-4个取代基取代,各取代基独立地选自卤素、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氧羰基、硝基、一或二(C1-4烷基)氨基,R4R3N-C1-6烷基、芳氧基、Het-C(=O)-C1-4烷基;
k)R3代表C1-4烷基;
l)R4代表C1-4烷基;
m)R7代表氢或卤素;
n)芳基代表苯基,或被卤素、C1-6烷基、多卤代C1-6烷基、C1-6烷氧羰基取代的苯基;
o)芳基1代表苯基或芴基,该苯基或芴基均任选地被一或二个取代基取代,各取代基独立地选自氧基、羧基、卤素、任选被羧基或C1-4烷氧羰基取代的C1-6烷基、C1-6烷氧基、C1-6烷氧羰基、氨基、芳基、Het;
p)Het代表一个含至少一个独立选自O、S、S(=O)p或N的杂原子的单环非芳族或芳族杂环,或代表一个含至少一个独立选自N的杂原子的双环非芳族或芳族杂环;该单环杂环或双环杂环任选地被一或二个取代基取代,各取代基独立地选自氧基或C1-6烷基;
q)Het1代表一个含至少一个独立选自S或N的杂原子的单环非芳族或芳族杂环,该单环杂环任选地被至少一个取代基、特别是一或二个取代基取代,各取代基独立地选自羟基、氧基、C1-6烷基、C1-6烷基羰基、芳基、Het;
r)p代表2。
优选的式(I)化合物是选自以下化合物:
其N-氧化物,可药用盐或溶剂化物。
本发明的另一实施方案是如上文所示的式(I”’)化合物的应用,其中该式(I”’)化合物是其中R2代表氢、C1-6烷基或C2-6烯基的一种化合物。
以上对式(I)化合物所述的实施方案,只要可能,也适用于式(I”’)化合物。
一般,其中Y代表-NRx-C(=O)-的式(I)化合物用式(I-a)表示,它能够制备如下:式(II)中间体与式(III)中间体在合适的脱水(偶联)剂(例如,N’-(乙基碳酰亚胺基)-N,N-二甲基-1,3-丙二胺-盐酸盐(EDCI),二环己基碳化二亚胺(DCC),羰基二咪唑(CDI),六氟磷酸1-[双(二甲基氨基)亚甲基]-1H-苯并三唑鎓(1-)3-氧化物(HBTU),六氟磷酸1-[双(二甲基氨基)亚甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU),四氟硼酸O-苯并三唑基四甲基异脲鎓(TBTU)或氰基膦酸二乙酯(DECP)存在下,任选地加入羟基苯并三唑或氯羟基苯并三唑,在合适的溶剂(例如N,N-二甲基甲酰胺、四氢呋喃或二氯甲烷)存在及任选地合适的碱(例如N,N-二异丙基乙胺或N,N-二乙基乙胺)存在下反应。
以上反应能够以快速合成反应的形式进行,因而使用熟知的用于快速合成的合适试剂,例如与合适的载体(如聚苯乙烯)连接的二环己基碳化二亚胺。对于反应混合物的纯化,也可以使用合适的快速合成试剂,例如1-乙烯基-4-(异氰酸甲酯基)苯聚合物与乙烯基苯。
式(I-a)化合物也可以制备如下:式(II)中间体与式(III’)中间体(其中W代表合适的离去基团,例如卤素,如氯等)在合适的碱(例如氢化钠、碳酸氢钠、N,N-二异丙基乙胺或N,N-二乙基乙胺)和合适的溶剂(例如N,N-二甲基甲酰胺,二氯甲烷,乙腈或四氢呋喃)存在下反应
其中X代表X1-NH-C(=O)-,X1代表一个直接键或Z的式(I)化合物用式(I-b)表示,它可以通过式(IV)中间体与式(V)中间体在合适的溶剂(例如乙腈,N,N-二甲基甲酰胺或二氯甲烷,或一种醇,例如甲醇)及任选地在合适的碱(例如N,N-二乙基乙胺)存在下反应来制备。式(IV)中间体是市场上可买到的或者可以通过R2-X1-NH2与碳酰氯在合适的溶剂(例如甲苯)存在下反应制备。
以上反应也可以以快速合成反应的形式进行,因而使用熟知的用于快速合成的合适试剂,例如对于反应混合物的纯化可以使用1-乙烯基-4-(异氰酸甲酯基)苯聚合物和乙烯基苯,以及与聚苯乙烯连接的三(2-氨基乙基)胺。
其中X1代表一个直接键的式(I-b)化合物被表示成(I-b-1),它可以制备如下:式(IV’)中间体与Cl3COC(=O)-Cl或O(=O)Cl2,任选地在HCl/乙醚存在和合适的溶剂(例如甲苯或乙腈)存在下反应,接着在合适的溶剂(例如乙腈、N,N-二甲基甲酰胺或二氯甲烷)存在及任选地在合适的碱(例如N,N-二乙基乙胺或N,N-二异丙基乙胺)存在下与式(V)中间体反应。
其中X代表X1-NH-C(=S)-,X1代表一个直接键或Z的式(I)化合物用式(I-c)表示,它可以通过中间体(VI)与中间体(V)在合适的碱(例如N,N-二乙基乙胺)和合适的溶剂(例如二氯甲烷或四氢呋喃)存在下反应制备。
其中X代表-X1-C(=O)-,X1代表一个直接键或Z的式(I)化合物用式(I-d)表示,就可以制备如下:式(VII)中间体与式(V)中间体在合适的脱水(偶联)剂(例如,N’-(乙基碳酰亚胺基)-N,N-二甲基-1,3-丙二胺-盐酸盐(EDCI),二环己基碳化二亚胺(DCC),羰基二咪唑(CDI),六氟磷酸1-[双(二甲基氨基)亚甲基]-1H-苯并三唑鎓(1-)3-氧化物(HBTU),六氟磷酸1-[双(二甲基氨基)亚甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU),四氟硼酸O-苯并三唑基四甲基异脲鎓(TBTU)或氰基膦酸二乙酯(DECP)存在下,任选地加入羟基苯并三唑或氯羟基苯并三唑,在合适的溶剂(例如N,N-二甲基甲酰胺、二氯甲烷,乙腈或四氢呋喃)存在下,以及任选地在合适的碱(例如N,N’-二异丙基乙胺或N,N-二乙基乙胺)存在下反应。式(VII)中间体与式(V)中间体的这一反应也可以在合适的活化剂(例如Cl-C(=O)-C(=O)-Cl)、合适的碱(例如N,N-二乙基乙胺)及合适的溶剂(例如N,N-二甲基甲酰胺)存在下进行。
其中X1代表一个直接键的式(I-d)化合物用式(I-d-1)表示,它可以通过其中W1代表合适的离去基团(例如卤素,比如氯等)的式(VII’)中间体与式(V)中间体在合适的碱(例如N-甲基吗啉)及合适的溶剂(例如N,N-二甲基甲酰胺)存在下反应制备。
其中X代表-S(=O)p-的式(I”’)化合物用式(I”’-e)表示,它可以通过其中W3代表合适的离去基团(例如卤素,比如氯等)的式(XVII)中间体与式(V)中间体在合适的碱(例如N,N-二异丙基乙胺或N,N-二乙基乙胺)和合适的溶剂(例如二氯甲烷)存在下反应制备。
其中X代表-C(=O)-C2-6链烯二基-的式(I)化合物用式(I-f)表示,它可以通过式(XVIII)中间体与式(V)中间体在合适的溶剂(例如醇,比如乙醇)存在下反应制备。
其中R2被R4R3N-C1-6烷基取代并用-R2’-C1-6烷基-NR3R4表示的式(I)化合物用式(I-g)表示,它可以通过式(IXX)中间体(其中W4代表一个合适的离去基团,例如CH3-S(=O)2-O-)与NHR3R4在合适的溶剂(例如乙腈)存在下反应制备。式(IXX)中间体可以通过相应的OH衍生物与CH3-S(=O)2Cl在合适的碱(例如吡啶)和合适的溶剂(例如二氯甲烷)存在下反应制备。
其中R1取代基被氨基取代的式(I)化合物可以从其中氨基功能被合适的保护基团(例如叔丁氧羰基)保护的相应化合物在合适的酸(例如三氟乙酸)和合适的溶剂(例如二氯甲烷)存在下制备。该被保护的化合物可以按照上文对式(I)化合物所述的合成方法,从式(II)中间体出发制备。
其中Y代表-C(=O)-NRx-的式(I)化合物用式(I-h)表示,它可以通过式(XXV)中间体与式(XXVI)中间体在DECP、合适的碱(例如N,N-二乙基乙胺或N,N-二异丙基乙胺)及合适的溶剂(例如二氯甲烷或乙腈)存在下反应制备。
其中R7代表被羟基取代的C1-4烷基的式(I)化合物用式(I-i)表示,它可以通过式(XLIII)中间体与合适的酸(例如HCl等)在合适的溶剂(例如醇,如2-丙醇)存在下反应制备。
式(I)化合物,其中X包含Z1,该Z1是被氨基取代的Z,X可用Z1(NH2)-X2表示,其中X2代表连接基团X的其余部分,该式(I)化合物用式(I-j)表示,它可以通过式(XLIV)化合物(其中p代表一个合适的离去基团,例如叔丁氧羰基)用合适的酸(例如三氟乙酸)在合适的溶剂(例如二氯甲烷)中去保护来制备。
式(I)化合物还可以按照本领域已知的基团转化反应将式(I)化合物彼此转化来制备。
式(I)化合物可以按照本领域已知的将三价氮转化成其N-氧化物的步骤转化成相应的N-氧化物形式。该N-氧化反应一般可通过式(I)起始物与合适的有机或无机过氧化物反应进行。合适的无机过氧化物包括,例如,过氧化氢,碱金属或碱土金属过氧化物,例如过氧化钠、过氧化钾;合适的有机过氧化物可以包括过氧酸,例如,过氧化苯甲酸或卤代过氧化苯甲酸(如3-氯代过氧化苯甲酸),过氧化链烷酸(例如过氧乙酸),烷基氢过氧化物(例如叔丁基氢过氧化物)。合适的溶剂是,例如,水,低级醇(例如乙醇等)、烃类(例如甲苯)、酮类(例如2-丁酮)、卤化烃类(例如二氯甲烷),以及这些溶剂的混合物。
其中R1或R2未被取代的式(I)化合物可以通过与C1-4烷基-S(=O)p-W5(其中W5代表合适的离去基团,例如卤素,比如氯等)在合适的碱(例如N,N-二乙基乙胺)和合适的溶剂(例如乙腈)存在下反应,转化成其中R1或R2含有C1-4烷基-S(=O)p-取代基的化合物。
其中R1或R2包含一个C1-6烷氧羰基取代基的式(I)化合物,可以通过与合适的碱(例如氢氧化钠)在合适的溶剂(例如二氧杂环己烷)存在下反应,转化成其中R1或R2含有羧基取代基的式(I)化合物。
其中R1或R2包含一个C1-6烷氧羰基取代基的式(I)化合物,还可以通过与合适的还原剂(例如LiBH)在合适的溶剂(例如四氢呋喃或二氧杂环己烷)存在下反应,转化成其中R1或R2含有CH2-OH取代基的式(I)化合物。
其中R1或R2包含一个C1-6烷氧羰基取代基的式(I)化合物,还可以通过与合适的酸(例如盐酸等)反应,转化成R1或R2未被取代的式(I)化合物。
其中R1或R2包含一个C1-5烷基羰基取代基的式(I)化合物,可以通过与合适的还原剂(例如NaBH4)在合适的溶剂(例如醇,比如甲醇)存在下反应,转化成其中R1或R2含有C1-5烷基-CH(OH)-取代基的式(I)化合物。
其中R1或R2含有C1-6烷氧基取代基的式(I)化合物,可以通过与合适的还原剂(例如BBr3)在合适的溶剂(例如二氯甲烷或二氯乙烷)存在下反应,转化成其中R1或R2含OH取代基的式(I)化合物。
其中R1或R2含羟基取代基的式(I)化合物,可以转化成其中R1或R2包含Het-C(=O)-取代基的式(I)化合物,其中Het代表一个任选取代的含至少一个N原子的单环饱和杂环,该杂环通过N原子与C(=O)基团连接,这一转化是通过与所述杂环在合适的脱水(偶联)剂(例如N’-(乙基碳酰亚胺基)-N,N-二甲基-1,3-丙二胺-盐酸盐(EDCI),二环己基碳化二亚胺(DCC),羰基二咪唑(CDI),六氟磷酸1-[双(二甲基氨基)亚甲基]-1H-苯并二唑鎓(1-)3-氧化物(HBTU)或六氟磷酸1-[双(二甲基氨基)亚甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU))存在下反应完成的,可任选地加入羟基苯并三唑或氯羟基苯并三唑,反应中有合适的溶剂(例如N,N-二甲基甲酰胺、二氯甲烷、乙腈或四氢呋喃)存在,并任选地在合适的碱(例如N,N-二异丙基乙胺或N,N-二乙基乙胺)存在下进行。这一反应也可以以快速合成反应的形式进行,为此要使用用于快速合成的熟知的合适试剂,例如连接在合适载体(如聚苯乙烯)上的二环己基碳化二亚胺(DCC)或羰基二咪唑(CDI)。对于反应混合物的纯化,也可以使用合适的快速合成试剂,例如1-乙烯基-4-(异氰酸甲酯基)苯聚合物与乙烯基苯。
本发明的式(I)化合物及一些中间体可以含有不对称的碳原子。该化合物和中间体的纯立体化学异构形式可以利用本领域已知的方法得到。例如,非对映异构体可以利用物理方法,例如选择性结晶或者色谱技术(例如逆流分配法,手性液相色谱法等)来分离。对映体可以从外消旋混合物按以下方法得到:先用合适的拆解剂(例如手性酸)将所述的外消旋混合物转化成非对映异构体的盐或化合物的混合物,然后利用例如选择性结晶或色谱技术(例如液相色谱等方法)将该非对映异构体的盐或化合物的混合物物理分离,最后将分离的非对映异构体的盐或化合物转化成相应的对映体。纯立体化学异构形式也可以由纯立体化学异构形式的合适中间体和起始物得到,条件是中间反应立体专一性地进行。
分离式(I)化合物和中间体的对映异构形式的另一种方法涉及液相色谱法或SCF(超临界流体)色谱法,特别是使用手相固定相。
一些中间体和起始物是已知化合物,可能有市售商品或者可以按照本领域已知的方法制备。
其中X代表X1-NH-C(=O)-,X1代表一个直接键或Z的式(II)中间体用式(II-a)表示,它可以制备如下:式(IV)中间体与式(VIII)中间体(其中p代表一个合适的保护基团,例如叔丁氧羰基)在合适的溶剂(例如二氯甲烷)存在下反应,然后将形成的式(IX)中间体在合适的酸(例如三氟乙酸)和合适的溶剂(例如二氯甲烷)存在下去保护。在进行去保护反应之前,可以任选地将式(IX)中间体通过在合适的碱(例如NaH)和合适的溶剂(例如N,N-二甲基甲酰胺)存在下与C1-4烷基卤化物(例如CH3I)反应,转化成式(IX’)中间体。
其中Rx代表氢的式(II-a)中间体用式(II-a-1)表示,它可以制备如下:式(IV)中间体与式(X)中间体在合适的溶剂(例如二氯甲烷)存在下反应,然后将形成的式(XI)中间体在合适的催化剂(例如碳载钯或Raney镍)以及任选地合适的催化剂毒物(例如噻吩溶液)和合适的溶剂(例如四氢呋喃或醇,比如甲醇)存在下氢化(H2或N2H4·H2O)。在进行氢化反应之前,可以任选地通过在合适的碱(例如NaH)和合适的溶剂(例如N,N-二甲基甲酰胺)存在下与C1-4烷基卤化物(例如CH3I)反应,将式(XI)中间体转化成式(XI’)中间体。
其中Rx代表氢,并且X1表示一个直接键的式(II-a)中间体用式(II-a-2)表示,它可以制备如下:式(IV’)中间体与Cl3COC(=O)-Cl反应,随后与式(X)中间体在合适的碱(例如N,N-二乙基乙胺)和合适的溶剂(例如甲苯)存在下反应,接着将形成的式(XX)中间体在合适的催化剂(例如碳载钯或Raney镍)、任选地合适的催化剂毒物(例如噻吩溶液以及合适的溶剂(例如四氢呋喃或醇,比如甲醇)存在下氢化(H2或N2H4·H2O)。在进行氢化反应之前,可以任选地通过在合适的碱(例如NaH)和合适的溶剂(例如N,N-二甲基甲酰胺)存在下与C1-4烷基卤化物(例如CH3I)反应,将式(XX)中间体转化成式(XX’)中间体。
其中X代表-O-C(=O)-的式(II)中间体用式(II-b)表示,它可以制备如下:式(XXVII)中间体与式(XXVIII)中间体(其中W3代表一个合适的离去基团,例如卤素,比如氯)在NaH和合适的溶剂(例如四氢呋喃)存在下反应,随后在下一步骤中将形成的式(XXIX)产物在H2气、合适的催化剂(例如碳载粗铂)、合适的催化剂毒物(例如噻吩)和合适的溶剂(例如乙酸)存在下氢化。
