CN102131781A - 1-(4-脲基苯甲酰基)哌嗪衍生物 - Google Patents
1-(4-脲基苯甲酰基)哌嗪衍生物 Download PDFInfo
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- CN102131781A CN102131781A CN2009801330788A CN200980133078A CN102131781A CN 102131781 A CN102131781 A CN 102131781A CN 2009801330788 A CN2009801330788 A CN 2009801330788A CN 200980133078 A CN200980133078 A CN 200980133078A CN 102131781 A CN102131781 A CN 102131781A
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- Prior art keywords
- methyl
- piperazine
- benzoyl
- urea groups
- tertiary butyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- HOIARKPBRNTSFS-UHFFFAOYSA-N [4-(piperazine-1-carbonyl)phenyl]urea Chemical class C1=CC(NC(=O)N)=CC=C1C(=O)N1CCNCC1 HOIARKPBRNTSFS-UHFFFAOYSA-N 0.000 title abstract 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 17
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 16
- 229910052736 halogen Chemical group 0.000 claims abstract description 12
- 150000002367 halogens Chemical group 0.000 claims abstract description 12
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 7
- 230000004060 metabolic process Effects 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 239000003814 drug Substances 0.000 claims abstract 2
- -1 piperazine-1-yl Chemical group 0.000 claims description 123
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 96
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 61
- 150000004885 piperazines Chemical class 0.000 claims description 29
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 claims description 29
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 13
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 12
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- 125000004122 cyclic group Chemical group 0.000 abstract 1
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- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 13
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 11
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- JYCGXZGGVUKKNQ-UHFFFAOYSA-N tert-butyl formate piperazine Chemical compound C(C)(C)(C)OC=O.N1CCNCC1 JYCGXZGGVUKKNQ-UHFFFAOYSA-N 0.000 description 11
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- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
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- 238000012799 strong cation exchange Methods 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
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- 229910052794 bromium Inorganic materials 0.000 description 6
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 6
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- 125000001072 heteroaryl group Chemical group 0.000 description 6
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Abstract
本发明涉及具有通式I的1-(4-脲基苯甲酰基)哌嗪衍生物，，其中R1为(C1-8)烷基，(C3-8)环烷基或(C3-8)环烷基(C1-3)烷基，其每一个可以被羟基，氰基或卤素取代；R2表示1或2个任选的卤素；R3为西(C1-6)烷基，(C3-6)环烷基或(C3-6)环烷基(C1-3)烷基，其每一个可以被一个或多个卤素取代；A表示杂芳基环系统，包含1-3选自N，O和S的杂原子，该环系统当X为C时为5-或6-元的，并且当X为N时为5元的；n为1或2；或者其药学可接受的盐；以及含有它的药物组合物；以及这些1-(4-脲基苯甲酰基)哌嗪衍生物在制备用于治疗或者预防动脉粥样硬化和与胆固醇和胆汁酸运输和代谢有关的相关病症的药物中的用途。
Description
本发明涉及1-(4-脲基苯甲酰基)哌嗪衍生物、含有它们的药物组合物和这些1-(4-脲基苯甲酰基)哌嗪衍生物在治疗动脉粥样硬化中的应用。
肝X受体(LXR)是在天然存在的氧化固醇结合后被激活、从而诱导靶基因转录的核受体家族。已经鉴别出了LXR的两个亚型(α和β)，且它们的配体-和DNA-结合域都表现出77％同源性。两个亚型在人类和啮齿动物之间是高度保守的，但是，它们的组织表达模式显著不同。LXRα的表达限于参与脂类代谢的组织，在肝中最高表达；在肾、脾、小肠和脂肪组织中也存在显著的水平。LXRβ的分布非常广泛，事实上已经在检查的每个组织中发现，包括肝和脑。LXRα和LXRβ都在巨噬细胞中表达。参见Costet等人，J.Biol.Chem 275：28240-28245(2000)。