式(III)中间体可以通过式(XII)中间体在合适的溶剂(例如水、四氢呋喃、二氧杂环己烷或醇,比如甲醇)存在下用合适的碱(例如氢氧化钾或氢氧化钠)水解制备。式(XII)中间体,其中R1代表Het1,Het1是被任选取代的苯基或任选取代的杂环取代的杂环,可以制备如下:被保护的杂环与任选取代的苯基在合适的催化剂(例如乙酸钯)、合适的催化剂配体(例如1,1’-(1,5-戊二基)双[1,1’-二苯基膦]、合适的碱(例如乙酸钾)和合适的溶剂)例如N-甲基吡咯烷-2-酮)存在下反应;或者使任选取代的杂环与带有合适的离去基团(例如卤素,比如溴、碘等)的任选取代的苯基反应,或与任选取代的带有合适离去基团(例如卤素,比如溴、碘等)的杂环,在合适的催化剂(例如乙酸钯)、合适的催化剂配体(例如1,3-丙二基双[二苯基膦]、合适的碱(例如乙酸钾或碳酸铯)及合适的溶剂(例如N-甲基吡咯烷-2-酮)反应。
其中Y代表-NRx-C(=O)-的式(V)中间体用式(V-a)表示,它可以制备如下:其中p代表合适的保护基团(例如苄基)的式(XIII)中间体与其中W2代表合适的离去基团(例如卤素,比如氯)的式(XIV)中间体在合适的碱(例如N,N-二乙基乙胺)和合适的溶剂(例如二氯甲烷)存在下反应,随后将形成的式(XV)中间体在合适的催化剂(例如碳载钯)和合适的溶剂(例如四氢呋喃和/或合适的醇,比如甲醇)存在下用H2去保护。
式(V-a)中间体也可以制备如下:式(XIII)中间体与式(III)中间体在合适的活化剂(例如草酰氯)、合适的碱(例如N,N-二乙基乙胺)和合适的溶剂(例如二氯甲烷或N,N-二甲基甲酰胺)存在下反应,随后将形成的式(XV)中间体在合适的催化剂(例如碳载钯)和合适的溶剂(例如四氢呋喃和/或合适的醇,比如甲醇)存在下用氢去保护。去保护反应也可以在作为去保护剂的氯甲酸1-氯乙酯和合适的溶剂(例如二氯甲烷和醇,比如甲醇)存在下进行。
式(V-a)中间体也可以按照以下反应方案制备,其中式(XXI)中间体的P代表合适的保护基团,例如苄氧羰基或叔丁氧基或苄基,W6代表合适的离去基团,例如卤素,比如氯等,使其与式(X)中间体在合适的碱(例如NaHCO3)和合适的溶剂(例如二氯甲烷)存在下反应,生成式(XXII)中间体,然后在下一步中,使式(XXII)中间体在合适的催化剂(例如碳载钯)和合适的溶剂(例如四氢呋喃和醇,比如甲醇)存在下氢化,生成式(XXIII)中间体。在下一步骤,该式(XXIII)中间体在合适的碱(例如NaHCO3)和合适的溶剂(例如乙腈)存在下与式(XIV)中间体反应,形成式(XXIV)中间体,将其在H2、合适的催化剂(例如碳载钯)、合适的溶剂(例如醇,比如甲醇)存在下,或在合适的酸(例如三氟乙酸或HCl)、合适的溶剂(例如二氯甲烷或二氧杂环己烷)存在下,或在甲酸铵、合适的催化剂(例如碳载钯)和合适的溶剂(例如醇,比如甲醇)存在下去保护。
在以上的反应方案中,式(XXIII)中间体还可以在合适的活化剂(例如SOCl2或Cl-C(=O)-C(=O)-Cl、合适的碱(例如N,N-二乙基乙胺或N,N-二异丙基乙胺)及合适的溶剂(例如二氯甲烷或N,N-二甲基甲酰胺)存在下与式(III)的中间体反应。或者,式(III)中间体可以与式(XXIII)中间体在合适的脱水(偶联)剂(例如N’-(乙基碳酰亚胺基)-N,N-二甲基-1,3-丙二胺-盐酸盐(EDCI),二环己基碳化二亚胺(DCC)、羰基二咪唑(CDI),六氟磷酸1-[双(二甲基氨基)亚甲基]-1H-苯并三唑鎓(1-)3-氧化物(HBTU),六氟磷酸1-[双(二甲基氨基)亚甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU),四氟硼酸O-苯并三唑基四甲基异脲鎓(TBTU)或氰基膦酸二乙酯(DECP))、任选加入的羟基苯并三唑或氯羟基苯并三唑、合适的溶剂(例如N,N-二甲基甲酰胺、二氯甲烷、乙腈或四氢呋喃)以及任选地合适的碱(例如N,N-二异丙基乙胺或N,N-二乙基乙胺)存在下反应。
式(XXIV)中间体也可以与C1-4烷基卤化物(例如CH3I)在合适的碱(例如NaH)和合适的溶剂(例如N,N-二甲基甲酰胺)存在下反应,形成式(XXIV’)的中间体,它可以按照上述方案去保护,形成式(V-a’)中间体。
其中Y代表-C(=O)-NRx-的式(V)中间体用式(V-b)表示,它可以制备如下:式(XXX)中间体(其中P代表一个合适的保护基团,例如苄基或叔丁氧羰基)与式(XXVI)中间体在合适的脱水(偶联)剂(例如N’-(乙基碳酰亚胺基)-N,N-二甲基-1,3-丙二胺-盐酸盐(EDCI),二环己基碳化二亚胺(DCC)、羰基二咪唑(CDI),六氟磷酸1-[双(二甲基氨基)亚甲基]-1H-苯并三唑鎓(1-)3-氧化物(HBTU),六氟磷酸1-[双(二甲基氨基)亚甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU),四氟硼酸O-苯并三唑基四甲基异脲鎓(TBTU)或氰基膦酸二乙酯(DECP))、任选地羟基苯并三唑或氯羟基苯并三唑、合适的溶剂(例如N,N-二甲基甲酰胺、二氯甲烷、乙腈或四氢呋喃)以及任选地合适的碱(例如N,N-二异丙基乙胺或N,N-二乙基乙胺)存在下反应,随后将形成的式(XXXI)中间体在合适的催化剂(例如碳载钯)和合适的溶剂(例如醇,比如甲醇)存在下用H2去保护,或者在合适的溶剂(例如醇,比如异丙醇,或二氯甲烷)存在下用合适的酸(例如HCl、三氟乙酸等)去保护。
式(IV)中间体,其中X1代表一个直接键,R2含有一个Het-C1-4烷基取代基,Het代表一个式(XXXII)表示的单环饱和含N杂环,该式(IV)中间体用式(IV-a)表示,它可以制备如下:式(XXXII)中间体与式(XXXIII)中间体在合适的脱水(偶联)剂(例如N’-(乙基碳酰亚胺基)-N,N-二甲基-1,3-丙二胺-盐酸盐(EDCI),二环己基碳化二亚胺(DCC)、羰基二咪唑(CDI),六氟磷酸1-[双(二甲基氨基)亚甲基]-1H-苯并三唑鎓(1-)3-氧化物(HBTU),六氟磷酸1-[双(二甲基氨基)亚甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU),四氟硼酸O-苯并三唑基四甲基异脲鎓(TBTU)或氰基膦酸二乙酯(DECP))、任选地羟基苯并三唑或氯羟基苯并三唑、合适的溶剂(例如N,N-二甲基甲酰胺、二氯甲烷、乙腈或四氢呋喃)以及任选地合适的碱(例如N,N-二异丙基乙胺或N,N-二乙基乙胺)存在下反应。形成的式(XXXIV)中间体随后可以在下一步中在合适的还原剂(例如硼烷)、合适的溶剂(例如四氢呋喃)存在下被还原成式(XXXV)中间体,它接着在HCl/乙醚存在下于合适的溶剂(例如甲苯或乙腈)中用碳酰氯转化成式(IV-a)中间体。
式(XXXIV)中间体也可以在HCl/乙醚和合适的溶剂(例如甲苯或乙腈或二氯甲烷)存在下用碳酰氯转化成式(IV-b)中间体。
式(IV-a)中间体也可以通过式(XXXII)中间体与式(XXXVI)中间体(其中W4代表一个合适的离去基团,例如卤素,比如氯等)在合适的溶剂(例如乙腈)存在下反应制备,形成的式(XXXV’)中间体可以如上文对中间体(XXXV)所述转化成式(IV-a)中间体。
式(VII)中间体可以通过式(XL)中间体在LiOH、酸(例如HCl)和合适的溶剂(例如醇,比如甲醇)存在下水解来制备。其中R2含有Het-C1-4烷基作为取代基的式(XL)中间体用式(XL-a)表示,它可以通过式(XLI)中间体(其中W5代表一个合适的离去基团,例如卤素,比如溴等)与式(XXXII)中间体反应制备。如下所述的式(XLI-a)中间体可以通过式(XLII)中间体与N-溴代丁二酰亚胺在2,2’-(1,2-二氮亚烯基)双[2-甲基丙腈]及合适的溶剂(例如CCl4)存在下反应来制备。其中X1代表CH2的式(XLII)中间体用式(XLII-a)表示,它可以通过式(XLV)中间体与金属钠在合适的C1-4烷基-OH存在下反应后加入合适的酸(例如硫酸)来制备。式(XLV)中间体可以通过式(IV’-a)中间体与1,1-二甲基乙基亚硝酸酯、CuCl2、1,1-二氯乙烯在合适的溶剂(例如乙腈)中反应制备。
其中X代表-X1-HN-C(=O)-的式(XXV)中间体用式(XXV-a)表示,它可以通过式(XXXVII)中间体在合适的碱(例如氢氧化钠)、合适的溶剂(例如二氧杂环己烷)存在下水解制备。式(XXXVII)中间体可以通过中间体(IV)与式(XXXVIII)中间体在合适的碱(例如N,N-二乙基乙胺)和合适的溶剂(例如二氯甲烷)存在下反应制备。
其中X代表-X1-C(=O)-的式(XXV)中间体用式(XXV-b)表示,它可以通过式(XXXVII-a)中间体在合适的碱(例如氢氧化钠)和合适的溶剂(例如二氧杂环己烷以及任选地一种醇,例如甲醇)存在下水解得到。式(XXXVII-a)中间体可以制备如下:式(IX)中间体与式(XXXVIII)中间体在合适的脱水(偶联)剂(例如N’-(乙基碳酰亚胺基)-N,N-二甲基-1,3-丙二胺-盐酸盐(EDCI),二环己基碳化二亚胺(DCC)、羰基二咪唑(CDI),六氟磷酸1-[双(二甲基氨基)亚甲基]-1H-苯并三唑鎓(1-)3-氧化物(HBTU),六氟磷酸1-[双(二甲基氨基)亚甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU),四氟硼酸O-苯并三唑基四甲基异脲鎓(TBTU)或氰基膦酸二乙酯(DECP))、任选地羟基苯并三唑或氯羟基苯并三唑、合适的溶剂(例如N,N-二甲基甲酰胺、二氯甲烷、乙腈或四氢呋喃)以及任选地合适的碱(例如N,N-二异丙基乙胺或N,N-二乙基乙胺)存在下反应。
式(XLIII-a)中间体可以按照以下反应方案制备。在第一步中,其中W12代表一个合适的离去基团(例如氟)的式(XLVI)中间体与3,4-二氢-2H-吡喃在4-甲基苯磺酸和合适的溶剂(例如二氯甲烷)的存在下反应,形成式(XLVII)中间体。该中间体在下一步中与式(XLVIII)中间体(其中P代表一个合适的离去基团,例如苄基)在Na2CO3和合适的溶剂(例如N,N-二甲基甲酰胺)存在下反应,形成式(XLIX)中间体。接着,该中间体在合适的催化剂(例如碳载铂)、催化剂毒物(例如噻吩)和合适的溶剂(例如四氢呋喃)存在下用H2氢化,形成式(L)中间体。该中间体随后与式(III)中间体在合适的脱水(偶联)剂(例如N’-(乙基碳酰亚胺基)-N,N-二甲基-1,3-丙二胺-盐酸盐(EDCI),二环己基碳化二亚胺(DCC)、羰基二咪唑(CDI),六氟磷酸1-[双(二甲基氨基)亚甲基]-1H-苯并三唑鎓(1-)3-氧化物(HBTU),六氟磷酸1-[双(二甲基氨基)亚甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU),四氟硼酸O-苯并三唑基四甲基异脲鎓(TBTU)或氰基膦酸二乙酯(DECP))、任选地羟基苯并三唑或氯羟基苯并三唑、合适的溶剂(例如N,N-二甲基甲酰胺、二氯甲烷、乙腈或四氢呋喃)以及任选地合适的碱(例如N,N-二异丙基乙胺或N,N-二乙基乙胺)存在下反应。式(L)中间体与式(III)中间体的这一反应也可以在合适的活化剂(例如Cl-C(=O)-C(=O)-Cl、合适的碱(例如N,N-二乙基乙胺)和合适的溶剂(例如N,N-二甲基甲酰胺)存在下进行。此反应可以以快速合成反应的形式进行,为此使用熟知的用于快速合成的合适试剂,例如与合适载体(如聚苯乙烯)连接的二环己基碳化二亚胺(DCC)。对于反应混合物的纯化,也可以使用合适的快速合成试剂,例如1-乙烯基-4-(异氰酸甲酯基)苯聚合物与乙烯基苯。在下一步骤,式(L1)中间体在合适的催化剂(例如碳载钯)、合适的碱(例如N,N-二乙基乙胺)和合适的溶剂(例如四氢呋喃)存在下用H2去保护,形成式(LII)中间体,它在下一步中与式(IV)中间体在合适的溶剂(例如二氯甲烷)存在下反应,得到式(XLIII-a)中间体。
式(XLIV-a)中间体可以制备如下:式(VII)中间体,其中X1被一个被保护的(P,例如叔丁氧羰基)氨基取代,该中间体用式(XII-a)表示,将其与式V中间体在合适的脱水(偶联)剂(例如N’-(乙基碳酰亚胺基)-N,N-二甲基-1,3-丙二胺-盐酸盐(EDCI),二环己基碳化二亚胺(DCC)、羰基二咪唑(CDI),六氟磷酸1-[双(二甲基氨基)亚甲基]-1H-苯并三唑鎓(1-)3-氧化物(HBTU),六氟磷酸1-[双(二甲基氨基)亚甲基]-5-氯-1H-苯并三唑鎓(1-)3-氧化物(HCTU),四氟硼酸O-苯并三唑基四甲基异脲鎓(TBTU)或氰基膦酸二乙酯(DECP))、任选地羟基苯并三唑或氯羟基苯并三唑、合适的溶剂(例如N,N-二甲基甲酰胺、二氯甲烷、乙腈或四氢呋喃)以及任选地合适的碱(例如N,N-二异丙基乙胺或N,N-二乙基乙胺)存在下反应。
其中X1代表CHOH的式(VII)中间体用式(VII-b)表示,它可以通过式(LIII)中间体在ZnBr2、Si(CH3)3-CN和酸(例如HCl)以及合适的溶剂(例如二氯甲烷)存在下还原得到。式(LIII)中间体可以通过式(LIV)中间体(其中W13代表一个合适的离去基团,例如卤素,比如溴等)与N,N-二甲基甲酰胺在BuLi和合适的溶剂(例如四氢呋喃)存在下反应制备。
药理学部分
如上所述,本发明涉及DGAT抑制剂,特别是DGAT1抑制剂,在提高一种或多种饱感激素的水平,特别是提高GLP-1水平方面的应用。本发明还涉及DGAT抑制剂,特别是DGAT1抑制剂,在制造用于抑制或治疗,特别是治疗能够从一种或多种饱感激素的水平升高中受益的疾病,尤其是治疗能够从GLP-1水平升高中受益的疾病的药物方面的应用。具体地说,血浆中或门静脉血中,尤其是血浆中的GLP-1水平得到提高。所谓GLP-1水平升高,例如GLP-1血浆水平升高或门静脉血中GLP-1水平升高,是指服用DGAT1抑制剂的实验对象的GLP-1水平比在相同条件下未服用DGAT1抑制剂的实验对象升高或增加。特别是,在禁食条件下或饭后,尤其是饭后,GLP-1水平升高。
升高GLP-1水平的化合物的治疗用途包括,但不限于,改善学习能力,增强神经保护作用,和/或缓解中枢神经系统的疾病或障碍的症状(例如通过调节神经发生)以及例如帕金森病、阿尔兹海默病、享廷顿病、ALS、中风、出血、脑血管意外、ADD和神经精神综合症的症状;将肝干细胞/祖细胞转化成功能性胰腺细胞;防止β细胞退化和刺激β细胞增殖;治疗胰腺炎;治疗肥胖症;抑制食欲和诱发饱感;治疗肠易激综合症或炎性肠病,例如节段性回肠炎和溃疡性结肠炎;降低与心肌梗死和中风有关的发病率和/或死亡率;治疗以无Q波心肌梗死为特征的急性冠状动脉综合症;减缓手术后的分解代谢变化;治疗冬眠心肌或糖尿病心肌病;抑制去甲肾上腺素的血浆血水平;增加尿钠排泄,降低尿钾浓度;治疗与中毒性血容量过多有关的状况或障碍,例如肾衰竭、充血性心力衰竭、肾病综合症、肝硬化、肺水肿和高血压;诱发变力响应和增大心收缩力;治疗多囊性卵巢综合症;治疗呼吸窘迫;通过非饮食途径,即,经由静脉内、皮下、肌内、腹膜内或其它注射或输入途径,改善营养状况;治疗肾病;治疗左心室收缩机能不良,例如,左心室收缩期射血分数异常;抑制胃窦十二脂肠活动性,例如,治疗或预防胃肠道障碍,例如腹泻、手术后倾倒综合症或肠易激综合症,以及作为内窥镜术前的前驱给药;治疗临界病性多发性神经病(CIPN)和全身炎性响应综合症(CIRS);调节甘油三酯水平和治疗血脂异常;治疗由缺血后血流再灌注引起的器官组织损伤(例如脑组织损伤);改善缺血和再灌注的脑组织的功能;治疗冠心病危险因子(CHDRF)综合症。能够从GLP-1的水平升高受益的其它疾病包括,但不限于,缺血性心肌顿抑;缺血/再灌注损伤;急性心肌梗死;左心室机能不良;血管病;神经病;包括与II型糖尿病有关的外周感受神经病;与骨有关的障碍,包括骨质疏松、肥胖症、糖尿病。因为对GLP-1的作用,DGAT抑制剂还可用于提供心脏保护作用。
支持以上说明的参考文献包括Experimental Neurology,Vol.203(2),pp293-301(2007);US7,186,683;J.Pharm.Exp.Ther.vol.312,No.1,pp 303-308(2005);Diabetes,vol.54,pp 146-151(2005);US2007/0021339,它们以参考引用的方式并入本文。
鉴于所述的DGAT抑制活性,特别是DGAT1抑制活性,本发明的式(I)化合物,其N-氧化物形式,可药用盐或溶剂化物,可以作为药物使用。特别是,本发明涉及作为药物使用的式(I)化合物,其中N-氧化物形式、可药用盐或溶剂化物,尤其是作为药物用于预防或治疗能够从GLP-1水平升高受益的疾病。特别是,本发明还涉及式(I)化合物制造药物的用途,该药物用于预防或治疗能够从GLP-1水平升高受益的疾病,例如上述的疾病和障碍。
鉴于DGAT抑制剂,特别是DGAT1抑制剂的上述应用,提供了一种治疗患有可以从GLP-1的水平升高受益的疾病的温血动物(包括人)的方法,或者一种预防温血哺乳动物(包括人)患上该疾病的方法,特别是一种治疗患有可以从GLP-1的水平升高受益的疾病的温血哺乳动物(包括人)的方法。所述方法包括向温血哺乳动物(包括人)施用有效数量的DGAT抑制剂,尤其是DGAT1抑制剂。
鉴于式(I)化合物的DGAT抑制活性,提供了一种治疗患有能够从GLP-1水平升高中受益的疾病的温血哺乳动物(包括人)的方法,或者一种预防温血哺乳动物(包括人)患上该疾病的方法,特别是一种治疗患有能够从GLP-1的水平升高中受益的疾病的温血哺乳动物(包括人)的方法。所述方法包括向温血哺乳动物(包括人)施用有效数量的式(I)化合物、其N-氧化物形式、可药用的盐或溶剂化物。
鉴于DGAT抑制活性,特别是DGHT1抑制活性,本发明还涉及一种式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物作为药物使用,特别是作为药物用于预防或治疗能够从抑制DGAT,特别是抑制DGAT1中受益的疾病。本发明还涉及式(I)化合物、其N-氧化物形式、可药用的盐或溶剂化物在制造用于预防或治疗能够从抑制DGAT(特别是DGAT1)中受益的疾病或障碍的药物中的应用。能够从抑制DGAT1,特别是抑制DGAT1中受益的疾病或障碍包括,但不限于,代谢障碍,例如肥胖症和与肥胖有关的障碍(包括外周血管病,心力衰竭,心肌缺血、脑缺血、心肌病),糖尿病,特别是II型糖尿病,以及由其引起的并发症(例如视网膜病、神经病、肾病),X综合症,胰岛素抗性,葡萄糖耐量受损,空腹血糖受损的状况,低血糖症,高血糖症,高尿酸血症,高胰岛素血症,胰腺炎,高胆固醇血症,高脂血症,血脂异常,混合型血脂异常,高甘油三酯血症和非酒精性脂肪肝病,脂肪肝,肠系膜脂肪增多,非酒精性脂肪肝炎,肝纤维化,代谢性酸中毒,酮体症,代谢障碍综合症;皮肤病症状,例如痤疮、牛皮癣;心血管病,例如动脉粥样硬化、动脉硬化、急性心力衰竭、充血性心力衰竭、冠状动脉病、心肌病、心肌梗死、心绞痛、高血压、低血压、中风,局部缺血,缺血再灌注损伤,动脉瘤,再狭窄和血管狭窄;肿瘤性疾病,例如实体肿瘤、皮肤癌、黑素瘤、淋巴瘤和内皮癌,比如,乳腺癌、肺癌、结直肠癌、胃癌、胃肠道的其它癌症(例如食管癌和胰腺癌)、前列腺癌、肾癌、肝癌、膀胱癌、宫颈癌、子宫癌、睾丸癌和卵巢癌;以及对于DGAT功能,特别是DGAT1功能的调节(特别是抑制)敏感或易起反应的其它疾病和状况。
可以从抑制DGAT,特别是抑制DGAT1中受益的具体疾病是选自肥胖症、高胆固醇血、高脂血、血脂异常、混合型血脂异常、高甘油三酯血、脂肪肝、非酒精性脂肪肝病、肝纤维化、非酒精性脂肪肝炎和糖尿病,特别是II型糖尿病。
鉴于式(I)化合物的DGAT抑制活性,提供了一种治疗患有能够从抑制DGAT中受益的疾病的温血哺乳动物(包括人)的方法,或预防温血哺乳动物(包括人)患上该病的方法。特别是治疗患有能够从抑制DGAT中受益的疾病的温血哺乳动物(包括人)的方法。所述方法包括向温血哺乳动物(包括人)施用有效量的式(I)化合物,其N-氧化物形式,可药用的盐或溶剂化物。
本发明还提供了用于预防或治疗可以从GLP-1水平升高或者从抑制DGAT(特别是DGAT1)中受益的疾病,特别是用于治疗可以从GLP-1水平升高或抑制DGAT(特别是DGAT1)中受益的疾病的组合物。该组合物含有治疗有效量的式(I)化合物、其N-氧化物形式、可药用的盐或溶剂化物,及可药用的载体。
本发明化合物可以配制成用于给药的各种药物形式。作为合适的组合物可以提到的是通常用于全身给药药物的所有各种组合物。为制备本发明的药物组合物,将作为活性成分的有效数量的特定化合物(任选地以盐形式)与可药用的载体结合成紧密的混合物,该载体可根据打算施用的制剂的形式采用各式各样的形式。这些药物组合物最好是适合(尤其是)口服、经直肠、透皮或肠道外注射给药的单元剂型。例如,在制备口服剂型的组合物时,在口服液体剂型例如混悬剂、浆剂、酏剂、乳剂和溶液剂的情形,可以使用任何常用的药用介质,例如,水、二醇类、油类、醇类等;或者在粉剂、丸剂、胶囊剂和片剂的情形,使用固体载体,例如淀粉、糖、高岭土、稀释剂、润滑剂、粘合剂、崩解剂等。因为容易服用,片剂和胶囊剂代表最方便的口服剂量单元形式,此时显然使用固体药物载体。对于肠道外组合物,载体通常包括无菌水(至少是大部分),但是可以包含其它成分,例如提高溶解度的成分。例如,可以配制注射溶液剂,其中载体包括盐水溶液,葡萄糖溶液或盐水和葡萄糖溶液的混合物。还可以配制可注射的混悬剂,此时可以使用合适的液体载体、悬浮剂等。还包括打算在使用前不久转化成液体形式制剂的固体形式制剂。在适合透皮给药的组合物中,载体任选地含有一种渗透增强剂和/或合适的润湿剂,任选地加入对皮肤不产生明显有害作用的任何性质的少量的合适添加剂。所述添加剂可以方便对皮肤施药和/或可以帮助配制所要的组合物。这些组合物可以以各种方式施用,例如,以透皮贴剂、点施剂或软膏剂的形式。
本发明的化合物也可以通过吸入或吹入的方式,利用在经由这一方式给药的领域使用的方法和制剂给药。例如,本发明化合物一般可以以溶液、悬浮液或干粉的形式向肺部施用。任何研制用来经由口腔或鼻吸入或吹入的释放溶液、悬浮液或干粉的系统,都适合本发明化合物的施用。
本发明化合物也可以以滴剂(特别是滴眼剂)的形式局部施用。所述的滴眼剂可以是溶液或悬浮液的形式。作为滴眼剂研发的用于递送溶液或悬浮液的任何系统都适合本发明化合物的施用。
将上述药物组合物配制成单元剂型特别方便,因为易于给药和剂量均一。这里所说的单元剂型是指适合作为单元剂量的物理上分离的单元,各单元含有经计算能产生预期疗效的预定数量的活性成分和与其结合的所需要的药物载体。这些单元剂型的实例是片剂(包括划痕或包衣片剂)、胶囊剂、丸剂、粉末包装、糯米纸囊剂、栓剂、注射用的溶液剂或混悬剂等,及其分离的多重剂型。
正如本领域技术人员所熟知的,准确的剂量和服药频率取决于使用的具体式(I)化合物,治疗的具体病症,所治疗病症的严重情况,具体患者的年龄、体重、性别、异常程度和一般健康状况,以及患者可能服用的其它药物。另外,所述的有效日剂量显然可以根据所治疗的对象的反应和/或根据开具本发明化合物处方的医师的判断而减小或增大。
根据给药方式,药物组合物优选含有0.05-99%重量,更优选0.1-70%,最好是0.1-50%的式(I)化合物,和1-99.95%、优选30-99.9%、更优选50-99.9%的可药用载体,所有百分数均以组合物的总重量为基础。
鉴于上述的DGAT抑制剂作用和/或DGAT抑制剂对GLP-1水平的作用,本发明还涉及:
a)DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,与二肽基肽酶-4抑制剂(DPP-4抑制剂)的联合。
DPP-4是广泛表达在很多组织,例如肝、肺、肾、肠刷状缘膜、淋巴细胞、内皮细胞中的一种跨膜细胞表面氨肽酶。DPP-4裂解在氨基端第二位含脯氨酸或丙氨酸残基的肽。很多胃肠激素是DPP-4的底物,其中包括GLP-1。因此,DPP-4抑制剂会抑制GLP-1的裂解,从而增加GLP-1的水平。于是,可以利用上述的联合将DGAT抑制剂的活性和DPP4抑制剂的活性相结合,以便升高GLP-1水平。与DPP4抑制剂一起施用DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物,其N-氧化物、可药用盐或溶剂化物,可以瞄准不同的机制以便实现GLP-1水平的升高。用这种方式,使用这样一种联合可以将为了升高GLP-1水平所需要的DGAT抑制剂和DPP4抑制剂的剂量,降低到低于DGAT抑制剂或DPP4抑制剂以单药治疗时的施用量。因此,这种联合可以减小或者消除单疗治疗的副作用,同时不干扰升高GLP-1水平的活性。
另外,DGAT抑制剂,特别是DGAT1抑制剂,尤是式(I)化合物、其N-氧化物形式、可药用的盐或溶剂化物,与DPP4抑制剂的联合可以作为药物使用。本发明还涉及一种产品,其中含有(a)一种DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物,其N-氧化物形式、可药用盐或溶剂化物,和(b)一种DPP4抑制剂,作为同时、分别或顺序使用的联合制剂,用于治疗能够从GLP-1水平升高中受益的疾病。这样一种联合或产品中的不同药物可以与可药用的载体一起结合成单一的制剂,或者它们可以各自与可药用的载体结合,存在于不同的制剂中。可以与本发明的DGAT抑制剂,特别是DGAT1抑制剂联合的该DPP4抑制剂可以是已知的DPP4抑制剂,例如西格列汀、维格列汀和沙格列汀。
b)DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,与GLP-1类似物的联合。该GLP-1类似物可以认为是DLP-1受体的激动剂。
同样,DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,与GLP-1类似物的联合可以作为药物使用。本发明还涉及一种产品,其中含有(a)一种DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,和(b)一种GLP-1类似物,作为同时、分别或顺序使用的联合制剂,用于治疗能够从GLP-1的水平升高受益的疾病。这样一种联合或产品中的不同的药物可以与可药用的载体一起结合成单一的制剂,或者它们可以各自与可药用的载体结合,存在于不同的制剂中。
可以与本发明的DGAT抑制剂联合的GLP-1类似物可以是已知的GLP-1类似物,例如艾塞那肽、长效缓释艾塞那肽或利拉糖肽。
c)DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,与抗糖尿病药物的联合。
同样,DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物,其N-氧化物形式、可药用盐或溶剂化物与抗糖尿病药的联合可以作为药物使用,本发明还涉及一种产品,其中含有:(a)一种DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,和(b)一种抗糖尿病药,作为同时、分别或顺序使用的联合制剂,用于治疗能够从GLP-1的水平升高或抑制DGAT中受益的疾病,例如糖尿病,特别是II型糖尿病。这样一种联合或产品中的不同药物可以与可药用的载体一起结合成单一的制剂,或者它们可以分别与可药用的载体结合,存在于不同的制剂中。可以与本发明的DGAT抑制剂联合的抗糖尿病药物可以是已知的抗糖尿病药,例如二甲双胍、格列本脲、罗格列酮、吡格列酮、瑞格列奈、格列美脲、阿卡波糖、格列齐特、格列吡嗪、那格列奈、甲苯磺丁脲、一种蛋白质酪氨酸磷酸酶1抑制剂或者11-β-羟基类固醇脱氢酶抑制剂。
d)DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,与磷酸二酯酶(PDE)抑制剂,特别是是PDE10A或PDE11A抑制剂的联合。磷酸二酯酶(PDE)抑制剂,特别是PDE10A或PDE11A抑制剂,已知是胰岛素促分泌剂,并通过抑制cAMP的水解增强GLP-1的信号传输。
同样,DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,与磷酸二酯酶(PDE)抑制剂,特别是PDE10A或PDE11A抑制剂的联合,能够作为药物使用。本发明还涉及一种产品,其中含有:(a)一种DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,和(b)一种磷酸二酯酶(PDE)抑制剂,特别是PDE10A或PDE11A抑制剂,作为同时、分别或顺序使用的联合制剂,用于治疗能够从GLP-1或DGAT抑制中受益的疾病,例如糖尿病,特别是II型糖尿病,或肥胖症。这样一种联合或产品中的不同药物可以与可药用的载体一起结合成单一的制剂,或者它们可以分别与可药用的载体结合,存在于不同的制剂中。所述的可以与本发明的DGAT抑制剂联合的磷酸二酯酶(PDE)抑制剂,特别是PDE10A或PDE11A抑制剂,可以是已知的PDE抑制剂,例如罂粟碱、PQ-10、潘生丁、异丁司特或他达拉非。
e)DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,与食欲抑制剂的联合。
同样,该DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物与食欲抑制剂的联合能作为药物使用。本发明还涉及一种产品,其中含有:(a)一种DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,和(b)一种食欲抑制剂,作为同时、分别或顺序使用的联合药物用于治疗能够从GLP-1水平升高或抑制DGAT中受益的疾病,例如糖尿病,特别是II型糖尿病,或肥胖症。这样一种联合或产品中的不同药物可以与可药用的载体一起结合成单一的制剂,或者它们可以分别与可药用的载体结合,存在于不同的制剂中。可以与本发明的DGAT抑制剂联合的食欲抑制剂可以是已知的食欲抑制剂,例如西布曲明和芬特明。
f)DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,与具有CNS(中枢神经系统)作用模式的减肥药(例如CB1拮抗剂或反向激动剂)的联合。
同样,DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物与具有CNS(中枢神经系统)作用模式的减肥药的联合,可以作为药物使用。本发明还涉及一种产品,其中含有:(a)一种DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,和(b)一种具有CNS(中枢神经系统)作用方式的减肥药,作为同时、分别或顺序使用的联合药物,用于治疗能够从GLP-1水平升高或DGAT抑制中受益的疾病,例如糖尿病,特别是II型糖尿病,或肥胖症。这样一种联合或产品中的不同药物可以与可药用的载体一起结合成单一的制剂,或者它们可以分别与可药用的载体结合,存在于不同的制剂中。可以与本发明的DGAT抑制剂联合的具有CNS(中枢神经系统)作用模式的减肥药可以是已知的减肥药,例如利莫纳班、奥利司他、SLV-319或MK-0364。