尚未完全理解LXR受体的作用，但是，LXR被公认为肝和周边组织中脂类代谢的主要调节剂，和ATP-结合盒运载体A1(ABCA1)基因的关键诱导物(Venkateswaran等人，Proc.Natl.Acad.Sci.USA.97：12097-12102(2000))。在人群体中，ABCA1基因的突变会导致高度致动脉粥样化的脂蛋白轮廓(Singaraja等人，Arterioscler.Thromb.Vasc.Biol.23：1322-1332(2003))，它们在最严重的情况下，会造成丹吉尔病和有关的过早动脉粥样硬化(参见Bodzioch等人，Nat.Genet.22：347-351(1999)和Rust等人，Nat.Genet.22：352-355(1999))。这种罕见的遗传性病症的特征在于非常低水平的高密度脂蛋白(HDL)、胆固醇酯的巨噬细胞积累和显著增加的动脉粥样硬化病的风险(Brooks-Wilson等人，Nat.Genet.22：336-345(1999))。
证据已经证实，人巨噬细胞和小肠的肠细胞中ABCA1的上调，由LXR活化来介导(Costet等人，同上)。此外，还已经证实，LXR激动剂会促进胆固醇流出。参见Claudel等人，Proc.Natl.Acad.Sci.USA.98：2610-2615(2001)。因此，LXR受体在巨噬细胞的胆固醇体内稳态中起关键作用，且晚期动脉粥样硬化斑块的局部环境内的抑制可能是该疾病的病理学的关键特征。
在最近几年中，已经在逐渐增加地报道了LXR激动剂在治疗动脉粥样硬化中的潜在效用。参见例如Levin等人，Arterioscler.Thromb.Vasc.Biol.25：135-142(2005)。动脉粥样硬化是一种动脉疾病，其可以不造成症状地存在许多年。但是，晚期动脉粥样硬化斑块可以变得易于破裂，促进急性血栓形成和诸如心肌梗死(MI)和中风等临床事件。在动脉粥样硬化斑块破裂和随后的临床事件中涉及的主要细胞类型是巨噬细胞。
预期通过降低动脉的胆固醇负担(通过ABCA1的上调)，以产生更稳定的损害并从而减少临床事件，发生LXR激动剂在动脉粥样硬化中的功效的主要机理。另外，由于ABCA1在肝生成新生HDL中的作用，LXR激动剂可以增加循环HDL水平。由于炎症的抑制(Joseph等人，Nat.Med.9：213-219(2003))和对葡萄糖代谢的影响，LXR激动剂存在其它抗-动脉粥样硬化效应的潜力。参见Latiffe等人，Proc.Natl.Acad.Sci.USA.100：5419-24(2003)。
仍然需要作为有效的LXR调节剂的化合物。
为此目的，本发明提供具有通式I的1-(4-脲基苯甲酰基)哌嗪衍生物
其中
R1为(C1-8)烷基，(C3-8)环烷基或(C3-8)环烷基(C1-3)烷基，其每一个可以被羟基，氰基或卤素取代；
R2表示1或2个任选的卤素；
R3为(C1-6)烷基，(C3-6)环烷基或(C3-6)环烷基(C1-3)烷基，其每一个可以被一个或多个卤素取代；
A表示杂芳基环系统，包括1-3选自N，O和S的杂原子，该环系统：当X为C时，为5-或6-元的，并且当X为N时为5元的；n为1或2；或者其药学可接受的盐。
在式I的定义中使用的术语(C1-8)烷基是指具有1-8个碳原子的支链或直链烷基，如辛基、己基、戊基、异戊基、丁基、异丁基、叔丁基、丙基、异丙基、乙基和甲基。
在式I的定义中使用的术语(C1-6)烷基是指具有1-6个碳原子的支链或直链烷基，如己基、戊基、丁基、异丁基、叔丁基、丙基、异丙基、乙基和甲基。
同样地，在式I的定义中使用的术语(C1-3)烷基是指具有1-3个碳原子的支链或直链烷基，如丙基、异丙基、乙基和甲基。
术语(C3-8)环烷基是指具有3-8个碳原子的环烷基，如环庚基、环己基、环戊基、环丁基和环丙基。
术语(C3-8)环烷基(C1-3)烷基是指被具有如上定义的(C3-8)环烷基取代的具有如上定义的(C1-3)烷基基团。实例是环丙基甲基，环丁基甲基，2-环丙基乙基，2-环丁基乙基等等。优选的(C3-8)环烷基(C1-3)烷基是环丙基甲基。
术语5-或6-元包括1-3个选自N，O和S的杂原子的杂芳基环系统A，意味着衍生自杂芳香环的1，3-二基亚杂芳基基团，所述的杂芳香环例如可举出唑，异
唑，二唑，噻二唑，呋喃，吡咯，吡唑，哌嗪，吡啶，嘧啶，咪唑，噻唑，噻二唑，噻吩等等。这样的5-元亚杂芳基的例子是
唑2，4-二基，异
唑3，5-二基，噻唑-2，4-二基，呋喃-2，5，-二基，噻吩-2，5-二基，吡唑-1，3-二基，吡咯-1，3-二基，咪唑-1，4-二基，四唑-2，5-二基，[1，2，4]
二唑-3，5-二基等等。6-元亚杂芳基的例子是吡啶-2，4-二基，吡啶-2，6-二基，嘧啶-2，4-二基，哒嗪-3，5-二基，吡嗪-2，6-二基等等。
术语卤素意味着F，Cl，Br或I。优选F和Cl。
优选式I的1-(4-脲基苯甲酰基)哌嗪衍生物，其中A表示呋喃-2，5，二基或吡啶-2，6-二基。
进一步优选的是式I的1-(4-脲基苯甲酰基)哌嗪衍生物，其中另外R2表示1或2个选自F和Cl的卤素。
更优选的是式I的1-(4-脲基苯甲酰基)哌嗪衍生物，其中另外R3是叔丁基。
本发明特别的1-(4-脲基苯甲酰基)哌嗪衍生物为：
-N-叔丁基-5-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(3-氟-4-(3-异丁基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(4-(3-(环丙基甲基)脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(3-氟-4-(3-新戊基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(3-氟-4-(3-异戊基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(4-(3-丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺盐酸盐；
-N-叔丁基-5-((4-(3-氯-4-(3-新戊基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(3-氯-4-(3-异丁基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(3-氯-4-(3-(环丙基甲基)脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(3-氯-4-(3-环丁基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(3-氯-4-(3-异戊基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(4-(3-丁基脲基)-3-氯苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(4-(3-(环丙基甲基)脲基)-2，3-二氟苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(2，3-二氟-4-(3-新戊基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(2，3-二氟-4-(3-异丁基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(4-(3-环丁基脲基)-2，3-二氟苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(4-(3-丁基脲基)-2，3-二氟苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(2，3-二氟-4-(3-异戊基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-6-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)吡啶酰胺；
-N-叔丁基-6-((4-(3-氟-4-(3-新戊基脲基)苯甲酰基)哌嗪-1-基)甲基)吡啶酰胺；
-N-叔丁基-6-((4-(3-氟-4-(3-异戊基脲基)苯甲酰基)哌嗪-1-基)甲基)吡啶酰胺；
-N-叔丁基-6-((4-(4-(3-(环丙基甲基)脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)吡啶酰胺；或其药学可接受的盐。
可以使用有机合成领域公知的一般合成方法制备本发明的1-(4-脲基苯甲酰基)哌嗪衍生物。用于合成其中X是C的式I化合物的合成途径描述在反应路线1中，且其中X是N的式I化合物的合成途径描述在反应路线2中。本领域技术人员了解反应路线1和2中式2-13的关键结构单元的添加次序可以改变并且仍然得到期望的式1产物。
按照反应路线1表示的途径，用式3的杂芳基酯衍生物，在溶剂例如二氯甲烷或乙腈中，在室温或升温、使用有机碱例如三乙胺或无机碱例如碳酸钾使式2的哌嗪中间体烷基化，其中Y表示氨基保护基，例如叔-丁氧羰基(t-Boc)，其中烷基(alkyl)表示低级烷基，优选甲基，且其中L表示离去基，例如氯、溴或OSO2Me，得到式4的中间体氨基酯衍生物。
在溶剂例如二氯甲烷中，使用偶合试剂例如N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐或1-丙烷膦酸环酐使用例如于甲醇/水的氢氧化钠使式4的中间体进行酯水解得到酸或酸的钠盐，其可以与式H2NR3的胺偶合，其中R3具有如上述所定义的含义，得到式5的酰胺衍生物。例如使用于二氯甲烷中的三氟乙酸使式5中间体中的Boc-保护的哌嗪氨基官能团脱保护，得到式6的中间体哌嗪衍生物，然后在溶剂例如二氯甲烷中使用偶合试剂例如N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐或1-丙烷膦酸环酐与式7的苯甲酸衍生物偶合，其中R2具有如上述所定义的含义，得到式8的苯胺中间体。通过与4-硝基苯基氯甲酸酯或碳酸(双(三氯甲基)酯(三光气)在溶剂例如二氯甲烷中、在室温或升温下反应活化这种苯胺中间体，然后在碱例如三乙胺或N，N-二异丙基乙胺的存在下与式R1NH2的胺反应，其中R1具有如上述所定义的含义，得到本发明式I的1-(4-脲基苯甲酰基)哌嗪衍生物。
反应路线1
按照反应路线2表示的途径，在溶剂例如二氯甲烷中在室温或升温下使式9的甲基化杂芳基衍生物与式R3-NCO的异氰酸酯反应，其中R3具有如上述所定义的含义，得到式10的脲衍生物。通过使用N-溴琥珀酰亚胺和过氧化苯甲酰在四氯化碳中、在室温或室温下溴化活化芳香甲基取代基，得到式11的中间体脲衍生物，其中离去基L是溴。
用式11的脲衍生物在溶剂例如二氯甲烷或乙腈中在室温或升温下、使用有机碱例如三乙胺或无机碱例如碳酸钾使式2的哌嗪衍生物烷基化，其中Y是N-保护基，例如叔-丁氧羰基(t-Boc)，然后使用三氟乙酸和二氯甲烷使Boc-基团脱保护，得到式12的哌嗪衍生物。
反应路线2
使式12的哌嗪衍生物与式7的苯甲酸衍生物，其中R2具有如上述所定义的含义，在溶剂例如二氯甲烷中借助于偶合试剂例如N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐或1-丙烷膦酸环酐反应，得到式13的苯胺中间体。可以通过与4-硝基苯基氯甲酸酯或(碳酸双(三氯甲基)酯(三光气)在溶剂例如二氯甲烷、在室温或升温下反应由式13的中间体制备本发明式I的1-(4-脲基苯甲酰基)哌嗪衍生物，其中X是N，然后在碱例如三乙胺或N，N-二异丙基乙胺的存在下添加期望的式R1NH2的胺，其中R1具有如上述所定义的含义。
可以使用本领域众所周知的方法由商购中间体制备式2的哌嗪衍生物、式3的酯衍生物、式7的4-氨基苯甲酸衍生物和式9的甲基化杂芳基衍生物。
上面使用的术语N-保护基是指常用于保护氨基基团的基团，像禾草灭羰基(alloxycarbonyl)(Alloc)基团，叔丁氧羰基(Boc)基团，苄氧羰基(Z)基团或者9-芴基甲氧基羰基(Fmoc)基团。根据保护基的性质，可以以不同方式去除这些和其它保护基。关于保护基和它们的去除方法的综述，参见T.W.Greene和P.G.M.Wuts，“ProtectiveGroups in Organic Synthesis”，第2版，1991，John Wiley & Sons，Inc.。
式I的1-(4-脲基苯甲酰基)哌嗪衍生物和它们的盐可以含有至少一个手性中心，且因此可以作为立体异构体存在，包括对映异构体和非对映异构体。本发明包括在它的范围内的前述立体异构体，和式I化合物的每种单独的R和S对映异构体和它们的盐，其基本上不含有、即含有小于5％、优选小于2％、尤其小于1％的其它对映异构体，和这样的对映异构体的任意比例的混合物，包括含有基本上等量的两种对映异构体的外消旋混合物。用于得到纯立体异构体的不对称合成方法是本领域熟知的，例如手性诱导合成或从手性中间体开始合成，对映选择性的酶转化，使用手性介质上的色谱法分离立体异构体或对映异构体。这样的方法描述在例如，Chirality in Industry(A.N.Collins编，G.N.Sheldrake和J.Crosby，1992；John Wiley)。
在本发明的另一个方面中，式I的1-(4-脲基苯甲酰基)哌嗪衍生物和它们的盐在任何结构位置可以包括一个或者多个非天然同位素。本发明的这些同位素标记的化合物可以例如用于关于它们的吸收、分布、代谢和排泄(ADME)的体内研究。同位素包括放射性同位素，例如氚或者14C。可选择地，化合物也可以用稳定的同位素例如氚，13C，18O或15N富集。11C和18F是要掺混到本发明化合物中的优选的同位素，用于作为PET(正电子成象术)示踪剂。
通过用无机酸(诸如氢氯酸、氢溴酸、磷酸和硫酸)或有机酸(诸如例如抗坏血酸、柠檬酸、酒石酸、乳酸、马来酸、丙二酸、延胡索酸、羟乙酸、琥珀酸、丙酸、醋酸、甲磺酸等)处理式I的1-(4-脲基苯甲酰基)哌嗪衍生物的游离碱，可以得到药学上可接受的盐。
本发明的化合物可以以未溶剂化形式以及与药学上可接受的溶剂(诸如水、乙醇等)的溶剂化形式存在。一般而言，对于本发明的目的，认为溶剂化形式与未溶剂化形式等效。
本发明另外提供了药物组合物，其包含与药学上可接受的辅剂混合的具有通式I的1-(4-脲基苯甲酰基)哌嗪衍生物或其药学上可接受的盐和任选的其它治疗剂。术语“可接受的”是指与组合物的其它成分相容，且对其受体无害。组合物包括例如适合口服、舌下、皮下、静脉内、硬膜外、鞘内、肌肉内、透皮、肺、局部或直肠给药等的那些，都是单位给药剂型。
对于口服给药，活性成分可以作为离散单位存在，诸如片剂、胶囊剂、散剂、颗粒剂、溶液、悬浮液等。
对于肠胃外给药，本发明的药物组合物可以存在于单位剂量或多剂量容器中，例如预定量的注射液，例如在密闭瓶和安瓿中，且也可以储存在冷冻干燥(低压冻干)条件下，只需要在使用前加入无菌液体载体，例如水。
与这样的药学上可接受的辅剂相混合，例如如标准参考文献Gennaro，A.R.等人，Remington：The Science and Practice ofPharmacy(第20版，Lippincott Williams & Wilkins，2000，具体参见第5部分：Pharmaceutical Manufacturing)所述，可以将活性剂压制成固体剂量单位，诸如丸剂、片剂，或加工成胶囊剂、栓剂或贴剂。借助于药学上可接受的液体，可以将活性剂制成液体组合物，例如注射制剂，其形式为溶液、悬浮液、乳状液，或喷雾剂，例如喷鼻剂。