g)DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,与降血脂药,例如3-羟基-3-甲基戊二酸单酰辅酶A(HMG-CoA)还原酶抑制剂、角鲨烯合酶抑制剂、FXR(类法尼醇X受体)和LXR(肝X受体)配体、消胆胺、贝特类、烟酸及阿斯匹林的联合。
同样,DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物和降血脂药的联合可以作为药物使用。本发明还涉及一种产品,其中含有:(a)DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,和(b)一种降脂药物,作为同时、分别或顺序使用的联合药物,用于治疗能够从GLP-1的水平升高或抑制DGAT中受益的疾病,例如糖尿病,特别是II型糖尿病,或肥胖症。这样一种联合或产品中的不同药物可以与可药用的载体一起结合成单一的制剂,或者它们可以分别与可药用的载体结合,存在于不同的制剂中。可以与本发明的DGAT抑制剂联合的降血脂药物可以是已知的降血脂药,例如,洛伐他汀、普伐他汀、辛伐他汀、西立伐他汀、美伐他汀、velostatin、氟伐他汀、达伐他汀、阿托伐他汀、罗苏伐他汀和西立伐他汀钠。
h)DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,和过氧化物酶体增殖物激活剂受体激动剂(例如非诺贝特)的联合。
同样,DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物和过氧化物酶体增殖物激活剂受体的激动剂(例如非诺贝特)的联合可以作为药物使用。本发明还涉及一种产品,其中含有:(a)一种DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,和(b)一种过氧化物酶体增殖物激活剂受体的激动剂(例如非诺贝特),作为同时、分别或顺序使用的联合制剂,用于治疗能够从GLP-1的水平升高或抑制DGAT中受益的疾病,例如糖尿病,特别是II型糖尿病,或肥胖症。这样一种联合或产品中的不同药物可以与可药用的载体一起结合成单一的制剂,或者它们可以分别与可药用的载体结合,存在于不同的制剂中。
i)DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,与抗高血压药的联合。
同样,DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物与抗高血压药的联合可以作为药物使用。本发明还涉及一种产品,其中含有:(a)一种DGAT抑制剂,特别是DGAT1抑制剂,尤其是式(I)化合物、其N-氧化物形式、可药用盐或溶剂化物,和(b)一种抗高血压药,作为同时、分别或顺序使用的联合制剂,用于治疗能够从GLP-1水平升高或抑制DGAT中受益的疾病,例如糖尿病,特别是II型糖尿病,或肥胖症。这样一种联合或产品中的不同药物可以与可药用的载体一起结合成单一的制剂,或者它们可以分别与可药用的载体结合,存在于不同的制剂中。可以与本发明的DGAT抑制剂联合的抗高血压药可以是已知的抗高血压药,例如,髓袢利尿剂(比如依他尼酸、呋塞米和托塞米),血管紧张素转化酶(ACE)抑制剂(比如,贝那普利、卡托普利、依那普利、福新普利、赖诺普利、莫昔普利、培哚普利、喹那普利、雷米普利和群多普利);钠钾ATP酶膜泵的抑制剂,例如地高辛;中性内肽酶(NEP)抑制剂;ACE/NEP抑制剂,例如奥马曲拉、山帕曲拉和法西多曲;血管紧张素II拮抗剂,例如坎地沙坦、依普罗沙坦、厄贝沙坦、氯沙坦、替米沙坦和缬沙坦,特别是缬沙坦;肾素抑制剂,例如地替吉仑、占吉仑、特拉吉仑、阿利结仑、RO66-1132和RO-66-1168;β-肾上腺素能受体阻断剂,例如,醋丁洛尔、阿替洛尔、倍他洛尔、比索洛尔、美托洛尔、纳多洛尔、普萘洛尔、索他洛尔和噻吗洛尔;变力剂,例如地高辛、多巴酚丁胺和米力农;钙通道阻断剂,例如氨氯地平、苄普地尔、地尔硫、非洛地平、尼卡地平、尼莫地平、硝苯地平、尼索地平和维拉帕米;醛固酮受体拮抗剂;和醛固酮含酶抑制剂。
以下实施例旨在示例说明本发明。
实验部分
在下文中,术语“m.p.”指熔点,“THF”指四氢呋喃,“EtOAc”指乙酸乙酯,“MeOH”指甲醇,“DIPE”指二异丙基醚,“DMF”指N,N-二甲基甲酰胺,“Et3N”指三乙胺,“DPPENT”指1,1’-(1,5-戊二基)双[1,1’-二苯基膦],“连接-N=C=O的树脂”是指用异氰酸基功能化的聚苯乙烯基树脂,例如1-乙烯基-4-(异氰酸甲酯基)苯聚合物与乙烯基苯,“PS-碳化二亚胺”指与聚苯乙烯树脂结合的N-环己基碳化二亚胺,“PS-NMM”是指3-(吗啉基)丙基聚苯乙烯磺酰胺(一种结合等当量N-甲基吗啉的树脂),“PS-TsOH”指聚苯乙烯-对甲苯磺酸,“PS-Trisamine”指三(2-氨乙基)氨基甲基聚苯乙烯HL(200-400目),“DECP”指氰基膦酸二乙酯,“Et2O”指乙醚,“p.a.”指分析用,“eq”指当量,“DIPEA”指二异丙基乙胺,“TFA”指三氟乙酸,“TBTU”指四氟硼酸O-苯并三唑基四甲基异脲鎓,“MP-carbonate”指大孔的三乙铵甲基聚苯乙烯碳酸酯(一种大孔的聚苯乙烯阴离子交换树脂,它是结合了等当量碳酸四烷基铵的一种树脂)。
ArgScoopTM树脂(Biotage)分配器是一种设计用于聚合物净化剂和反应试剂的适当分配的容积可变的树脂收集器。
MiniBlockTM(Mettler Toledo)是设计用于平行合成的一种灵活的容易使用的工具。
A.中间体的制备
实施例A1
a.中间体1的制备
将[4-(4-哌啶基)苯基]氨基甲酸1,1-二甲基乙酯(0.025mol)在CH2Cl2(100ml)中的混合物于冰浴上冷却并搅拌,逐滴加入1,3-二氯-2-异氰酸基苯(0.027mol)在CH2Cl2(25ml)中的溶液。将反应混合物温热至室温,在室温下搅拌1小时。滤出形成的沉淀,用DIPE洗并且干燥。产量:6.2g中间体1。蒸发相应的滤液溶剂。残余物用DIPE湿磨,过滤并干燥。产量:4.2g中间体1。
b.中间体2的制备
将中间体1(按照A1.a制备)(0.022mol)和三氟乙酸(25ml)在CH2Cl2(250ml)中的混合物于室温下搅拌2小时。蒸发溶剂。残余物用DIPE湿磨,过滤并干燥。将此级分(11.2g)通过加入氨水转化成游离碱。用CH2Cl2萃取该混合物。将分离的有机层干燥,过滤,蒸除溶剂。产量:7.6g中间体2。
c.中间体3的制备
将2-[[1,1-二甲基乙氧基)羰基]氨基]苯甲酸(0.001mol)溶在DMF(5ml)中得到储备溶液(I)。将一部分储备溶液(I)(1.2ml,含0.00024mol 2-[[1,1-二甲基乙氧基)羰基]氨基]苯甲酸)倒入MiniBlock中。用ArgoScoop加入PS-碳化二亚胺(1.9mmol/g,0.0004mol)。加入1-羟基-1H-苯并三唑(0.00030mol)在DMF(1ml)中的溶液,将混合物摇动30分钟。加入中间体2(按照A1.b制备)(0.0002mol)在DMF(3.5ml)中的溶液,将反应混合物摇动过夜。用ArgoScoop加入MP-Carbonate(2.8mmol/g,0.00090mol)和连接N=C=O的树脂(1.8mmol/g)(0.0002mol)。将反应混合物摇动过夜,然后过滤。加入CH2Cl2(4mL),将混合物摇动2小时。将混合物过滤,蒸发滤液的溶剂(溶剂蒸发器)。残余物(±0.120g)用HPLC纯化。收集产物级分并进行后处理。产量:0.008g中间体3。
实施例A2
a.中间体4的制备
将1-(4-硝基苯基)哌嗪(0.02413mol)在CH2Cl2p.a.(100ml)中的混合物于冰浴上搅拌。然后逐滴加入1,3-二氯-2-异氰酸基苯(0.02660mol)在CH2Cl2p.a(20ml)中的溶液,同时将反应混合物在冰浴上搅拌。将反应混合物温热至室温并在室温下搅拌2小时。滤出反应混合物,用DIPE(适量)洗。将沉淀真空干燥。产量:8.923g中间体4(94%,黄色粉末)。
b.中间体5的制备
将中间体4(按照A2.a制备)(0.047mol)在MeOH(200ml)、THF(200ml)和NH3/MeOH(100ml)中的混合物在室温下搅拌15分钟,然后在室温(大气压力)下用Pt/C 5%(4g)作为催化剂,于噻吩溶液(3ml,4%DIPE溶液)存在下氢化。在吸收H2(3当量)之后,滤除催化剂(产物也是沉淀,因此通过用CH2Cl2洗过滤残留物将其溶解)。蒸除合并的滤液的溶剂。产量:14.616g中间体5。
实施例A3
a.中间体6的制备
将2-甲基-4-噻唑羧酸乙酯(0.1mol)、1-碘代-4-(1-甲基乙基)苯(0.3mol)、KOAc(0.3mol)、Pd(OAc)2(0.005mol)和DPPENT(0.001mol)在1-甲基-2-吡咯烷酮(150ml)中的混合物于140℃搅拌24小时。将反应混合物倒入水中,用EtOAc萃取4次。将有机层合并,用水洗2次,干燥,过滤,蒸发溶剂。产量:中间体6(粗品,用于下一反应步骤,不作进一步纯化)。
b.中间体7的制备
将中间体6(按照A3.a制备)(约0.1mol,粗品)在H2O(500ml)和MeOH(500ml)中的混合物于室温下搅拌。分批加入KOH(0.3mol),将反应混合物在室温下搅拌一个周末,蒸发溶剂。残余物溶在水中,将该混合物用CH2Cl2洗3次,分离各层。将水相酸化至pH=3。该酸性混合物用CH2Cl2萃取4次。将分离的有机层干燥,过滤,蒸发溶剂。残余物(21g)用HPLC纯化(梯度洗脱,使用(0.5%的NH4OAc水溶液/CH3CN90/10)/MeOH/CH3CN)。收集产物级分,蒸发溶剂。残余物溶在水中,酸化至pH=2-3。该混合物用CH2Cl2萃取。将分离的有机层干燥,过滤,蒸发溶剂。将残余物(10g)在DIPE中搅拌,过滤和干燥。产量:中间体7(粗品,原样用于下一反应步骤)。
实施例A4
a.中间体8的制备
将4-[4-(苯甲基)-1-哌嗪基]苯胺(0.185mol)在CH2Cl2p.a(1500ml)和Et3N(50ml)中的混合物在冰浴上搅拌5分钟。逐滴加入4’-(三氟甲基)-[1,1’-联苯基]-2-羰基氯(0.37mol)。将混合物搅拌3小时,有机层用水洗,干燥,蒸发溶剂。残余物在DIPE中湿磨。滤出沉淀物将其干燥。产量:99.8g中间体8(100%)。
b.中间体9和10的制备
中间体9
中间体10(HCl盐(1∶1))
将中间体8(按照A4.a制备)(0.19mol)在MeOH(600ml)和THF(600ml)中的混合物以Pd/C 10%(3g)作为催化剂氢化过夜。在吸收H2(1当量)之后,滤出催化剂,将滤液蒸发。残余物在DIPE中湿磨。滤出沉淀并且干燥。产量:76g(94%)。将一部分该化合物按照本领域已知的方法转化成盐酸盐,得到中间体10(HCl盐)。(此级分的一部分(1g)自2-丙醇中重结晶,滤出沉淀和干燥,产量:0.36g中间体10)。余下的粗产物溶在水中,用Na2CO3将该混合物碱化,然后用CH2Cl2萃取。分离有机层,干燥,蒸发溶剂。残余物在DIPE中湿磨。滤出沉淀并干燥之。产量:中间体9。
实施例A5
a.中间体11的制备
将[4’-(三氟甲基)-[1,1’-联苯基]-2-羧酸(0.09mol)在CH2Cl2(500ml)和DMF(5ml)中的混合物搅拌,逐滴加入乙二酰二氯(0.09mol)。将该混合物搅拌1小时(混合物A)。将4[1-(苯甲基)-4-哌啶基]苯胺盐酸盐(0.046mol)在CH2Cl2(500ml)和Et3N(20ml)中于冰浴上搅拌,并将此混合物加到混合物A中。将反应混合物搅拌和回流过夜,然后冷却,用水洗。分离有机层,干燥,过滤,蒸发溶剂。残余物在硅胶上用柱色谱法纯化(洗脱剂:CH2Cl2/CH3OH 98/2)。收集所要的产物级分,蒸发溶剂。残余物在DIPE中湿磨。滤出沉淀,干燥。产量:5.6g中间体11。
b.中间体12的制备
将中间体11(按照A5.a制备(0.025mol)在CH3OH(250ml)中的混合物用Pd/C 10%(2g)作为催化剂在50℃氢化过夜。在吸收H2(1当量)之后,滤出催化剂,蒸发滤液。残余物在DIPE中湿磨。滤出沉淀,干燥。产量:7.7g中间体12(73%)。
实施例A6
a.中间体13的制备
在搅拌下向4-[1,2,3,6-四氢-1-(苯甲基)-4-吡啶基]苯胺(按照WO2002/081460中的说明制备,其内容以参考引用的方式并入本文)(0.095mol)在CH2Cl2p.a.(300ml)和Et3N(50ml)中的混合物逐滴加入[4’-(三氟甲基)-1,1’-联苯基]-2-羰基氯(0.12mol)。将混合物搅拌过夜,倒入水中后搅拌30分钟。分离有机层,洗涤,干燥,过滤和蒸发溶剂。残余物在DIPE中湿磨。滤出沉淀并干燥之。产量:43g(88%)。一部分(2g)该级分自乙醇中重结晶。滤出沉淀将其干燥。产量:1.32g中间体13。
b.中间体14的制备
在搅拌下向中间体13(按照A6.a制备)(0.039mol)在1,2-二氯乙烷(500ml)中的混合物逐滴加入氯甲酸1-氯乙酯(0.078mol)。将混合物搅拌30分钟,然后搅拌和回流过夜。蒸发溶剂,加入CH3OH(500ml)。将混合物搅拌和回流过夜。蒸发溶剂。残余物在DIPE中湿磨。滤出沉淀干燥。产量:20.8g中间体14(HCl盐)。
实施例A7
a.中间体15的制备
将2-碘苯甲酸甲酯(0.20mol)、2-乙基-4-甲基噻唑(0.20mol)、Pd(OAc)2(1120g)、1.3-丙二基双[二基基膦](4.120g)和Cs2CO3(65g)在1-甲基-2-吡咯烷酮(200ml)中的混合物于140℃搅拌36小时。加入更多的Cs2CO3(32.5g)和2-碘苯甲酸甲酯(0.1mol)及催化剂,将反应混合物在140℃搅拌16小时。将反应混合物倒入水中,用EtOAc萃取。有机层合并后用水洗,干燥,过滤,蒸发溶剂。产量:中间体15(粗品,原样用于下一反应步骤)。
b.中间体16的制备
将中间体15(按照A7.a制备)(0.00765mol)在THF(20ml)、CH3OH(20ml)和NaOH(1N,20ml)中的混合物于室温下搅拌16小时。蒸发溶剂,残余物溶于水中。将该混合物用CH2Cl洗3次,分层各层。水相用1N HCl(20ml)酸化。酸化的混合物用CH2Cl2萃取。将分离的有机层干燥,过滤,蒸发溶剂。残余物在DIPE中搅拌,过滤后干燥。产量:0.450g中间体16。
实施例A8
a.中间体17的制备
将2-甲基-4-噻唑羧酸乙酯(0.054mol)、5-溴-1,3-苯并二氧杂环戊烯(0.18mol)、Pd(OAc)2(1.041g)、1,3-丙二基双[二苯基膦](3.831g)和KOAc(18.6g)在1-甲基-2-吡咯烷酮(30ml)中的混合物于140℃搅拌16小时。将反应混合物倒入水中,用EtOAc萃取。合并的有机层用水洗,干燥,过滤,蒸发溶剂。产量:中间体17(粗品,原样用于下一反应步骤)。
b.中间体18的制备
将中间体17(按照A8.a制备)(0.054mol)在CH3OH(100ml)和1N NaOH(100ml)中的混合物于室温下搅拌16小时。蒸发溶剂,残余物溶在水中。用CH2Cl2洗该混合物2次。分离各层,水相用1N HCl(100ml)中和。该混合物用CH2Cl2萃取3次,分离的有机层干燥后过滤,蒸发溶剂。产量:2.5g中间体18。
中间体2-甲基-5-(3-三氟甲基苯基)噻唑-4-羧酸
相应地制备(见B1.b)