为了制备固体剂量单位，预见到诸如填充剂、着色剂、聚合粘合剂等常规添加剂的使用。一般而言，可以使用不干扰活性化合物的功能的任意药学上可接受的添加剂。适用于将本发明的活性剂制成固体组合物的载体包括以适当量使用的乳糖、淀粉、纤维素衍生物等或其混合物。对于肠胃外给药，可以使用水混悬液、等渗盐水溶液和无菌注射溶液，其含有药学上可接受的分散剂和/或润湿剂，诸如丙二醇或丁二醇。
本发明另外包括上文所述的药物组合物，其与适合所述组合物的包装材料相组合，所述包装材料包括关于将所述组合物用于上文所述用途的说明书。
发现本发明的1-(4-脲基苯甲酰基)哌嗪衍生物是LXRα和/或LXRβ的调节剂，具体地具有对它们的激动剂活性，因而可以用于预防和减少动脉粥样硬化和与胆固醇和胆汁酸运输和代谢有关的相关病症的风险，所述病症例如高胆固醇血症(例如冠心病)、胆固醇胆石、脂质积累病、糖尿病和肥胖症。
本发明的化合物也潜在地可用于其它适应症，例如：
炎性疾病：
已经证实，LXR的配体活化会抑制许多炎性途径，例如白介素1-β、白介素-6、环氧化酶-2，且最近证实会直接抑制C-反应性蛋白表达。参见Blaschke等人，Circ.Res.99：88-99.(2006)。本发明的化合物可能在炎性疾病的炎症抑制中具有治疗效用，所述炎性疾病例如：接触性皮炎(参见Fowler等人，J.Invest.Dermatol.120：246-55.(2003)；神经炎症性疾病诸如多发性硬化(Zhang-Gandhi和Drew.J.Neuroimmunol.183：50-59.(2007))和自身免疫脑脊髓炎。参见Hindinger等人，J.Neurosci.Res.84：1225-1234(2006)。
增生性血管疾病：
已经证实，在体外和体内泡沫化损伤之后，LXR配体T0901317会抑制血管平滑肌细胞增殖和新内膜形成。因此，本发明的化合物可能在增生性血管疾病中具有治疗效用。参见Blaschke等人，Circ.Res.95：110-123(2004)。
糖尿病/代谢综合征：
近期的文献已经证实了LXR激动剂在胰岛素耐受性和糖尿病动物模型中的功效，因此，本发明的化合物可能在糖尿病和代谢综合征的治疗中具有潜在治疗效用(参见Liu等人，Endocrinology.147：5061-5068(2006)；Fernandez-Veledo等人，Diabetologia.49：3038-3048(2006))。
癌症：
在前列腺癌动物模型中，LXR激动剂T0901317延迟了肿瘤的进展。本发明的化合物可能潜在地用于治疗前列腺癌。参见Chuu等人，Cancer.Res.66：6482-6486(2006)。
神经变性疾病：
通过细胞胆固醇水平的调节，LXR激动剂可以减少β-淀粉样蛋白在脑中的沉积。另外，已经证实，T0901317会降低β-淀粉样蛋白的沉积，并且提高记忆力。参见Riddell等人，Mol.Cell.Neurosci.34：621-628(2007)。因此，本发明的激动剂衍生物可能在诸如阿尔茨海默病等神经变性疾病中具有治疗效用。
联合治疗：
本发明的化合物可以与另一种治疗剂相组合，所述另一种治疗剂用于治疗其它代谢病症，例如：高血压、高血脂、血脂异常、糖尿病、慢性炎性病症、肥胖症，和其中胆固醇逆行转运的增强和/或LDL∶HDL比的提高是潜在地临床上有益的任意病症。这样的治疗的实例是：3-羟基-3-甲基-戊二酰-CoA还原酶(HMG CoA还原酶)的抑制剂(例如阿托伐他汀、普伐他汀、辛伐他汀、洛伐他汀、罗舒伐他汀和其它)，胆固醇吸收抑制剂(例如依折麦布)，胆汁多价螯合剂(例如考来烯胺)，微粒体甘油三酯转移蛋白(MTP)抑制剂，过氧化物酶体增殖子-激活的受体调节剂(例如莫格列他、罗格列酮、贝特类和其它)，胆固醇酯转移蛋白抑制剂，烟酸衍生物(例如Niaspan
等)，酰基辅酶A：胆固醇酰基转移酶(ACAT)抑制剂(例如eflucimibe)，法尼酯X受体调节剂，用于治疗代谢综合征或II型糖尿病的治疗，例如二甲双胍。本发明的化合物可以与抗炎治疗(例如aspirin)和神经变性疾病的治疗(例如AriceptExelon
Reminyl
和Ebixa
)相组合。
本发明的化合物可以以足够的量施用给人足够的时间，以缓解症状。对于人而言，例证性的日剂量水平可以在0.001-50mg/kg体重的范围内，优选0.01-20mg/kg体重的日剂量。
下面的实施例例证了本发明。
一般实验
高效液相色谱法(HPLC)
HPLC纯化用于该实验部分中，且是指高效液相色谱法。可以用于纯化化合物的一般方法的一些实例是：使用5％乙腈/95％水至100％乙腈的标准梯度的酸性反相HPLC(水/乙腈/0.1％三氟醋酸)，或使用10％乙腈/90％水至100％乙腈的标准梯度的碱性反相HPLC(水/乙腈/0.1％氨溶液)。紫外检测例如254nM用于收集HPLC级分。该描述提供了一般方法，且设备类型、柱、流动相、检测波长、溶剂梯度和运行时间的变体也可以用于纯化化合物。
游离碱和盐
通过酸性HPLC纯化后，通过常见的一般方法，可以将碱性产物分离为三氟醋酸盐，或释放为游离碱，所述方法例如：强阳离子交换色谱法(使用2M在甲醇中的氨洗脱)，或二氧化硅碳酸酯柱色谱法，或在有机溶剂(例如醋酸乙酯)和水性基质(例如碳酸氢钠)之间分配，分离有机层，用无机固体(例如硫酸镁)干燥，过滤，并在减压下浓缩。
通过标准的方法，也可以将产物的游离碱转化成盐酸盐，所述方法例如：将游离碱溶于二氯甲烷中，并加入2M在醚中的氢氯酸，在减压下浓缩，得到盐酸化物盐。
缩写：
Boc：叔丁氧基羰基；CDCl3：氯仿-d；CD3OD：甲醇-d4；(CD3)2SO：二甲基亚砜-d6；HPLC：高效液相色谱法；HATU：O-(7-氮杂苯并三唑-1-基)-N，N，N，N-四甲基脲六氟磷酸盐；SCX：强阳离子交换；三光气：二(三氯甲基)碳酸酯。
实施例1
N-叔丁基-2-((4-(4-(3-环丁基脲基)苯甲酰基)哌嗪-1-基)甲基)
唑-4-甲酰胺2，2，2-三氟乙酸酯
A：甲基2-(哌嗪-1-基甲基)
唑-4甲酸酯2，2，2-三氟乙酸酯
在室温下用甲基(2-氯甲基)
唑-4甲酸酯(1.0g，5.70mmol；分部分加入)处理叔丁基-1-哌嗪甲酸酯(1.06g，5.70mmol)和N，N-二异丙基乙胺(2.98mL，17.1mmol)的二甲基亚砜(10mL)溶液并且搅拌过夜。混合物用乙酸乙酯稀释并且用饱和氯化钠水溶液洗涤。在硫酸镁上干燥有机层，过滤并且浓缩得到中间体叔丁基4-((4-(甲氧基羰基)
唑2-基)甲基)哌嗪-1-甲酸酯(MS(ESI)m/z 325.7[M+H]+)。在室温下将中间体溶于二氯甲烷(15mL)并且用三氟乙酸(5mL)逐滴处理。搅拌混合物4小时然后在真空下浓缩获得标题化合物(1.60g)。MS(ESI)m/z226.1[M+H]+。
B：乙基4-(3-环丁基脲基)苯甲酸酯
将环丁基胺(27.91g，392.4mmol，33.5mL)逐滴加入4-异氰酸苯甲酸乙酯(25g，130.8mmol)于二氯甲烷中的搅拌溶液。搅拌40分钟后，将已经形成的固体沉淀物滤除并且干燥以得到标题化合物(30.28g)。MS(ESI)m/z 263.1[M+H]+
C：4-(3-环丁基脲基)苯甲酸
将4-(3-环丁基脲基)苯甲酸乙酯(49.9mmol，13.1g)混悬在乙醇(400ml)中，并且用4M氢氧化钠(300mmol，74.9ml)处理。然后将混合物在回流下搅拌18小时。使反应体系冷却，用甲苯(100mL)稀释并且在真空下浓缩。用5M盐酸水溶液酸化到pH 3产生白色固体。该固体通过真空过滤收集，用冷乙醇洗涤并且真空下干燥，获得标题化合物作为白色粉末(11.0g)。
1H NMR(CD3OD，400MHz)：δ1.73(2H，m)，1.92(2H，m)，2.32(2H，m)，4.22(1H，m)，7.45(2H，d)，7.90(2H，d)
D：甲基2-((4-(4-(3-环丁基脲基)苯甲酰基)哌嗪-1-基)甲基)
唑-4甲酸酯
向甲基2-(哌嗪-1-基甲基)
唑-4-甲酸酯2，2，2-三氟乙酸酯(174mg，513μmol)和于N，N-二甲基甲酰胺(5mL)中的4-(3-环丁基脲基)苯甲酸(120mg，513μmol)的N，N-二甲基甲酰胺(3mL)溶液中加入N，N-二异丙基乙胺(357μL，2.05mmol)，然后加入O-(7-氮杂苯并三唑-1-基)-N，N，N，N-四甲基脲六氟磷酸盐(293mg，770μmol；HATU)。将混合物在室温下搅拌22小时然后在真空下浓缩。该残余物溶解在乙酸乙酯中用饱和氯化铵水溶液和盐水洗涤。有机相在硫酸镁上干燥，过滤并且在真空下浓缩。粗残余物应用到硅胶柱上并且用于正己烷中的25％乙酸乙酯洗脱，获得标题化合物(34mg)。MS(ESI)m/z 442.1[M+H]+
E：2-((4-(4-(3-环丁基脲基)苯甲酰基)哌嗪-1-基)甲基)
唑-4-
甲酸2，2，2-三氟乙酸酯
在室温下将甲基2-((4-(4-(3-环丁基脲基)苯甲酰基)哌嗪-1-基)甲基)唑-4甲酸酯(30mg，68μmol)溶于甲醇/水(5∶1；3mL)的混合物。加入氢氧化锂(20mg，477μmol；单水合物)，并且搅拌混合物1小时。将混合物浓缩至接近干燥，用水(2mL)稀释并且通过加入浓盐酸使其到pH 2-3。通过酸性反相HPLC纯化粗溶液，得到标题化合物(32mg)。MS(ESI)m/z 428.1[M+H]+
F：1-(4-(1-((4-(叔丁基氨基甲酰基)
唑2-基)甲基)哌嗪-4-羰
基)苯基)-3-环丁基脲2，2，2-三氟乙酸酯
向2-((4-(4-(3-环丁基脲基)苯甲酰基)哌嗪-1-基)甲基)
唑-4-甲酸2，2，2-三氟乙酸酯(8mg，15μmol)于N，N-二甲基乙酰胺(1mL)的溶液中加入O-(7-氮杂苯并三唑-1-基)-N，N，N，N-四甲基脲六氟磷酸盐(5.7mg，15μmol；HATU)，叔丁基胺(1.6μL，15μmol)和N，N-二异丙基乙胺(3.9μL，23μmol)。将反应混合物在室温下搅拌20小时然后在真空下浓缩。通过酸性反相HPLC纯化粗残余物，得到标题化合物(5.6mg)。MS(ESI)m/z 483.1[M+H]+
按照类似方式制备下列化合物：
1B：N-环丁基-2-((4-(4-(3-环丁基脲基)苯甲酰基)哌嗪-1-基)甲
基)
唑-4-甲酰胺
MS(ESI)m/z 481.1[M+H]+
1C：N-仲-丁基-2-((4-(4-(3-环丁基脲基)苯甲酰基)哌嗪-1-基)甲
基)
唑-4-甲酰胺2，2，2-三氟乙酸酯，外消旋体
MS(ESI)m/z 483.1[M+H]+。
1D：2-((4-(4-(3-环丁基脲基)苯甲酰基)哌嗪-1-基)甲基)-N-环戊
基-
唑-4-甲酰胺2，2，2-三氟乙酸酯
MS(ESI)m/z 495.1[M+H]+。
实施例2
N-叔丁基-2-((4-(4-(3-(环丙基甲基)脲基)-3-氟苯甲酰基)哌嗪
-1-基)甲基)噻唑-4-甲酰胺
A：2-((4-(叔丁氧羰基)哌嗪-1-基)甲基)噻唑-4-甲酸乙酯
合并1-哌嗪甲酸叔丁酯(1.811g，9.72mmol)，2-氯甲基噻唑-4-甲酸乙酯(2g，9.72mmol)，碳酸钾(2.69g，19.45mmol)和碘化钠(0.292g，1.945mmol)，在乙腈中在回流下搅拌2小时。减压浓缩该反应体系，将残余物溶于二氯甲烷，过滤。减压浓缩滤液，得到标题化合物(4.38g)。
MS(ESI)m/z 356.5[M+H]+
B：2-((4-(叔丁氧羰基)哌嗪-1-基)甲基)噻唑-4-甲酸钠
合并2-((4-(叔丁氧羰基)哌嗪-1-基)甲基)噻唑-4-甲酸乙酯(4.3871g，12.34mmol)和氢氧化钠(0.494g，12.34mmol)，在乙醇中在回流状态下搅拌3小时。减压浓缩该反应体系，得到标题化合物(3.56g)。MS(ESI)m/z 328.3[M+H]+
C：4-((4-(叔丁基氨基甲酰基)噻唑-2-基)甲基)哌嗪-1-甲酸叔丁
酯
向2-((4-(叔丁氧羰基)哌嗪-1-基)甲基)噻唑-4-甲酸钠(3.596g，10.29mmol)、叔丁基胺(0.753g，10.29mmol，1.082mL)和三乙胺(3.12g，30.9mmol，4.29mL)在二氯甲烷(50mL)中的溶液中加入1-丙烷膦酸环酐(13.10g，20.58mmol，12.25mL，50％的乙酸乙酯溶液)。减压浓缩该反应体系，将残余物溶于乙酸乙酯，用碳酸氢钠(x3)和盐水洗涤。减压浓缩有机相，得到标题化合物(2.10g)。MS(ESI)m/z 283.5[M+H]+
D：N-叔丁基-2-(哌嗪-1-基甲基)噻唑-4-甲酰胺
将4-((4-(叔丁基氨基甲酰基)噻唑-2-基)甲基)哌嗪-1-甲酸叔丁酯(2.1g，5.49mmol)溶于二氯甲烷(20mL)。加入2，2，2-三氟乙酸(20mL)，将该反应混合物搅拌2小时。减压浓缩该反应体系，通过SCX柱色谱法纯化，得到标题化合物(1.28g)。MS(ESI)m/z 283.4[M+H]+
E：2-((4-(4-氨基-3-氟苯甲酰基)哌嗪-1-基)甲基)-N-叔-丁基噻
唑-4-甲酰胺
向4-氨基-3-氟苯甲酸(0.703g，4.53mmol)、N-叔丁基-2-(哌嗪-1-基甲基)噻唑-4-甲酰胺(1.28g，4.53mmol)和三乙胺(0.459g，4.53mmol，0.630mL)在二氯甲烷中的溶液中加入1-丙烷膦酸环酐(2.88g，4.53mmol，2.70mL，50％的乙酸乙酯溶液)。减压浓缩该反应体系，将残余物溶于乙酸乙酯，用碳酸氢钠(x3)和盐水洗涤。减压浓缩有机相，得到标题化合物(0.87g)。MS(ESI)m/z 420.3[M+H]+
F：N-叔丁基-2-((4-(4-(3-(环丙基甲基)脲基)-3-氟苯甲酰基)哌 嗪-1-基)甲基)噻唑-4-甲酰胺
合并2-((4-(4-氨基-3-氟苯甲酰基)哌嗪-1-基)甲基)-N-叔-丁基噻唑-4-甲酰胺(100mg，0.238mmol)和氯甲酸4-硝基苯酚酯(48mg，0.238mmol)，在室温在二氯甲烷中搅拌1小时。加入环丙基甲基胺(50.9mg，0.715mmol，62μl)，将该反应体系搅拌30分钟。用水稀释该反应混合物，流过疏水玻璃料。真空浓缩有机相，通过酸性反相HPLC纯化，得到标题化合物(5mg)。MS(ESI)m/z 517.3[M+H]+
按照类似方式制备下列化合物：
2B：N-叔丁基-2-((4-(4-(3-环丁基脲基)苯甲酰基)哌嗪-1-基)甲
基)-噻唑-4-甲酰胺
MS(ESI)m/z 517.5[M+H]+
2C：N-叔丁基-2-((4-(4-(3-异戊基脲基)苯甲酰基)哌嗪-1-基)甲
基)噻唑-4-甲酰胺
MS(ESI)m/z 533.5[M+H]+
实施例3
N-叔丁基-5-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)
甲基)呋喃-2-甲酰胺
A：4-((5-(甲氧羰基)呋喃-2-基)甲基)哌嗪-1-甲酸叔丁酯
合并1-哌嗪甲酸叔丁酯(2.134g，11.46mmol)、5-(氯甲基)-2-糠酸甲酯(2g，11.46mmol)、碳酸钾(3.17g，22.91mmol)和碘化钠(0.343g，2.291mmol)，在乙腈中在回流下搅拌2小时。减压浓缩该反应体系，将残余物溶于二氯甲烷，过滤。减压浓缩滤液，得到标题化合物(4.99g)。MS(ESI)m/z 325.3[M+H]+
B：5-((4-(叔丁氧羰基)哌嗪-1-基)甲基)呋喃-2-甲酸钠