实施例A9
a.中间体19的制备
将3-吡咯烷-1-基苯胺(8g,0.0478mol)溶在CH2Cl2(50ml)中,先加入Et3N(25ml,0.178mol),然后加入4-[4-(苯甲基)-1-哌嗪基]苯甲酸(11.27g,0.038mol)和更多的CH2Cl2(100ml),最后加入DECP(11.37ml,0.0761mol),将反应混合物搅拌18小时。随后,将该混合物在NaHCO3溶液中搅拌。分离各层,将有机层干燥(MgSO4),过滤,将溶剂蒸发,并用甲苯共蒸发。残余物在硅胶上用柱色谱法纯化(洗脱剂:CH2Cl2/MeOH 98/2)。收集最纯的级分,蒸发溶剂。残余物在乙醚中搅拌,过滤,用乙醚洗。将产物干燥(50℃,48小时,真空中)。产量:9.437g中间体19(55%)。
b.中间体20的制备
将Pd/C(10%,1g)在N2气流下悬浮于MeOH(150ml)中。加入中间体19(5.62g,0.0126mol),将反应混合物在50℃于H2气氛下搅拌,直至吸收了1当量H2。在硅藻土上滤出催化剂。蒸发溶剂并用甲苯共蒸发。残余物在乙醚中搅拌,过滤。将产物真空干燥(50℃,18小时)。产量:4.23g中间体20(96%)。
实施例A10
a.中间体21的制备
向4-氨基-3,5-二氯苯乙酸(2.86g,0.013mol)中加入CH2Cl2(75ml),搅拌该混合物。加入Et3N(5.5ml,0.0391mol)和吡咯烷(1.3ml,0.0158mol),最后加DECP(2.5ml,0.015mol)。将反应混合物在N2气流下放置几分钟,然后关闭该容器。18小时后加入NaHCO3溶液,分离各层。将分离出的有机层干燥(MgSO4),过滤,蒸发溶剂,并用甲苯共蒸发。残余物(4.317g)用柱色谱法在硅胶上纯化(洗脱剂:CH2Cl2/MeOH 97/3)。收集所要的级分,蒸发溶剂并用甲苯共蒸发。产量:3.104g中间体21(88%)。
b.中间体22的制备
向中间体21(2.88g,0.0105mol)在THF(60ml,无水)中的溶液加入硼烷的THF溶液(30ml,0.03mol,1M溶液),将反应混合物回流18小时。随后将该混合物冷却至室温,在搅拌下加到在冰浴上冷却的水(300ml)和浓盐酸(300ml)的溶液中。将该混合物回流30分钟后,放在冰浴上冷却,慢慢加入K2CO3粉末使该混合物碱化。在pH 8时向混合物中加入CH2Cl2和H2O(用于萃取)。分离各层,将有机层干燥(MgSO4),过滤,蒸发溶剂,并用甲苯共蒸发。残余物在乙醚中搅拌,用1N HCl萃取此混合物2次。将HCl层合并,用NaHCO3中和至pH 8,用CH2Cl2和H2O萃取。分离各层,有机层用MgSO4干燥,过滤,蒸发溶发并用甲苯共蒸发。将残余物干燥(50℃,18小时,真空下)。将产物在乙醚中与HCl/乙醚(15ml,1M)一起搅拌。滤出产物,用乙醚洗,得到3.05g中间体22(98%;HCl)。
c.中间体23的制备
将中间体22(3g,0.0101mol)于室温下溶在HCl/乙醚溶液(10ml,0.01mol;1M溶液)和CH3CN(150ml,无水)中。将该混合物搅拌30分钟,分批加入20%碳酰氯/甲苯(7.6ml,0.0152mo1),将混合物搅拌20小时,过滤,蒸发该混浊的滤液并用甲苯(无水)共蒸发,得到2.89g粗品中间体23(定量产率,HCl盐)。
实施例A11
a.中间体24和25的制备
中间体24(游离碱)
中间体25(.HCl)
在搅拌下向吡咯烷(15.84g,0.223mol)在CH3CN(250ml)中的溶液分批加入2,6-二氯-4-氯甲基苯胺(11g,0.0445mol)。将反应混合物置于水浴中(放热反应)。蒸发溶剂,残余物溶在CH2Cl2(150ml)和50%饱和的NaHCO3溶液(100ml)中。搅拌该混合物15分钟。分离有机层,干燥(MgSO4),过滤,蒸发溶剂并用甲苯共蒸发。将油质残余物(11.46g)在DIPE(30ml)中搅拌15分钟,然后将DIPE再蒸发。残余物与2.65g另一批合并,将整个粗品产物在硅胶上用柱色谱法纯化(洗脱剂:CH2Cl2/MeOH 95/5)。将纯级分合并,蒸发溶剂并用甲苯共蒸发。残余物在DIPE(25ml)中搅拌。从固体中倒出DIPE,得到DIPE层(*)和固体。将残留在固体上的DIPE蒸发,并将固体在50℃真空干燥,得到2.75g中间体24(28.18%)。将流出柱子的不纯级分合并,蒸发溶剂并用甲苯共蒸发。将残余物(7.45g)溶在DIPE(20ml)中,加入6N的HCl/2-丙醇(5ml)并激烈搅拌。形成了浅黄色油状物,它在连续搅拌后变成固体。滤出该固体,用DIPE洗,得到滤液(*)和固体。将固体在50℃真空干燥。产量:5.19g中间体25(41.37%,盐酸盐)。将滤液(*)和DIPE层(*)合并,蒸发溶剂。残余物(2.59g)溶于CH2Cl2和NaHCO3水溶液中。分离各层,将有机层干燥(MgSO4),过滤,将溶剂蒸发一部分。浓缩的溶液在硅胶上再纯化(洗脱剂:CH2Cl2/MeOH 95/5)。收集纯级分,蒸发溶剂并用甲苯共蒸发。将残余物干燥(50℃,18小时,真空)。产量:1.85g中间体24(17%)。
b.中间体26的制备
在搅拌下向中间体24(4.6g 0.0188mol)在CH3CN(75ml,p.a.在分子筛上干燥)和CH2Cl2(10ml,p.a.)中的溶液加入HCl/Et2O(10.32ml,0.0206mol,1M),将混合物搅拌1小时,形成了沉淀。将反应混合物在冰浴上冷却,加入20%碳酰氯/甲苯(14.073ml),搅拌3小时。加入另一份20%碳酰氯/甲苯(7ml),将反应混合物于室温下再搅拌18小时。将产物过滤,用CH3CN洗3次,在50℃真空干燥1小时,得到5.45g中间体26(94%,盐酸盐)。此中间体立即用于下一反应步骤(吸湿性中间体)。
c-1.中间体27的制备
在搅拌下向中间体26(4.9g,0.0159mol)和CH2Cl2(100ml)的混合物中加入1-(4-乙氧羰基苯基)哌嗪(3.732g,0.0159mol)。加入Et3N(4.478ml),将该溶液在室温下搅拌18小时。然后用NaHCO3饱和水溶液洗该混合物,干燥(MgSO4),过滤,蒸发溶剂。残余物在Et2O中搅拌,滤出固体,用乙醚洗3次,在50℃真空干燥。产量:6.55g中间体27(81%)。
c-2.中间体37的制备
在搅拌下向1-(4-硝基苯基)哌嗪(5g,24mmol)在Et3N(10ml,7.2mmol)和CH2Cl2(125ml,p.a.)中的溶液分批加入中间体26(约24mmol,粗品)(温度接近约30℃)。将反应混合物在室温下搅拌4小时,然后用水洗。将分离的有机层干燥(MgSO4),过滤,蒸发溶剂。残余物在硅胶上过滤(洗脱剂:CH2Cl2/MeOH 96/4)。将最纯的级分合并,蒸发溶剂并用甲苯共蒸发。残余物在DIPE中搅拌,过滤和干燥(50℃,真空)。产量:2.9g中间体37。
d-1.中间体28的制备
向1,4-二氧杂环己烷(75ml)中加入中间体27(5.88g,0.0116mol),搅拌该混合物。加入NaOH溶液(35ml,0.035mol,1M),将混合物在室温下搅拌72小时。随后加入MeOH(25ml),再搅拌72小时。然后加入HCl(35ml,1N),将混合物搅拌18小时。滤出固体,用水洗。将固体干燥(50℃,24小时,真空)。产量:4.88g中间体28(88%)。
d-2.中间体38的制备
将中间体37(2.19g,0.00458mol)在乙酸(125ml)中的溶液在噻吩溶液(0.3ml,4%DIPE溶液)存在下用Pt/C 5%(0.5g)作为催化剂氢化。在吸收3当量H2后,滤出催化剂。蒸发溶剂(40℃水浴),残余物在CH2Cl2中搅拌,用半饱和的NaHCO3水溶液洗该溶液。将有机层干燥(MgSO4),过滤,蒸发溶剂。残余物在硅胶上纯化(洗脱剂:CH2Cl2/MeOH 93/7)。将所要的级分合并,蒸发溶剂并用甲苯共蒸发,得到中间体38。
实施例A12
a.中间体29的制备
在室温和搅拌下,向1-叔丁氧羰基-4-(4-氨基苯基)哌嗪(15.12g,0.0545mol)和3-(1-吡咯烷基)苯甲酸(11.47g,0.06mol)在Et3N(23ml,0.164mol)和CH2Cl2(200ml)中的溶液加入DECP(12.5ml,0.0836mol)。20小时后,加入NaHCO3饱和溶液,分离各层。将CH2Cl2层干燥(MgSO4),过滤,蒸发溶剂并用甲苯共蒸发。残余物在乙醚中搅拌,过滤,用乙醚洗后干燥(50℃,20小时,真空)。产量:24.682g中间体29(90%)。
b.中间体30的制备
在室温和搅拌下,向中间体29(15g,0.03mol)在CH2Cl2(50ml)中的溶液加入TFA(25ml)。18小时后将溶剂蒸发。残余物在水和CH2Cl2中搅拌,用Na2CO3粉末和NaHCO3中和至混合物呈碱性。将反应混合物搅拌48小时,然后分离各层。将有机层干燥(MgSO4),过滤,蒸发溶剂并用甲苯共蒸发。将残余物在DIPE中搅拌,过滤,干燥(50℃,18小时,真空)。随后,将产物在CH3CN中回流,冷却至室温,滤出固体并干燥之(50℃,18小时,真空)。产量:8.580g中间体30(75%)。
实施例A13
a.中间体31的制备
向4-氨基-3,5-二氯苯乙酸(0.754g,0.00343mol)中加入CH2Cl2(25ml),将混合物搅拌。加入Et3N(1.45ml,0.0103mol)和1-甲基哌嗪(0.46ml,0.00415mol)。加入DECP(0.65ml,0.00391mol),用N2吹洗该混合物后关掉。将反应混合物在室温下搅拌72小时。随后,将混合物在NaHCO3饱和水溶液中搅拌,分离各层。将有机层干燥(MgSO4),过滤,蒸发溶剂并用甲苯共蒸发。残余物在CH2Cl2和K2CO3饱和水溶液中搅拌,分离各层(加入额外量的H2O以便更好地分离)。将CH2Cl2层干燥(MgSO4),过滤,蒸发溶剂并用二甲苯共蒸发。残余物溶在DIPE中,加入HCl/2-丙醇(3ml,6N)。将混合物搅拌15小时,然后滤出固体,用DIPE洗,在50℃真空干燥1小时。产量:1.3g中间体31(99%,HCl盐)。
b.中间体32的制备
在0℃下将中间体31(1.3g,0.00384mol)溶于HCl/乙醚(4.2ml,0.0042mol,1M溶液)和CH3CN(20ml,无水)中。在搅拌下加入20%的碳酰氯/甲苯溶液(5.8ml,0.0116mol)。2小时后撤除冰浴,将混合物在室温下搅拌50小时。加入额外量的20%碳酰氯/甲苯溶液(1.92ml),将混合物搅拌36小时。然后加入第三份20%碳酰氯/甲苯溶液(1ml),将混合物搅拌18小时。蒸发溶剂并用无水甲苯共蒸发。残余物(1g粗品中间体32,定量产率,盐酸盐)原样直接用于下一反应步骤。
实施例A14
a.中间体33和33’的制备
中间体33 中间体33′
在搅拌下于水浴中向1-甲磺酰基哌嗪(2.971g,0.0181mol)和二异丙基胺(8.2ml,0.058mol)在CH3CN(100ml)中的溶液分批加入2,6-二氯-4-氯甲基苯胺(3.68g,0.0149mol)。将反应混合物在室温下搅拌18小时。产物用反相高效液相色谱法(ShandonC18BDS(碱钝化硅胶)8μm,250g,I.D.5cm)纯化。使用有3个流动相的梯度。相A:90%(0.5%NH4OAc水溶液)+10%CH3CN;相B:CH3OH;相C:CH3CN)。收集不同的产物级分进行后处理。蒸发溶剂并用甲苯共蒸发,得到2.24g中间体33’和0.732g所要的中间体33(18%)。
b.中间体34的制备
将中间体33(0.732g,0.00266mol)溶在HCl乙醚溶液(3.2ml,0.0032mol,1M)和CH3CN(20ml,无水)中,室温下搅拌该混合物30分钟。然后分批加入20%碳酰氯/甲苯溶液(2ml,0.004mol,2M)。将反应混合物搅拌3小时,然后蒸发溶剂并用无水甲苯共蒸发。残余物(盐酸盐形式的粗品中间体34)溶在CH2Cl2中,该溶液立即用于下一反应步骤。
实施例A15
a.中间体35的制备
在N2气氛和搅拌下,向2,6-二氯苯酚在THF(50ml,p.a.在分子筛上干燥)中的溶液分批加入NaH(0.396g,0.0099mol,60%)。将该混合物搅拌15分钟,然后加入4-(4-硝基苯基)-1-哌嗪羰基氯(0.89g,0.0033mol)。室温下继续搅拌反应混合物1小时,然后回流18小时。将混合物冷却至室温并倒入冰水(200ml)中。搅拌该混合物15小时,然后滤出产物,用水洗,在50℃真空干燥。产量:1.3g中间体35(99%)。
b.中间体36的制备
将中间体35(1.3g,0.00328mol)在乙酸(50ml)和噻吩溶液(6.901mol,0.00328mol,4%DIPE溶液)中的溶液用Pt/c 5%(0.3g)作为催化剂氢化。在吸收了当量H2之后,滤出催化剂。将滤液蒸发并用甲苯共蒸发2次。残余物溶在CH2Cl2中,用NaHCO3饱和水溶液洗该溶液。分离各层,将有机层干燥(MgSO4),过滤,蒸发溶剂并用甲苯共蒸发。将残余物在乙醚中搅拌,过滤,用乙醚洗3次。产物在50℃真空干燥。产量:0.94g中间体36。
实施例A16
a.中间体39的制备
2,6-二氯-4-甲基苯乙酸甲酯(10.27g,0.044mol)溶在100ml CCl4中,然后加入N-溴代丁二酰亚胺(0.053mol)和2,2’-(1,2-二氮亚烯基)双[2-甲基丙腈](0.0022mol),将形成的混合物回流10小时。将溶液冷却,流过一个硅胶层。用CCl4(约100ml)和己烷(约200ml)洗该硅胶。合并的滤液减压浓缩,得到的残余物在冷却后变成晶体(12.85g)。自己烷中重结晶后得到10.30g中间体39。
b.中间体40的制备
中间体39(8.682g)和吡咯烷(6.86ml)混合并在90-100℃加热5分钟。加50ml水,形成的混合物用CH2Cl2(3×50ml)萃取。将合并的有机层分离,用硫酸钠干燥,减压蒸发。得到的残余物(8.178g,棕色油状物)用HCl乙醚溶液(2M,25ml)处理,得到半晶态的沉淀。倒出多余的HCl乙醚溶液,加入一些乙醚(约30ml),在搅拌下逐滴加入一些丙酮直至形成晶状产物。滤出形成的沉淀,用丙酮洗,空气干燥。产量:5.347g中间体40(盐酸盐)。
c.中间体41的制备
将中间体40(5.00g,14.76mmol)和LiOH·H2O(1.24g,29.53mmol)溶在水(20ml)和甲醇(40ml)的混合物中,回流20分钟。然后加入3ml浓盐酸,将混合物减压浓缩。加入5ml浓盐酸,形成的悬浮液用丙酮(约20ml)稀释。将该悬浮液回流5分钟,冷却至室温。滤出形成的浅黄色晶状产物,用丙酮洗,空气中干燥。产量:3.791g中间体41(盐酸盐)(79%)。
实施例A17
a.中间体42的制备
将4-(4-氨基苯基)-1-哌嗪羧酸1,1-二甲基乙基酯(1.00g,3.61mmol),1,3-苯二甲酸1-甲酯(4.33mmol),四氟硼酸O-苯并三唑基四甲基异尿鎓(TBTU)(5.03mmol)和Et3N(1.50ml,10.7mmol)在CH3CN(10ml)中混合,并在室温下搅拌5分钟。从反应混合物中过滤出晶体产物,用水洗,在空气中干燥。产量:1.262g中间体42(80%)。
b.中间体43的制备