合并4-((5-(甲氧羰基)呋喃-2-基)甲基)哌嗪-1-甲酸叔丁酯(4.99g，15.39mmol)和氢氧化钠(0.616g，15.39mmol)，在回流状态下搅拌3小时。减压浓缩该反应体系，得到标题化合物(4.59g)。MS(ESI)m/z 311.4[M+H]+
C：4-((5-(叔丁基氨基甲酰基)呋喃-2-基)甲基)哌嗪-1-甲酸叔丁
酯
向5-((4-(叔丁氧羰基)哌嗪-1-基)甲基)呋喃-2-甲酸钠(4.558g，13.72mmol)、2-甲基丙-2-胺(1.003g，13.72mmol，1.441mL)和三乙胺(4.16g，41.1mmol，5.72mL)在二氯甲烷中的溶液中加入1-丙烷膦酸环酐(17.46g，27.4mmol，16.33mL，50％的乙酸乙酯溶液)。将该反应体系搅拌2小时，然后减压浓缩。将残余物溶于乙酸乙酯，用碳酸氢钠、水和盐水洗涤。减压浓缩有机相，得到标题化合物(2.4g)。MS(ESI)m/z366.3[M+H]+
D：N-叔丁基-5-(哌嗪-1-基甲基)呋喃-2-甲酰胺
将4-((5-(叔丁基氨基甲酰基)呋喃-2-基)甲基)哌嗪-1-甲酸叔丁酯(6.57mmol，2.4g)溶于二氯甲烷(20mL)。加入2，2，2-三氟乙酸(20mL)，将该反应混合物搅拌2小时。减压浓缩该反应体系，通过SCX色谱法纯化，得到标题化合物(1.51g)。MS(ESI)m/z 266.4[M+H]+
E：5-((4-(4-氨基-3-氟苯甲酰基)哌嗪-1-基)甲基)-N-叔-丁基呋
喃-2-甲酰胺
向4-氨基-3-氟苯甲酸(0.883g，5.69mmol)、N-叔丁基-5-(哌嗪-1-基甲基)呋喃-2-甲酰胺(1.51g，5.69mmol)和三乙胺(0.576g，5.69mmol，0.791mL)在二氯甲烷中的溶液中加入1-丙烷膦酸环酐(3.62g，5.69mmol，3.39mL，50％的乙酸乙酯溶液)。将该反应体系搅拌2小时，然后减压浓缩。将残余物溶于乙酸乙酯，用碳酸氢钠、水和盐水洗涤。减压浓缩有机相，得到标题化合物(0.93g)。MS(ESI)m/z 403.6[M+H]+
F：N-叔丁基-5-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)
甲基)呋喃-2-甲酰胺
合并5-((4-(4-氨基-3-氟苯甲酰基)哌嗪-1-基)甲基)-N-叔-丁基呋喃-2-甲酰胺(113mg，0.280mmol)和氯甲酸4-硝基苯酚酯(56mg，0.238mmol)，在二氯甲烷中在室温搅拌1小时。加入环丁基胺(59.6mg，0.839mmol，71.6μl)，将该反应体系搅拌30分钟。用水稀释该反应混合物，流过疏水玻璃料。真空浓缩有机相，通过酸性反相HPLC纯化，得到标题化合物(10mg)。MS(ESI)m/z 500.3[M+H]+
按照类似方式制备下列化合物：
3B：N-叔丁基-5-((4-(3-氟-4-(3-异戊基脲基)苯甲酰基)哌嗪-1-
基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 516.5[M+H]+
实施例4
N-叔丁基-5-((4-(3-氟-4-(3-异丁基脲基)苯甲酰基)哌嗪-1-基)
甲基)呋喃-2-甲酰胺
将5-((4-(4-氨基-3-氟苯甲酰基)哌嗪-1-基)甲基)-N-叔-丁基呋喃-2-甲酰胺(实施例3；0.05g，0.124mmol)和N，N-二异丙基乙胺(0.028mL)溶于二氯甲烷(5mL)。滴加双(三氯甲基)碳酸酯(0.014g，0.046mmol)，将该反应体系保持搅拌30分钟。向该反应体系中加入N，N-二异丙基乙胺(0.094mL)，然后加入2-甲基丙-1-胺(0.018g，0.248mmol，0.025mL)，将该反应体系再搅拌2小时。用水稀释该反应混合物，流过疏水玻璃料。真空浓缩有机相，通过碱性反相HPLC纯化，得到标题化合物(5mg)。
MS(ESI)m/z 502.5[M+H]+
按照类似方式制备下列化合物：
4B：N-叔丁基-5-((4-(4-(3-(环丙基甲基)脲基)-3-氟苯甲酰基)哌
嗪-1-基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 500.5[M+H]+
4C：N-叔丁基-5-((4-(3-氟-4-(3-新戊基脲基)苯甲酰基)哌嗪-1-
基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 516.3[M+H]+
实施例5
使用与实施例1-4中描述的类似的方法制备下列化合物：
5A：N-叔丁基-5-((4-(4-(3-丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)
甲基)呋喃-2-甲酰胺盐酸盐
MS(ESI)m/z 502.5[M+H]+
5B：N-环丁基-5-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1- 基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 498.5[M+H]+
5C：N-环丁基-5-((4-(3-氟-4-(3-异丁基脲基)苯甲酰基)哌嗪-1-
基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 500.4[M+H]+
5D：(R)-N-仲-丁基-5-((4-(4-(3-(环丙基甲基)脲基)苯甲酰基)哌 嗪-1-基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 482.4[M+H]+
5E：5-((4-(4-(3-(环丙基甲基)脲基)-3-氟苯甲酰基)哌嗪-1-基) 甲基)-N-(1-甲基环丙基)呋喃-2-甲酰胺
MS(ESI)m/z 498.5[M+H]+
5F：5-((4-(4-(3-(环丙基甲基)脲基)-3-氟苯甲酰基)哌嗪-1-基)
甲基)-N-(3，3-二氟环丁基)呋喃-2-甲酰胺
MS(ESI)m/z 534.3[M+H]+
5G：N-叔丁基-5-((4-(3-氯-4-(3-新戊基脲基)苯甲酰基)哌嗪-1- 基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 532.5[M+H]+
5H：N-叔丁基-5-((4-(3-氯-4-(3-异丁基脲基)苯甲酰基)哌嗪-1-
基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 518.8[M+H]+
5I：N-叔丁基-5-((4-(3-氯-4-(3-(环丙基甲基)脲基)苯甲酰基)哌
嗪-1-基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 516.5[M+H]+
5J：N-叔丁基-5-((4-(3-氦-4-(3-异戊基脲基)苯甲酰基)哌嗪-1-
基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 532.3[M+H]+
5K：N-叔丁基-5-((4-(4-(3-丁基脲基)-3-氯苯甲酰基)哌嗪-1-基)
甲基)呋喃-2-甲酰胺
MS(ESI)m/z 518.5[M+H]+
5L：N-叔丁基-5-((4-(3-氯-4-(3-环丁基脲基)苯甲酰基)哌嗪-1-
基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 516.5[M+H]+
5M：N-叔丁基-5-((4-(3-氯-4-(3-(2-羟基-2-甲基丙基)脲基)苯甲
酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 534.5[M+H]+
5N：N-叔丁基-5-((4-(3-氯-4-(3-((1-羟基环丙基)甲基)脲基)苯
甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 532.3[M+H]+
5O：N-叔丁基-5-((4-(3-氯-4-(3-((1-异氰基环丙基)甲基)脲基)
苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 541.5[M+H]+
如下制备合成中需要的1-(氨基甲基)环丙烷腈：
步骤1：向1-氰基环丙烷羧酸乙酯(35.9mmol，5g)、二甲氧基乙烷(100mL)和甲醇(10mL)的混合物中缓慢加入硼氢化钠(287mmol，10.87g)，将该混合物在室温搅拌18小时。用饱和碳酸氢钠缓慢稀释该溶液，然后用10％甲醇/二氯甲烷(x3)萃取。合并有机层，用硫酸钠干燥，真空浓缩，得到中间体1-(羟基甲基)环丙烷腈(2.36g)。
1H NMR(CDCl3，400MHz)：δ0.99(2H，m)，1.28(2H，m)，2.5(1H，br s)，3.62(2H，s)
步骤2：用三乙胺(48.6mmol，6.83mL，4.92g)且分部份地用甲磺酰氯(31.6mmol，2.445mL，3.62g)处理1-(羟基甲基)环丙烷腈(24.30mmol，2.36g)在二氯甲烷(30mL)中的搅拌混合物，保持该反应混合物在0℃。将该溶液搅拌1小时，然后用饱和碳酸氢钠稀释，用10％甲醇/二氯甲烷(x3)萃取。合并有机层，减压浓缩，得到中间体甲磺酸(1-氰基环丙基)甲酯(3.77g)。
1H NMR(CDCl3，400MHz)：δ1.18(2H，m)，1.46(2H，m)，3.14(3H，s)，4.18(2H，s)
步骤3：将甲磺酸(1-氰基环丙基)甲酯(21.52mmol，3.77g)和叠氮化钠(43.0mmol，2.80g)在N，N-二甲基甲酰胺(40mL)中的搅拌混合物加热至120℃～18小时。将该混合物冷却，用水和乙酸乙酯稀释。分离有机层，用硫酸钠干燥，减压浓缩，得到油状物。将该油状物溶于乙醚，用水洗涤，干燥，减压浓缩，得到中间体1-(叠氮基甲基)环丙烷腈(1.8g)，为油状物。
1H NMR(CDCl3，400MHz)：δ1.02(2H，m)，1.36(2H，m)，3.38(2H，s)
步骤4：向1-(叠氮基甲基)环丙烷腈(14.74mmol，1.8g)在甲醇中(20mL)中的溶液中加入包含水(200μL)的10％钯/碳(14.74mmol，200mg)。将该混合物在3巴的氢气气氛中在室温搅拌过夜。通过过滤除去催化剂，减压浓缩滤液，得到标题化合物(1.3g)。
1H NMR(CDCl3，400MHz)：δ0.87(2H，m)，1.23(2H，m)，2.76(2H，s)
5P：N-叔丁基-5-((4-(4-(3-(环丙基甲基)脲基)-2，3-二氟苯甲酰
基)哌嗪-1-基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 518.5[M+H]+
5Q：N-叔丁基-5-((4-(2，3-二氟-4-(3-新戊基脲基)苯甲酰基)哌嗪
-1-基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 534.5[M+H]+
5R：N-叔丁基-5-((4-(4-(3-丁基脲基)-2，3-二氟苯甲酰基)哌嗪
-1-基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 520.3[M+H]+
5S：N-叔丁基-5-((4-(2，3-二氟-4-(3-异丁基脲基)苯甲酰基)哌嗪
-1-基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 520.7[M+H]+
5T：N-叔丁基-5-((4-(2，3-二氟-4-(3-异戊基脲基)苯甲酰基)哌嗪
-1-基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 534.3[M+H]+
5U：N-叔丁基-5-((4-(4-(3-环丁基脲基)-2，3-二氟苯甲酰基)哌嗪
-1-基)甲基)呋喃-2-甲酰胺
MS(ESI)m/z 518.5[M+H]+
实施例6
5-((4-(4-(3-(环丙基甲基)脲基)苯甲酰基)哌嗪-1-基)甲基)-N-
叔-戊基噻吩-2-甲酰胺
A：4-(3-(环丙基甲基)脲基)苯甲酸乙酯
向在二氯甲烷(40mL)中的环丙基甲胺(57.5mmol，4.99ml，4.09g)加入在二氯甲烷(45mL)中的4-异氰酸苯甲酸乙酯(52.3mmol，10g)，将该反应体系搅拌过夜。然后减压浓缩该反应体系，得到标题化合物(14.7g)。
1H NMR(CDCl3，400MHz)：δ0.2(2H，m)0.5，(2H，m)0.95(1H，m)1.4(3H，t)，3.1(2H，m)4.35(2H，q)，5.15(1H，br s)，7.0，1H，7.4(2H，d)8.0(2H，d)
B：4-(3-(环丙基甲基)脲基)苯甲酸
将4-(3-(环丙基甲基)脲基)苯甲酸乙酯(55.3mmol，14.5g)混悬于乙醇(400ml)，加入4M氢氧化钠(332mmol，83mL)。然后回流该反应体系，直到皂化完成为止。通过蒸发除去乙醇，用浓盐酸中和反应体系。收集白色沉淀，用水洗涤。真空干燥该物质，得到标题化合物(12.1g)。
1H NMR((CD3)2SO，400MHz)：δ0.2(2H，m)0.5，(2H，m)0.95(1H，m)，3.0(2H，m)6.35(1H，br s)7.4(2H，d)7.8(2H，d)8.9(1H，brs)
C：4-(4-(3-(环丙基甲基)脲基)苯甲酰基)哌嗪-1-甲酸叔丁酯
将哌嗪-1-甲酸叔丁酯(45.8mmol，8.53g)和4-(3-(环丙基甲基)脲基)苯甲酸(45.8mmol，10.73g)在二氯甲烷(200mL)中混合，加入三乙胺(103mmol，14.36ml，10.43g)，然后加入1-丙烷膦酸环酐(68.7mmol，40.7mL，43.7g，50％的乙酸乙酯溶液)。将该反应体系搅拌1小时，然后倾入饱和碳酸氢钠溶液，用二氯甲烷萃取。干燥有机相(硫酸镁)，过滤，减压浓缩得到标题化合物(17.13g)。
MS(ESI)m/z 403.5[M+H]+
D：1-(环丙基甲基)-3-(4-(哌嗪-1-羰基)苯基)脲
将4-(4-(3-(环丙基甲基)脲基)苯甲酰基)哌嗪-1-甲酸叔丁酯(46.7mmol，18.78g)溶于二氯甲烷(30mL)，加入三氟乙酸(233mmol，17.33ml，26.6g)。将该反应体系搅拌1小时，然后减压浓缩。将粗物质与乙醚一起研磨，高度真空干燥后得到白色粉末。将该白色粉末溶于水，用碳酸钠谨慎达到pH 10。然后用二氯甲烷萃取水相，干燥合并的有机相，过滤，减压浓缩得到标题化合物(13.4g)。
1H NMR(CDCl3，400MHz)：δ0.2(2H，m)0.5，(2H，m)0.95(1H，m)2.2(2H，s，br)，2.8(4H，br s)，3.6(4H，br s)，5.8(1H，m)7.2(4H，m)
E：5-((4-(4-(3-(环丙基甲基)脲基)苯甲酰基)哌嗪-1-基)甲基)噻
吩-2-甲酸甲酯
将1-(环丙基甲基)-3-(4-(哌嗪-1-羰基)苯基)脲(4.25mmol，1.286g)、5-(溴甲基)噻吩-2-甲酸甲酯(4.25mmol，1g)和碳酸钾(12.76mmol，1.764g)在室温在乙腈(20mL)中搅拌18小时。减压浓缩该反应混合物，将得到的残余物溶于二氯甲烷，用水洗涤，用硫酸钠干燥，真空浓缩，得到标题化合物(1.764g)。MS(ESI)m/z 457.5[M+H]+
F：5-((4-(4-(3-(环丙基甲基)脲基)苯甲酰基)哌嗪-1-基)甲基)噻
吩-2-甲酸