向中间体42(1.262g,2.87mmol)和15ml二氧杂环己烷的混合物中加入4N的HCl/1,4-二氧杂环己烷溶液(5ml,20mmol)。形成的浆体在45-50℃搅拌30分。将该混合物冷却至室温,滤出晶态产物,用丙酮、己烷洗,真空干燥。产量:1.118g中间体43(95%,二盐酸盐)。
B.最终化合物的制备
实施例B1
a.化合物1的制备
将1-(1,1-二甲基乙基)-1,3-氮杂环丁烷二羧酸酯(0.001mol)溶在DMF(5ml)中得到储备溶液(I)。一部分储备溶液(I)(1.2ml,含0.00024mol 1-(1,1-二甲基乙基)-1,3-氮杂环己烷二羧酸酯)倒入MiniBlock中。用ArgoScoop加入PS-碳化二亚胺(1.9mmol/g)(0.0004mol)。加入1-羟基-1H-苯并三唑(0.00030mol)在DMF(1ml)中的溶液,将混合物摇动30分钟。加入中间体2(按照A1.b制备)(0.0002mol)在DMF(3.5ml)中的溶液,将反应混合物摇动过夜。用ArgoScoop加入MP-carbonate(2.8mmol/g,0.00090mol)和连接NCO的树脂(1.8mmol/g)(0.0002mol)。将反应混合物摇动过夜,然后过滤。加入CH2Cl2(4ml),将混合物摇动2小时。将该混合物过滤,蒸发滤液的溶剂(溶剂蒸发器)。残余物(±0.120g)用HPLC纯化。收集产物级分并进行后处理。产量:0.014g化合物1。
b.化合物2的制备
将中间体7(按照A3.b制备)(0.00012mol)溶在DMF(1.2ml)中。加入PS-碳化二亚胺(2.1mmol/g)(0.0002mol)和1-羟基-1H-苯并三唑(0.00015mol)。将反应混合物摇动30分,加入中间体5(按照A2.b制备)(0.0001mol)在DMF(2ml)中的溶液。将反应混合物摇动过夜。加入MP-Carbonate(6.2mmol/g)(0.00045mol)和连接-N=C=O的树脂。室温下摇动该混合物过夜。将混合物过滤,加入CH2Cl2(2ml),摇动混合物1小时,然后再过滤。蒸发滤液的溶剂(溶剂蒸发器)。不纯的残余物用HPLC法纯化。收集产物级分并进行后处理。产量:0.0128g化合物2。
化合物65按照上述步骤制备,只是反应物中间体7应当用2-甲基-5-(3-三氟甲基苯基)噻唑-4-羧酸(按照A8.b制备)代替。
化合物18按照上述步骤制备,只是反应物中间体7应当用中间物16(按照A7.b制备)代替。
c.化合物3的制备
将中间体7(按照A3.b制备)(0.00012mol)溶在DMF(1.2ml)中,加入PS-碳化二亚胺(2.1mmol/g)(0.0002mol)和1-羟基-1H-苯并三唑(0.00015mol)。将反应混合物摇动30分。加入中间体2(按照A1.b制备)(0.0001mol)在DMF(2ml)中的溶液。将反应混合物摇动过夜。加入MP-Carbonate(6.2mmol/g)(0.00045mol)和连接-N=C=O的树脂(0.0001mol)。室温下摇动混合物过夜。将混合物过滤,加入CH2Cl2(2ml)。将混合物摇动1小时,然后再过滤。蒸发滤液的溶剂(溶剂蒸发器)。不纯的残余物用HPLC法纯化。收集产物级分并作后处理。产量:0.015g化合物3。
化合物54按照上述步骤制备,但是反应物中间体7应当用2-甲基-5-(3-三氟甲基苯基)噻唑-4-羧酸(按照A8.6制备)代替。
化合物55按照上述步骤制备,但是反应物中间体7应当用中间体18(按照A8.b制备)代替。
d.化合物4的制备
向2-(2-呋喃基)苯甲酸在DMF(1.2ml)中的溶液加入PS-碳化二亚胺和1-羟基-1H-苯并三唑在DMF(1ml)中的溶液,然后在室温下摇动1小时。接着向反应混合物中加入中间体5(按照A2.b制备)在DMF(1ml)中的溶液。将反应混合物在室温下摇动过夜,加入MP-Carbonate(适量)和连接N=C=O的树脂聚合物(适量)并再次摇动过夜。将反应混合物过滤形成滤液F1。残余物在CH2Cl2(3ml)中摇动2小时。将混合物过滤,形成滤液F2。F1和F2合并,蒸发溶剂。残留物用反相高效液相色谱法(ShandonC18BDS(碱钝化硅胶)8μm,250g,I.D.5cm)纯化。使用具有所述流动相的梯度(相A:(0.5%NH4OAc水溶液)/CH3CN 90/10);相B:CH3OH(任选的);相C:CH3CN。收集所要的产物级分并作后处理。产量:0.002g化合物4。
实施例B2
a.化合物5的制备
将异氰酸甲酯基环己烷(0.00011mol)溶在DMF(3ml)中,加入中间体9(按照A4.b制备)(0.0001mol)。将反应混合物在室温下摇动2小时。加入PS-Trisamine(3.2mmol/g)(0.0001mol)和连接树脂的-N=C=O(1.8mmol/g)(0.0001mol)。将反应混合物在室温下摇动过夜,过滤后加入CH2Cl2(2ml)。将该混合物摇动1小时,过滤,蒸发滤液的溶剂。产量:0.051g化合物5。
b.化合物6的制备
将中间体9(按照A4.b制备)(0.00023mol)和PS-NMM(2.03mmol/g)(0.00023mol)在DMF(3ml)中的混合物搅拌15分钟。加入2,6-二氯苯甲酰氯(0.00035mol)在DMF(1ml)中的溶液,将混合物搅拌2小时。加入更多的PS-NMM(2.03mmol/g,Argonaut)(0.05g),将混合物搅拌10分钟。加入额外的2,6-二氯苯甲酰氯,室温下搅拌反应混合物过夜。加入PS-Trisamine(4.35mmol/g,Novabiochem)(0.0002mol),将混合物搅拌4小时。将反应混合物过滤,滤液与PS-TsOH(0.1g)一起搅拌过夜。将混合物过滤,滤液用HPLC法在Purospher Star RP-18(20g,5μm;洗脱剂:((0.5%NH4OAc水溶液)/CH3CN90/10)/CH3OH/CH3CN,0分钟:75/25/0;10.00分:0/50/50;16.00分:0/0/100;18.10-20分:75/25/0)上纯化。收集所要的级分,蒸发有机溶剂。浓缩的水溶液用CH2Cl2萃取,蒸发溶剂。产量:0.127g化合物6。
c.化合物7的制备
将1-异氰酸基-2-甲基苯(0.00011mol)溶于DMF(3ml),加入中间体12(按照A5.b制备)(0.0001mol)。将反应混合物在室温下摇动2小时,加入PS-Trisamine(0.0001mol,3.2mmol/g)和连接树脂的-N=C=O(1.8mmol/g)(0.0001mol)。将反应混合物在室温下摇动过夜,过滤,加入2ml CH2Cl2。将混合物摇动1小时,过滤,蒸发滤液中的溶剂。不太纯的残余物用HPLC纯化。收集产物级分并作后处理。产量:0.0048g化合物7。
实施例B3
a.化合物8的制备
将中间体9(按照A4.b制备)(0.00023mol)和Et3N(0.1mol)在CH2Cl2(5ml)中的混合物搅拌至完全溶解。加入1,3-二氯-2-异硫代氰酸基苯(0.0003mol),将混合物摇动过夜。用NH4Cl饱和水溶液(2ml)洗该混合物,经Extrelut过滤,蒸发萃取液的溶剂。残余物用HPLC在Hyperprep RP-C18BDC(100g,1008μm;洗脱剂:[(0.5%NH4OAc水溶液)/CH3CN 90/10]/CH3OH/CH3CN,0分钟:75/25/10;10分钟:0/50/50;16分:0/0/100;18.10-20.00分:75/25/0)上纯化。收集纯级分并作后处理。产量:0.059g化合物8。熔点:224.5℃。
b.化合物9的制备
将中间体9(按照A4.b制备)(0.00023mol)和Et3N(0.1ml)在无水CH2Cl2(5ml)中的混合物搅拌至完全溶解。加入1,3-二氯-2-异氰酸基苯(0.0003mol),将反应混合物摇动过夜,然后过滤,沉淀用CH2Cl2洗后干燥。产量:0.104g化合物9。熔点:289.0℃。
实施例B4
化合物10的制备
三氟乙酸盐
将中间体3(按照A1.c制备)(约0.0002mol,粗品中间体)和三氟乙酸(0.2ml)在CH2Cl2(2ml)中的混合物在室温下摇动4小时。蒸发部分溶剂(溶剂蒸发器)。向浓缩液中加入甲苯,将该混合物在旋转蒸发仪上共沸蒸馏。产量:0.008g化合物10。
实施例B5
化合物11的制备
向中间体5(按照A2.b制备)(0.000275mol)、1-甲基-5-氧代-3-吡咯烷羧酸(0.000275mol)、1-羟基-1H-苯并三唑(0.000028mol)和N-乙基-N-(1-甲基乙基)-2-丙胺(0.000329mol)在于3分子筛上干燥过的THF(5ml)中的混合物加入N’-(乙基碳酰亚胺基)-N,N-二甲基-1,3-丙二胺-盐酸盐(0.000302mol),然后在室温下搅拌64小时。在N2气下蒸发溶剂,残留物在CH3OH(5ml)和水(5ml)中搅拌,然后加热至沸。令混合物在不搅拌的情况下冷却至室温,滤出沉淀,用CH3OH洗,真空干燥过夜。产量:0.082g化合物11。
实施例B6
化合物129的制备
将中间体20(0.55g,1.569mmol)(按照A9.b制备)溶于Et3N(1.1ml)和CH2Cl2(50ml)。加入粗品中间体23(0.448g)(按照A10.c制备)和CH2Cl2(100ml)。将反应混合物搅拌48小时,然后在饱和NaHCO3水溶液中搅拌。加入CH2Cl2/MeOH(90/10)和水,分离各层。将分离的有机层干燥(MgSO4),过滤,蒸发溶剂。残余物在DIPE中搅拌后过滤。产物用EtOH和DIPE洗1次。将产物在50℃真空干燥18小时。产量:0.727g化合物129(73%)。
实施例B7
化合物130的制备
在室温和搅拌下向中间体28(0.57g,0.00119mol)(按照A11.d-1制备)和3-(1-吡咯烷基)苯胺(0.25g,0.00143mol)在Et3N(0.671ml,0.00478mol)和CH2Cl2(35ml)中的溶液加入DECP(0.357ml,0.00239mol)。48小时后,加入另一份DECP(0.0893ml),将混合物在室温下搅拌3小时。再加入Et3N(0.336ml),将混合物搅拌18小时。加入饱和NaHCO3水溶液,搅拌该混合物。分离各层,将CH2Cl2层用MgSO4干燥,过滤,蒸发溶剂并用甲苯共蒸发。残余物用快速色谱法纯化(硅胶,洗脱剂:CH2Cl2/MeOH,从99/1至97/3)。收集所要的级分,蒸发溶剂。残余物(0.491g)用反相高效液相色谱法纯化(ShandonC18BDS(碱钝化硅胶)8μm,250g,I.D.5cm)。采用有3个流动相的梯度。相A:90%的0.5%NH4OAc水溶液+10%CH3CN;相B:CH3OH;相C:CH3CN。收集所要的级分,将溶剂部分蒸发。加入NaHCO3饱和水溶液,有机产物用CH2Cl2萃取。分离各层,CH2Cl2层用MgSO4干燥,过滤,蒸发溶剂并用甲苯共蒸发。残余物用DIPE中搅拌,滤出固体,在50℃真空干燥72小时。产量:0.184g化合物130。
实施例B8
化合物131的制备
向中间体20(0.175g,0.499mmol)在CH3CN(5ml,无水)和DMF(2ml,无水)中的溶液加入2,6-二氯苯乙酸(0.102g,0.499mmol)和DIPEA(0.6ml)。加入DEPC(1.2当量),将反应混合物在室温下搅拌1小时。蒸发溶剂,残余物用快速硅胶色谱法纯化。收集所要的级分,蒸发溶剂,得到0.155g化合物131(58%)。
实施例B9
化合物136的制备
将中间体32(0.5g,0.00152mol)(按照A13.b制备)在CH2Cl2(10ml)中搅拌。将此混合物在搅拌下加到中间体30(0.54g,0.00153mol)(按照A12.b制备)在Et3N(1ml,0.00712mol)和CH2Cl2(20ml)中的溶液中。2小时后,加入CH2Cl2(50ml)和半饱和的NaHCO3溶液(适量),将混合物搅拌。随后,加入MeOH(10ml)和CH2Cl2(10ml),搅拌18小时。然后将混合物静置48小时,但各层未适当地分离。因此,将混合物经硅藻土过滤。分离各层,将有机层干燥(MgSO4),过滤,蒸发溶剂并与甲苯共蒸发,得到1.006g。粗产物用反相高效液相色谱法纯化(ShandonC18BDS(碱钝化硅胶)8μm,250g,I.D.5cm)。采用了流动相梯度。相A:0.25%NH4HCO3水溶液;相B:CH3OH;相C:CH3CN。收集所要的级分,蒸发溶剂,直到只有水相。该水层用NaHCO3中和。将分离的有机层干燥(MgSO4),过滤,蒸发溶剂并用甲苯共蒸发。残余物在乙醚中搅拌,滤出固体,得到0.032g化合物136。
实施例B10
化合物137的制备
将中间体30(0.465g,0.00133mol)(按照A12.b制备)溶在CH2Cl2(10ml)和Et3N(1ml,0.00712mol)中,生成棕色的混浊混合物。将中间体34(0.4g,0.00133mol)(按照A14.b制备)溶于CH2Cl2(10ml),加到该棕色的混浊混合物中。将反应混合物搅拌1小时后过滤,洗涤(CH2Cl2 2次,CH3CN 1次,再用CH2Cl2 1次)。将固体在50℃真空干燥18小时。产量:0.505g化合物137(56%)。
实施例B11
化合物139的制备
在搅拌下向中间体36(0.564g,0.00154mol)(按照A15.b制备)和3-(1-吡咯烷基)苯甲酸(0.309g,0.00162mol)在CH2Cl2(20ml,p.a.)和三乙胺(0.433ml,0.00308mol)中的溶液加入DECP(0.253ml,0.00169mol)。将反应混合物在N2气氛下搅拌18小时,然后加入NaHCO3饱和水溶液(15ml),将混合物搅拌2小时。加入CH2Cl2/MeOH 90/10(10m),将混合物搅拌1小时。分离各层,有机层用水洗,干燥(MgSO4),过滤,蒸发溶剂。残余物在Et2O/EtOAc(10ml/10ml)中搅拌,过滤,洗(EtOAc/Et2O,先用1/1,然后0/1),在50℃真空干燥。产量:0.655g化合物139(79%)。
实施例B12
化合物140的制备
在搅拌下向中间体38(2.1g,0.00468mol)(按照A11.d-2制备)和1,3-苯二甲酸1-甲酯(0.886g,0.00492mol)在Et3N(1.316ml,0.00937mol)和CH2Cl2(100ml,p.a.)中的溶液加入DECP(1.167ml,0.00703mol)。将反应混合物于室温下搅拌18小时,然后加入NaHCO3饱和水溶液(50ml)和CH2Cl2/MeOH(1∶1,40ml)。将混合物搅拌15分。分离各层,有机层用水(50ml)搅拌,在分液漏斗中放置过夜。滤出有机层中的沉淀,用CH2Cl2洗,在50℃真空干燥,得到0.54g化合物140(19%)。将滤液蒸发,残余物在丙酮中搅拌,过滤,用丙酮洗,50℃下真空干燥,得到1g化合物140(35%)。
实施例B13
化合物145的制备
将TBTU(4.20mmol)和Et3N(2.08ml,15.0mmol)加到中间体41(3.60mmol)(按照A16.3制备)在CH3CN(10ml)中的悬浮液里。室温下搅拌该混合物10分钟,然后加入中间体43(2.71mmol)(按照A17.b制备)。将混合物在室温下搅拌5小时。滤出晶体产物,用少量丙酮洗,在空气中干燥。产量:1.46g化合物145(85%)。
表1至7列出了与以上实施例之一类似地制备的化合物
表1:
表2:
表3:
表4:
表5:
表6:
表7:
c.分析部分
(LC)MS
对于本发明化合物的(LC)MS鉴定,使用以下方法。
通用步骤A
HPLC测定用一台Alliance HT 2790(Wates)系统进行,该系统包括一个带脱气器的四元泵,自动进样器,柱保温箱(设定在40℃,除非另外说明),二极管阵列检测器(DAD)和在以下各个方法中指定的柱子。流出柱子的液流被分流到MS光度计。MS检测器配置有电喷雾离解源。采用0.1秒的停留时间在1秒内从100扫描至1000,获得质谱。毛细针压为3kV,源温保持在140℃。使用氮气作为喷雾气体。数据采集用Waters-Micromass MassLynx-Openlynx数据系统完成。
通用步骤B
LC测定用一台Acquity UPLC(Waters)系统进行,该系统包括一个二元泵,一个样品组织器,柱加热器(设定在55℃)、二极管阵列检测器(DAD)和以下各个方法中指定的柱子。流出柱子的液流被分流到MS光度计。MS检测器配置有电喷雾离解源。采用0.02秒的停留时间在0.18秒内从100扫描至1000以得到质谱。毛细针压为3.5kV,源温保持在140℃。使用氮作为喷雾气体。用Waters-MicromassMassLynx-Openlynx数据系统完成数据采集。
通用步骤C
化合物的LCMS是用Surveyor MSQTM(Thermo Finnigan,USA)完成的,该仪器包括一个光电二极管阵列检测器(PDA;190-800nm)和一只在以下各个方法中指定的柱子。流出柱子的液流被分流到MS光度计。该MS检测器配置有APCI(常压化学离解,+或-离子)。通过在0.3秒内从45扫描到1000(原子量单位)获得质谱。典型的APCI条件使用10μA的电晕放电电流和30V的锥电压。APCI探头温度为640℃。使用氮作为喷雾气体。数据采集用XcaliburTM数据系统进行。
方法1
除了通用步骤B之外:反相UPLC(超高效液相色谱)在一台桥接的乙基硅氧烷/二氧化硅杂合物(BEH)C18柱(1.7μm,2.1×50mm,Waters Acquity)上以0.8ml/min的流速进行。使用2个流动相(流动相A:0.1%甲酸的水/甲醇(95/5)溶液;流动相B:甲醇)运行以下梯度条件:在1.3分内从95%A和5%B到5%A和95%B,并保持0.2分。注射体积为0.5μl。对于正离解模式锥压为10V,负离解模式为20V。
方法2
除了通用步骤A以外;反相HPLC在Xterra MS C18柱(3.5μm,4.6×100mm)上以1.6ml/min的流速进行。使用3个流动相(流动相A:95%的25mM乙酸铵+5%乙腈;流动相B:乙腈;流动相C:甲醇)运行以下梯度条件:在6.5分内从100%A到1%A、49%B和50%C,于1分钟内到1%A和99%B,在此条件保持1分钟,重新用100%A平衡1.5分)。使用10μl的注射体积。锥压对于正离解模式为10V,负离解模式为20V。
方法3(仅MS)
对于一些化合物只记录了质谱(无R(t))。MS检测器配置有电喷雾离解源。采用0.1秒的停留时间在1秒内从100扫描至1000,获得质谱。毛细针压为3kV,源温保持在140℃。使用氮作为喷雾气体。数据采集用Waters-Micromass MassLynx-Openlynx数据系统完成。锥压对于正离解模式为10V,对于负离解方式为20V。
方法4
除了通用步骤A以外:柱加热器设定在45℃。在一台Xterra MS C18柱(3.5μm,4.6×100mm)上以1.6ml/min的流速进行HPLC。使用3个流动相(流动相A:0.1%甲酸的水/甲醇(95/5)溶液;流动相B:乙腈;流动相C:甲醇)运行以下梯度条件:在7分钟内从100%A到1%A、49%B和50%C,保持该条件1分钟。注射体积为10μl。对于正离解模式,锥压为10V。
方法5
除了通用步骤A以外:柱加热器设定在45℃。在一台Atlantis C18柱(3.5μm,4.6×100mm)上以1.6ml/min的流速进行反相HPLC。使用2个流动相(流动相A:70%甲醇+30%水;流动相B:0.1%甲酸的水/甲醇(95/5)溶液)运行以下梯度条件:在9分钟内从100%B至5%B+95%A,并保持该条件3分钟。注射体积为10μl。对于正离解模式,锥压为10V,对于负离解模式为20V。
方法6
除了通用步骤A以外:柱加热器设定在60℃。在一台Xterra MS C18柱(3.5μm,4.6×100mm)上以1.6ml/min的速度进行反相HPLC。使用3个流动相(流动相A:95%25mM乙酸铵+5%乙腈;流动相B:乙腈;流动相C:甲醇)运行以下梯度条件:在6.5分内从100%A至50%B和50%C,在0.5分内至100%B,保持该条件1分钟,用100%A再平衡1.5分。注射体积为10μl。锥压对于正离解模式为10V,对于负离解模式为20V。
方法7
除了通用步骤C以外:反相HPLC在Waters Xterra MS C18柱(3.5μm,2.1×30mm)上以流速1.0ml/min进行。使用2个流动相(流动相A:0.1%甲酸水溶液;流动相B:乙腈)。先保持100%A 0.1分钟,然后在3分钟内施用梯度至5%A和95%B,并保持0.8分。注射体积为1μl。柱子为室温。
表8:(LC)MS分析数据-Rt代表保留时间(分),[MH]+代表化合物(游离碱)的质子化质量。方法指(LC)MS使用的方法。
化合物编号 | Rt | [MH]+ | 方法 |
1 | - | 547 | 3 |
2 | 1.46 | 608 | 1 |
3 | 1.48 | 607 | 1 |
4 | 1.24 | 535 | 1 |
5 | 1.40 | 565 | 1 |
6 | n.d. | n.d. | |
7 | 1.39 | 558 | 1 |
8 | n.d. | n.d. | |
9 | n.d. | n.d. | |
10 | 5.61 | 483 | 2 |
11 | 4.24 | 490 | 2 |
12 | 1.35 | 538 | 1 |
13 | 1.16 | 552 | 1 |
14 | 1.33 | 535 | 1 |
15 | 1.19 | 536 | 1 |
16 | 1.23 | 536 | 1 |
17 | 1.30 | 566 | 1 |
18 | - | 594 | 3 |
19 | 1.38 | 562 | 1 |
20 | 1.38 | 562 | 1 |
21 | 1.21 | 535 | 1 |
22 | 0.88 | 535 | 1 |
23 | 0.92 | 535 | 1 |
24 | 0.92 | 535 | 1 |
25 | 1.16 | 535 | 1 |
26 | 1.17 | 563 | 1 |
27 | 1.29 | 563 | 1 |
28 | 1.30 | 563 | 1 |
29 | 1.04 | 536 | 1 |
30 | 1.25 | 551 | 1 |
31 | 1.11 | 551 | 1 |
化合物编号 | Rt | [MH]+ | 方法 |
33 | 1.12 | 537 | 1 |
34 | 1.25 | 545 | 1 |
35 | 1.41 | 601 | 1 |
36 | - | 559 | 3 |
37 | 1.23 | 552 | 1 |
38 | 1.19 | 554 | 1 |
39 | 1.27 | 554 | 1 |
40 | 1.21 | 554 | 1 |
41 | 1.15 | 602 | 1 |
42 | 1.12 | 602 | 1 |
43 | 1.11 | 602 | 1 |
44 | 0.86 | 571 | 1 |
45 | 1.04 | 585 | 1 |
46 | 4.04 | 447 | 2 |
47 | 4.41 | 477 | 2 |
48 | 5.25 | 479 | 2 |
49 | 4.23 | 475 | 2 |
50 | - | 579 | 3 |
51 | - | 561 | 3 |
53 | 1.43 | 633 | 1 |
54 | 1.37 | 609 | 1 |
55 | 1.26 | 593 | 1 |
56 | 1.29 | 544 | 1 |
57 | - | 578 | 3 |
58 | 1.38 | 626 | 1 |
59 | 1.37 | 626 | 1 |
60 | - | 558 | 3 |
61 | - | 586 | 3 |
62 | 1.43 | 600 | 1 |
63 | - | 570 | 3 |
64 | - | 598 | 3 |
化合物编号 | Rt | [MH]+ | 方法 |
65 | 1.40 | 634 | 1 |
66 | - | 627 | 3 |
67 | 1.32 | 599 | 1 |
68 | 1.43 | 629 | 1 |
69 | 1.36 | 525 | 1 |
70 | 1.32 | 559 | 1 |
71 | 1.41 | 587 | 1 |
72 | 1.40 | 617 | 1 |
73 | 1.14 | 588 | 1 |
74 | 1.32 | 559 | 1 |
75 | 1.35 | 573 | 1 |
76 | 1.42 | 587 | 1 |
77 | 1.41 | 587 | 1 |
78 | 1.40 | 601 | 1 |
79 | 1.44 | 601 | 1 |
80 | 1.33 | 575 | 1 |
81 | 1.41 | 589 | 1 |
82 | 1.37 | 573 | 1 |
83 | 1.36 | 587 | 1 |
84 | 1.31 | 605 | 1 |
85 | 1.40 | 587 | 1 |
86 | 1.43 | 603 | 1 |
87 | 1.43 | 617 | 1 |
88 | - | 623 | 3 |
89 | 1.35 | 579 | 1 |
90 | 1.31 | 563 | 1 |
91 | - | 671 | 3 |
92 | - | 590 | 3 |
93 | 1.39 | 591 | 1 |
94 | 1.33 | 593 | 1 |
95 | 1.30 | 604 | 1 |
化合物编号 | Rt | [MH]+ | 方法 |
96 | 1.33 | 659 | 1 |
97 | - | 779 | 3 |
98 | - | 659 | 3 |
99 | 1.39 | 647 | 1 |
100 | 1.43 | 651 | 1 |
101 | 1.32 | 618 | 1 |
102 | 1.36 | 607 | 1 |
103 | 1.37 | 651 | 1 |
104 | 1.41 | 665 | 1 |
105 | 1.41 | 637 | 1 |
106 | 1.33 | 603 | 1 |
107 | 1.34 | 508 | 1 |
108 | 1.38 | 572 | 1 |
109 | 1.44 | 586 | 1 |
110 | 1.39 | 586 | 1 |
111 | 1.35 | 604 | 1 |
112 | 1.43 | 586 | 1 |
113 | 1.36 | 592 | 1 |
114 | 1.35 | 658 | 1 |
115 | 1.45 | 650 | 1 |
116 | 1.39 | 617 | 1 |
117 | 1.42 | 606 | 1 |
118 | 1.43 | 650 | 1 |
119 | - | 508 | 3 |
120 | - | 562 | 3 |
121 | 1.36 | 556 | 1 |
122 | 1.41 | 584 | 1 |
123 | 1.35 | 586 | 1 |
124 | 1.20 | 585 | 1 |
125 | 1.23 | 541 | 1 |
126 | 1.17 | 546 | 1 |
化合物编号 | Rt | [MH]+ | 方法 |
127 | 1.38 | 631 | 1 |
128 | 1.36 | 572 | 1 |
129 | 5.69 | 635 | 2 |
130 | 5.75 | 621 | 6 |
131 | 1.38 | 537 | 1 |
132 | 8.42 | 552 | 5 |
133 | 0.94 | 600 | 1 |
134 | 1.27 | 536 | 1 |
135 | 5.52 | 513 | 2 |
136 | 1.03 | 678 | 1 |
化合物编号 | Rt | [MH]+ | 方法 |
137 | 7.14 | 651 | 2 |
138 | 1.48 | 652 | 7 |
139 | 7.04 | 539 | 4 |
140 | 5.12 | 610 | 2 |
141 | 1.43 | 470 | 1 |
142 | 1.34 | 492 | 1 |
143 | 1.40 | 624 | 7 |
144 | n.d. | n.d. | - |
145 | 0.96 | 609 | 1 |
146 | 0.89 | 595 | 1 |
表9:(LC)MS分析数据-Rt指保留时间(分),[MH]-代表化合物的去质子的质量(负模式),方法指(LC)MS使用的方法。
化合物编号 | Rt | [MH]- | 方法 |
52 | - | 573 | 3 |
32 | 1.05 | 535 | 1 |
熔点
对于一些化合物,使用DSC 823e(Mettler-Toledo)测定了熔点(m.p)。熔点是用30℃/分的温度梯度测定的,最高温度为400℃。数值为峰值。结果收集在表10。
表10
化合物编号 | m.p.(℃) |
132 | 238.13 |
136 | 254.77 |
化合物编号 | m.p.(℃) |
137 | 270.85 |
139 | 212.69 |
化合物编号 | m.p.(℃) |
140 | 247.52 |
对于一些化合物,使用Sanyo Gallenkamp的Gallenkamp装置测定熔点。
化合物138:198-199℃;化合物143:249-250℃;
化合物133:237-239℃;化合物145:218-221℃;
化合物146:208-210℃。
D.药理学实例
A).测定本发明化合物对DGAT1活性的抑制作用
本发明化合物对DGAT1活性的抑制活性在一项单孔试验中进行筛选,使用含DGAT1的膜制剂和含DGAT1底物的胶束,并且用辐射发光现象测定紧靠Flashplate表面形成的放射性的三酰基甘油。
该试验在WO 2006/067071中有详细说明,其内容以参考引用的方式并入本文。
DGAT1活性指的是,辅酶A活化的脂肪酸由于酶DGAT1而转移到1,2-二酰基甘油的3位,从而形成甘油三酯分子。
试验步骤1:DGAT1的表达
将人DGAT1(NM 012079.2)克隆到pFastBac载体中,该载体含有翻译起始区,一个如文献中所述的N端FLAG-标志,和一个在ATG之前的病毒Kozak序列(AAX)以促进在昆虫细胞内的表达。表达按文献中所述
(Cases,S.,Smith,S.J.,Zheng,Y.,MyersH.M.,Lear,S.R.,Sande,E.,Novak,S.,Collins,C.,Welch,C.B.,Lusis,A.J.,Erickson,S.K.and Farese,R.V.(1998)Proc.Natl.Acad.Sci.USA 95,13018-13023.)
用SF9细胞进行。
试验步骤2:DGAT1膜的制备
离心(13000rpm,15分钟,-4℃)收集转染72小时的SF9细胞,在2×500ml裂解缓冲液(0.1M蔗糖,50mM KCl,40mM KH2PO4,30mMEDTA,pH7.2)中裂解。将细胞用细胞破碎机均化。在-4℃于1380rpm离心15分钟后(SN倒走),将沉淀重新悬浮在500ml裂解缓冲液中,在34000rpm(100000g)下超离心60分(4℃)收集全细胞膜。收集到的膜再悬浮于裂解缓冲液中,分成小份,与10%甘油一起在-80℃储存直至使用。
试验步骤3:制备含DGAT底物的胶束
材料
a)1,2-二油酰-sn-甘油,10mg/ml(1,2-二酰基甘油(DAG))
溶在乙腈中,在氮气下蒸发该乙腈溶液,在氯仿中重组至最终浓度10mg/ml。
b)L-α-磷脂酰胆碱,1mg/ml(磷脂酰胆碱(PC))溶在氯仿中至最终浓度1mg/ml,4℃储存。
c)L-α-磷脂酰-L-丝氨酸,1mg/ml,(磷脂酰丝氨酸(PS))
溶在氯仿中至最终浓度1mg/ml,4℃储存。
方法
向在厚玻璃器皿中的10ml L-α-磷脂酰胆碱(1mg/ml)和10ml L-α-磷脂酰-L-丝氨酸(1mg/ml)中加入1ml二油酰-sn-甘油(10mg/ml)。在氮气下蒸发,并放在冰上15分钟。通过在冰上超声,重新分散在10mlTris/HCl(10nM,pH7.4)中。超声过程包括在超声浴中超声10秒,然后在冰上冷却10秒,重复此超声循环,直至得到均匀的溶液(约耗费15分钟)。将这样得到的胶束在-20℃储存直到后来使用,其中含最终浓度为1.61mM的DAG。
试验步骤4:DGAT Flash Plate
TM
试验
材料
a)试验缓冲液
50mM Tris-HCl(pH7.4),150mM MgCl2,1mM EDTA,0.2%BSA。
b)N-乙基马来酰亚胺,5M
5g溶在最终体积为8ml的100%DMSO中,分小份在-20℃储存备用。
c)底物混合物(对于384孔板=3840μl)
612μl胶束储备液(最终51μM)
16.6μl油酰CoA 9.7mM
23μl[3H]-油酰CoA(49Ci/mmol,50μCi/ml)
3188.4μl Tris pH7.4,10mM
d)酶混合物(对于384孔板=3520μl)(5μg/ml)
将11.73μl DGAT膜储备液(1500μg/ml储备液)加到3508μl试验缓冲液中。
e)终止混合液(对于384孔板=7.68ml)(250mM)
将384μl N-乙基马来酰亚胺(5M)加到3.456ml 100%DMSO中,再用3.84ml 10%DMSO稀释3.84ml上述溶液。
方法
膜制剂中的DGAT活性利用红移的Basic Image FlashPlaleTM(PerkinElmer Cat.No.SMP400),按照384孔格式,在含有50μM DAG、32μg/mlPC/PS和8.4μM[3H]-油酰CoA(比活性30nCi/孔),最终体积为50μl的50mM Tris-HCl(pH7.4)、150mM MgCl2、1mM EDTA和0.2%BSA中进行测定。
详细地说,向30μl试验缓冲液中加入10μl酶混合液和10μl底物混合液,任选地有1μl DMSO(空白和对照)或1μl要试验的化合物存在。将反应混合物在37℃培养120分钟,加入20μl终止混合液使酶促反应停止。将板密封,令囊泡在室温下沉淀过夜。将板在1500rpm离心5分钟,在Leadseeker中测定。
用不同浓度的试验化合物进行实验,根据%CTRLmin(归一化对照样的%)计算和画出曲线。%CTRLmin按照公式1计算,
公式1:%CTRLmin=(样品-LC)/(HC-LC)
其中HC(高对照)指在含有酶和底物,但没有试验化合物的孔内测得的辐射发光值的中位值;LC(低对照)指在含有底物,但没有酶和试验化合物的孔内测得的背景辐射发光值的中位值;样品指在含有底物、酶和特定浓度试验化合物的孔内测得的辐射发光值的中位值。
计算出的%CTRLmin值构成一个S形剂量响应下行曲线,由此曲线计算pIC50值(-logIC50,其中IC50代表试验化合物对DGAT1活性产生50%抑制作用的浓度)。表11列出了式(I)化合物pIC50值。
为了确定本发明化合物对于DGAT1与对DGAT2相比的选择性,还对以上试验略加修改以得到对DGAT2的最佳试验条件,测定了本发明化合物对DGAT2的抑制活性。所试验的化合物对于DGAT2(人DGAT2(NM 032564)按照J.Biolog.Chem.276(42),pp38870-38876(2001)中所述克隆和表达)不显示抑制活性。
表11:pIC50值(IC50值用M表示;pIC50=-logIC50)
化合物编号 | pIC50 |
12 | 8.87 |
13 | 7.96 |
4 | 7.61 |
14 | 9.01 |
15 | 7.89 |
16 | 7.92 |
17 | 8.68 |
18 | 7.39 |
19 | 6.84 |
20 | 7.51 |
21 | 8.05 |
22 | 5.86 |
23 | 7.48 |
24 | 6.46 |
25 | 7.15 |
26 | 6.40 |
27 | 8.41 |
28 | 8.30 |
29 | 6.11 |
30 | 8.35 |
31 | 6.57 |
32 | 5.48 |
33 | 5.71 |
34 | 7.69 |
35 | 6.93 |
36 | 8.76 |
37 | 8.76 |
38 | 7.96 |
39 | 6.42 |
化合物编号 | pIC50 |
40 | 8.18 |
41 | 7.72 |
42 | 5.93 |
43 | 6.36 |
44 | 7.00 |
45 | 7.25 |
46 | 5.62 |
47 | 5.27 |
48 | 5.45 |
10 | 6.49 |
49 | 5.05 |
1 | 8.09 |
50 | 6.53 |
51 | 6.31 |
52 | 7.76 |
3 | 5.93 |
53 | 5.83 |
54 | 6.15 |
55 | 7.58 |
56 | 6.48 |
57 | 6.19 |
58 | 6.45 |
59 | 5.69 |
60 | 7.76 |
61 | 6.37 |
62 | 6.26 |
63 | 6.92 |
64 | 6.88 |
11 | 5.95 |
化合物编号 | pIC50 |
2 | 6.95 |
65 | 6.69 |
66 | 7.23 |
67 | 6.83 |
6 | 5.04 |
68 | 5.14 |
8 | 6.67 |
69 | 5.10 |
5 | 5.12 |
70 | 5.26 |
71 | 5.45 |
72 | 5.11 |
73 | 5.45 |
74 | 5.96 |
75 | 5.67 |
76 | 5.12 |
77 | 5.35 |
78 | 5.12 |
79 | 5.19 |
80 | 5.26 |
81 | 5.09 |
82 | 6.57 |
83 | 5.81 |
84 | 5.28 |
85 | 6.75 |
86 | 5.01 |
87 | 5.13 |
88 | 5.86 |
89 | 5.77 |
化合物编号 | pIC50 |
90 | 5.53 |
91 | 5.82 |
92 | 5.63 |
93 | 5.32 |
94 | 6.83 |
9 | 7.52 |
95 | 6.39 |
96 | 6.28 |
97 | 6.31 |
98 | 5.58 |
99 | 5.74 |
100 | 5.81 |
101 | 6.28 |
102 | 6.77 |
103 | 6.70 |
104 | 5.70 |
105 | 5.48 |
106 | 5.14 |
107 | 5.61 |
7 | 5.46 |
108 | 5.35 |
109 | 5.02 |
110 | 6.02 |
111 | 5.34 |
112 | 6.57 |
113 | 5.97 |
114 | 5.91 |
115 | 5.71 |
116 | 5.66 |
化合物编号 | pIC50 |
117 | 6.50 |
118 | 6.20 |
119 | 5.33 |
120 | 5.37 |
121 | 5.31 |
122 | 5.82 |
123 | 5.38 |
124 | 5.17 |
化合物编号 | pIC50 |
125 | 8.55 |
126 | 8.02 |
127 | 7.60 |
128 | 6.18 |
129 | 8.27 |
130 | 8.14 |
131 | 7.51 |
132 | 7.34 |
化合物编号 | pIC50 |
133 | 6.67 |
134 | 5.89 |
135 | 5.03 |
136 | 8.74 |
137 | 8.38 |
138 | 7.94 |
139 | 8.19 |
140 | 7.90 |
化合物编号 | pIC50 |
141 | 6.96 |
142 | 6.75 |
143 | 5.48 |
144 | 5.13 |
145 | 6.95 |
146 | 5.47 |
B).关于试验化合物对GLP-1血浆水平的影响的活体内研究
DGAT抑制剂造成的GLP-1血浆浓度的升高可以研究如下:
将狗禁食22小时。在时间0,用胃管向动物管饲含18%脂肪(w/w)的液体膳食。试验化合物与膳食一起经口施入。然后,测定餐后的GLP-1血浆浓度。于是,在预定的时间间隔将血液收集在冰冷却的VacutainersEDTA-血浆管中,测定在0时(刚好进食前)和用药0.5、1、2、4、6、8及24小时后抽取的样品中的GLP-1浓度。每个剂量组内包括6只狗(3只雄性和3只雌性),将血浆GLP-1分布图与在相同条件、但未施用试验化合物时预先测定的它们本身的GLP-1分布图比较。
血浆中的GLP-1测定用LINCO Research的胰高血糖素样肽-1(活性)ELISA试剂盒96孔板进行。
E.组合物实施例
在这些实施例中所说的“活性成分”(a.i.)始终是指式(I)化合物,包括其任何立体化学异构形式,N-氧化物,可药用的盐,或溶剂化物;特别是任何一种示例化合物。
本发明制剂的典型处方实例如下:
1.片剂
活性成分 5-50mg
磷酸氢二钙 20mg
乳糖 30mg
滑石粉 10mg
硬脂酸镁 5mg
土豆淀粉 至200mg
2.混悬剂
水基混悬剂是配制用于口服,使其每毫升含1-5mg活性成分,50mg羧甲基纤维素钠,1mg苯甲酸钠,500mg山梨醇,加水至1ml。
3.注射剂
将1.5%(w/v)的活性成分在0.9%NaCl溶液中搅拌,配制成肠外组合物。
4.软膏剂
活性成分 5-1000mg
硬脂醇 3g
羊毛脂 5g
白凡士林 15g
水 至100g
Claims (21)
1.一种式(I)化合物
包括其任何立体化学异构形式,或者它们的可药用盐,其中
A代表CH或N;
虚线在A是碳原子的情况下代表一个任选存在的键;
X代表-O-C(=O)-,-NH-C(=O)-,-CH2-C(=O)-,-Z-NH-C(=O)-,-NH-C(=S)-;
Z代表C1-6链烷二基;
Y代表-C(=O)-NH-或-NH-C(=O)-;
R1代表芳基1或Het1;
R2代表环己基;2,3-二氢-1,4-苯并二氧杂环己烯基;被3个选自卤素和甲基的取代基取代的吡啶基;或苯基,其中所述苯基任选地被至少一个取代基取代,各取代基独立地选自以下基团:卤素,C1-6烷基,C1-6烷氧基,C1-6烷基硫基,C1-6烷氧羰基,硝基,一或二(C1-4烷基)氨基,R4R3N-C1-6烷基,苯基氧基,哌嗪基-C(=O)-C1-4烷基、其中该哌嗪基被一个甲基取代,哌啶基-C1-4烷基,吡咯烷基-C1-4烷基;
R3代表C1-4烷基;
R4代表C1-4烷基;
R7代表氢或卤素;
芳基代表苯基或被至少一个取代基取代的苯基,各取代基独立地选自以下基团:卤素,C1-6烷基,多卤代C1-6烷基,C1-6烷氧羰基;
芳基1代表苯基或芴基,每个所述苯基或芴基任选地被一个或二个取代基取代,各取代基独立地选自氧代、羧基、卤素、任选被羧基或C1-4烷氧羰基取代的C1-6烷基、C1-6烷氧基、C1-6烷氧羰基、氨基、芳基、Het;
Het代表一个含有至少一个独立选自O、S、S(=O)p或N的杂原子的5或6元单环非芳族或芳族杂环,所述5或6元单环杂环任选地被一个或两个取代基取代,各取代基独立地选自氧代或C1-6烷基;或者Het代表苯并咪唑基;
Het1代表一个含有至少一个独立选自S或N的杂原子的4、5或6元单环非芳族或芳族杂环,所述4、5或6元单环杂环任选地被至少一个取代基取代,各取代基独立地选自:羟基,氧代,C1-6烷基,C1-6烷氧羰基,1,3-苯并二氧杂环戊烯基,被一个选自C1-6烷基和三氟甲基的取代基取代的苯基;
p代表2;
条件是,以下化合物不包括在内:
2.权利要求1的化合物,其具有下式结构
包括其任何立体化学异构形式,或者它们的可药用盐,其中
A代表CH或N;
虚线在A代表碳原子的情形下代表一个任选存在的键;
X代表-NH-C(=O)-,-CH2-C(=O)-,-Z-NH-C(=O)-,-NH-C(=S)-;
Z代表C1-6链烷二基;
Y代表-C(=O)-NH-或-NH-C(=O)-;
R1代表芳基1或Het1;
R2代表环己基,2,3-二氢-1,4-苯并二氧杂环己烯基或苯基,其中所述苯基任选地被至少一个取代基取代,各取代基独立地选自以下基团:卤素,C1-6烷基,C1-6烷氧基,甲基硫基,C1-6烷氧羰基,硝基,一或二(C1-4烷基)氨基,R4R3N-C1-6烷基,苯基氧基;
R3代表C1-4烷基;
R4代表C1-4烷基;
芳基代表苯基或被至少一个取代基取代的苯基,各取代基独立地选自以下基团:卤素,C1-6烷基,三氟甲基,C1-6烷氧羰基;
芳基1代表苯基或芴基,每个所述苯基或芴基任选地被一个或二个取代基取代,各取代基独立地选自氧代、羧基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧羰基、氨基、芳基、Het;
Het代表含至少一个独立选自O、S、S(=O)p或N的杂原子的5或6元单环非芳族或芳族杂环;所述的5或6元单环杂环任选地被1或2个取代基取代,各取代基独立地选自以下基团:氧代或C1-6烷基;或Het代表苯并咪唑基;
Het1代表含至少一个独立选自S或N的杂原子的4、5或6元单环非芳族或芳族杂环;所述的4、5或6元单环杂环任选地被至少一个取代基取代,各取代基独立地选自以下基团:羟基,氧代,C1-6烷基,C1-6烷氧羰基,1,3-苯并二氧杂环戊烯基,被一个选自C1-6烷基和三氟甲基的取代基取代的苯基;
p代表2;
条件是,不包括以下化合物
3.权利要求1的化合物,其中X代表-NH-C(=O)-或-CH2-C(=O)-。
4.权利要求1-3中任一项的化合物,其中A代表N。
5.权利要求1-3中任一项的化合物,其中R1代表苯基,所述苯基任选地被一个或二个取代基取代,各取代基独立地选自氧代、羧基、卤素、任选被羧基或C1-4烷氧羰基取代的C1-6烷基、C1-6烷氧基、C1-6烷氧羰基、氨基、芳基、Het;
Het代表一个含有至少一个独立选自O、S、S(=O)p或N的杂原子的5或6元单环非芳族或芳族杂环,所述5或6元单环杂环任选地被一个或两个取代基取代,各取代基独立地选自氧代或C1-6烷基;或Het代表苯并咪唑基。
6.权利要求1-3中任一项的化合物,其中R2代表环己基、2,3-二氢-1,4-苯并二氧杂环己烯基或苯基,其中所述苯基任选地被1-4个取代基取代。
9.权利要求7的化合物,其中R3a和R3b各自独立地代表卤素或C1-6烷基。
10.权利要求9的化合物,其中R3a和R3b代表卤素。
11.权利要求1或3的化合物,其中R7代表氢。
12.权利要求1的化合物,其中X代表-O-C(=O)-,-NH-C(=O)-,-CH2-C(=O)-,-Z-NH-C(=O)-,-NH-C(=S)-;Z代表C1-6链烷二基;R1代表芳基1或Het1;R2代表环己基,2,3-二氢-1,4-苯并二氧杂环己烯基,被3个选自卤素和甲基的取代基取代的吡啶基,或苯基,其中所述苯基任选地被1-4个取代基取代,各取代基独立地选自卤素;C1-6烷基;C1-6烷氧基、甲基硫基、C1-6烷氧羰基、硝基、一或二(C1-4烷基)氨基、R4R3N-C1-6烷基、苯基氧基、哌嗪基-C(=O)-C1-4烷基,其中该哌嗪基被一个甲基取代、哌啶基-C1-4烷基、吡咯烷基-C1-4烷基;R3代表C1-4烷基;R4代表C1-4烷基;R7代表氢或卤素;p代表2。
13.权利要求12的化合物,其中芳基代表苯基或被卤素、C1-6烷基、多卤代C1-6烷基、C1-6烷氧羰基取代的苯基;
Het代表一个含至少一个独立选自O、S、S(=O)p或N的杂原子的5或6元单环非芳族或芳族杂环,所述的5或6元单环杂环任选地被一或二个取代基取代,各取代基独立地选自氧代或C1-6烷基;或Het代表苯并咪唑基;
Het1代表一个含至少一个独立选自S或N的杂原子的4、5或6元单环非芳族或芳族杂环,所述4、5或6元单环杂环任选地被一或二个取代基取代,各取代基独立地选自羟基、氧代、C1-6烷基、C1-6烷氧羰基、1,3-苯并二氧杂环戊烯基、被一个选自C1-6烷基和三氟甲基的取代基取代的苯基。
15.一种药物组合物,其中含有可药用的载体和作为活性成分的治疗有效量的权利要求1-14中任一项的化合物。
16.权利要求1-14中任一项的化合物在制造药物方面的用途,该药物用于预防或治疗得益于抑制DGAT的疾病,所述疾病选自肥胖症、血脂异常、脂肪肝、肝纤维化或糖尿病。
17.权利要求16的用途,其中所述血脂异常是混合型血脂异常。
18.权利要求16的用途,其中所述血脂异常是高脂血症。
19.权利要求18的用途,其中所述高脂血症是高胆固醇血症或高甘油三酯血症。
20.权利要求16的用途,其中所述脂肪肝是非酒精性脂肪肝病。
21.权利要求16的用途,其中所述脂肪肝是非酒精性脂肪肝炎。
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JO2972B1 (en) | 2007-06-08 | 2016-03-15 | جانسين فارماسوتيكا ان. في | Piperidine / piperazine derivatives |
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AR066169A1 (es) | 2007-09-28 | 2009-07-29 | Novartis Ag | Derivados de benzo-imidazoles, utiles para trastornos asociados con la actividad de dgat |
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WO2017157873A1 (en) | 2016-03-17 | 2017-09-21 | F. Hoffmann-La Roche Ag | 5-ethyl-4-methyl-pyrazole-3-carboxamide derivative having activity as agonist of taar |
US11224590B2 (en) * | 2018-03-16 | 2022-01-18 | Anji Pharmaceuticals Inc. | Compositions and methods for treating severe constipation |
CN108440468B (zh) * | 2018-04-17 | 2022-09-23 | 南华大学 | 2-(苯并呋喃-5-基)苯酚及其作为抗癌药物的应用 |
CN110128346A (zh) * | 2019-05-17 | 2019-08-16 | 南开大学 | 一类联芳酰胺吡唑衍生物及其制备方法和用途 |
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EP2155198A2 (en) | 2010-02-24 |
JO2972B1 (en) | 2016-03-15 |
AU2008258558A1 (en) | 2008-12-11 |
US20100210618A1 (en) | 2010-08-19 |
TW200916449A (en) | 2009-04-16 |
JP5443343B2 (ja) | 2014-03-19 |
CL2008001668A1 (es) | 2009-07-17 |
US8946228B2 (en) | 2015-02-03 |
ES2522617T3 (es) | 2014-11-17 |
RU2478628C2 (ru) | 2013-04-10 |
WO2008148849A3 (en) | 2009-04-16 |
CN101678013A (zh) | 2010-03-24 |
AU2008258558B2 (en) | 2013-11-07 |
US9227935B2 (en) | 2016-01-05 |
US20160081997A1 (en) | 2016-03-24 |
PA8783401A1 (es) | 2009-01-23 |
AR066153A1 (es) | 2009-07-29 |
TWI438197B (zh) | 2014-05-21 |
CA2687243A1 (en) | 2008-12-11 |
BRPI0812923A2 (pt) | 2014-12-09 |
EP2155198B1 (en) | 2014-08-13 |
MX2009013334A (es) | 2010-01-20 |
JP2010529085A (ja) | 2010-08-26 |
CA2687243C (en) | 2016-07-12 |
PE20090820A1 (es) | 2009-06-27 |
UY31134A1 (es) | 2009-03-02 |
WO2008148849A8 (en) | 2009-07-09 |
WO2008148849A2 (en) | 2008-12-11 |
RU2009148796A (ru) | 2011-07-20 |
US20150087629A1 (en) | 2015-03-26 |
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