合并5-((4-(4-(3-(环丙基甲基)脲基)苯甲酰基)哌嗪-1-基)甲基)噻吩-2-甲酸甲酯(3.86mmol，1.764g)和氢氧化钠(3.86mmol，0.155g)，在甲醇中加热至回流18小时。减压浓缩该反应混合物，通过SCX柱色谱法纯化得到的残余物，得到标题化合物(1.00g)。
MS(ESI)m/z 443.3[M+H]+
G：5-((4-(4-(3-(环丙基甲基)脲基)苯甲酰基)哌嗪-1-基)甲
基)-N-叔-戊基噻吩-2-甲酰胺
合并5-((4-(4-(3-(环丙基甲基)脲基)苯甲酰基)哌嗪-1-基)甲基)噻吩-2-甲酸(100mg，0.226mmol)、N，N-二异丙基乙胺(99mg，0.127mL，0.452mmol)和叔-戊基胺(39mg，0.452mmol)，在二氯甲烷中搅拌。加入1-丙烷膦酸环酐(216mg，0.202mL，0.339mmol，50％的乙酸乙酯溶液)，将该反应体系在室温搅拌1小时。用饱和碳酸氢钠溶液洗涤该反应混合物，用硫酸钠干燥，真空浓缩，通过反相酸性制备型HPLC纯化，得到标题化合物(5mg)。MS(ESI)m/z 512.8[M+H]+
按照类似方式制备下列化合物：
6B：N-叔丁基-5-((4-(4-(3-(环丙基甲基)脲基)苯甲酰基)哌嗪-1-
基)甲基)噻吩-2-甲酰胺
MS(ESI)m/z 498.5[M+H]+
实施例7
N-叔丁基-3-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)
甲基)-1H-吡唑-1-甲酰胺
A：N-叔丁基-3-甲基-1H-吡唑-1-甲酰胺
向在二氯甲烷(30mL)中的异氰酸叔丁酯(1.57mL，1.34g，13.70mmol)中加入3-甲基-1H-吡唑(0.98mL，1g，12.18mmol)。将该混合物在室温搅拌过夜，然后真空浓缩。通过硅胶色谱法纯化粗物质(用二氯甲烷洗脱)得到标题化合物(2.1g)。
1H NMR(CD3OD，400MHz)：δ1.46(9H，s)，2.28(3H，s)，6.14(2H，d)，7.02(1H，br s)，8.08(1H，d)
B：3-(溴甲基)-N-叔丁基-1H-吡唑-1-甲酰胺
在四氯化碳(12mL)中的N-叔丁基-3-甲基-1H-吡唑-1-甲酰胺(609mg，3.36mmol)中加入N-溴琥珀酰亚胺(849mg，4.77mmol)和过氧化苯甲酰(114mg，0.470mmol)。将该混合物加热至回流过夜，然后用水和乙酸乙酯稀释。分离有机层，干燥，减压浓缩。通过硅胶色谱法纯化粗物质(用于庚烷中的10％乙酸乙酯洗脱)，得到标题化合物(280mg)。
1H NMR(CDCl3，400MHz)：δ1.47(9H，s)，4.43(2H，d)，6.42(1H，d)，6.99(1H，br s)，8.14(1H，d)
C：4-(4-氨基-3-氟苯甲酰基)哌嗪-1-甲酸叔丁酯
向搅拌的4-氨基-3-氟苯甲酸(4.97g，32.04mmol)、哌嗪-1-甲酸叔丁酯(5.97g，32.04mmol)和三乙胺(10mL)在二氯甲烷(100mL)中的溶液中加入1-丙烷膦酸环酐(20mL，50％的乙酸乙酯溶液，滴加)。将该反应混合物搅拌1小时，然后用乙酸乙酯稀释，用碳酸钾(水溶液)洗涤，干燥(硫酸镁)，减压浓缩得到标题化合物(9.5g)。MS(ESI)m/z：324.5[M+H]+。
D：4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-甲酸叔丁酯
将4-(4-氨基-3-氟苯甲酰基)哌嗪-1-甲酸叔丁酯(9.5g，29.41mmol)溶于二氯甲烷(100mL)，加入4-硝基苯基氯甲酸酯(5.93g，29.41mmol)。将该反应混合物搅拌20小时，加入环丁基胺(7.5mL，88.2mmol)。2小时后，对该反应混合物进行硅胶色谱(用二氯甲烷至二氯甲烷/乙酸乙酯洗脱)，得到标题化合物(2.8g)。MS(ESI)m/z：421.0[M+H]+
E：1-环丁基-3-(2-氟-4-(哌嗪-1-羰基)苯基)脲
将4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-甲酸叔丁酯(2.8g，66.67mmol)、三氟乙酸和二氯甲烷搅拌20小时，然后减压浓缩。将残余物溶于二氯甲烷/甲醇，上强阳离子交换柱，用二氯甲烷/甲醇洗涤。用于甲醇中的2M氨洗脱柱，得到标题化合物(1.6g)。MS(ESI)m/z：321.4[M+H]+
F：N-叔丁基-3-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)
甲基)-1H-吡唑-1-甲酰胺
向在乙腈(3.9mL)中的3-(溴甲基)-N-叔丁基-1H-吡唑-1-甲酰胺(102mg，0.392mmol)中加入1-环丁基-3-(2-氟-4-(哌嗪-1-羰基)苯基)脲(126mg，0.392mmol)和三乙胺(109μl，79mg，0.782mmol)。向该混合物中加入匙尖碘化钠。将该混合物加热至回流过夜，然后用水和乙酸乙酯稀释。分离有机层，干燥，减压浓缩。通过硅胶色谱法纯化残余物，用于二氯甲烷中的2％甲醇洗脱。将残余物溶于二氯甲烷/甲醇，上强阳离子交换柱，用二氯甲烷/甲醇洗脱。用于甲醇中的2M氨洗脱柱，得到标题化合物(44mg)。
MS(ESI)m/z 500.3[M+H]+
实施例8
N-叔丁基-4-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)
甲基)吡啶酰胺
A：N-叔丁基-4-甲基吡啶酰胺
合并4-甲基吡啶-2-甲酸(500mg，3.65mmol)、三乙胺(1.27g，12.5mmol，1.75mL)和叔-丁基胺(267mg，3.65mmol)，在二氯甲烷(10mL)中搅拌。滴加1-丙烷膦酸环酐(4.82g，7.5mmol，4.5mL，50％的乙酸乙酯溶液)，将该反应体系在室温搅拌1小时。减压浓缩该反应混合物，将得到的残余物溶于乙酸乙酯，用饱和碳酸氢钠溶液洗涤，用硫酸钠干燥有机相，真空浓缩，得到标题化合物(376mg)。MS(ESI)m/z 193.4[M+H]+
B：4-(溴甲基)-N-叔-丁基吡啶酰胺
在氯苯(5mL)中合并N-叔丁基-4-甲基吡啶酰胺(100mg，0.52mmol)和N-溴琥珀酰亚胺(46mg，0.52mmol)，在日光灯下搅拌1小时。减压浓缩该反应混合物。将得到的残余物溶于二氯甲烷，用水洗涤。用硫酸钠干燥有机相，真空浓缩，得到标题化合物(120mg)。MS(ESI)m/z 271.5[M+H]+
C：N-叔丁基-4-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)
甲基)吡啶酰胺
合并4-(溴甲基)-N-叔-丁基吡啶酰胺(70mg，0258mmol)、1-(环丁基甲基)-3-(2-氟-4-(哌嗪-1-羰基)苯基)脲(83mg，0.258mmol)和碳酸钾(106mg，0.744mmol)，在乙腈中加热至回流1小时。减压浓缩该反应混合物，通过反相酸性制备型HPLC纯化得到的残余物，得到标题化合物(41mg)。MS(ESI)m/z 511.6[M+H]+
实施例9
N-叔丁基-6-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)
甲基)吡啶酰胺
A：6-((甲基磺酰氧基)甲基)吡啶甲酸甲酯
合并6-(羟基甲基)吡啶甲酸酯(200mg，1.196mmol)和三乙胺(363mg，3.588mmol，0.5mL)，在0℃在二氯甲烷(2mL)中搅拌。加入甲磺酰氯(206mg，1.794mmol)，将该反应体系在1小时内温至室温。用水洗涤该反应体系，用硫酸钠干燥，真空浓缩，得到标题化合物(293mg)。MS(ESI)m/z 246.3[M+H]+
B：6-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)吡
啶甲酸甲酯
合并6-((甲基磺酰氧基)甲基)吡啶甲酸甲酯(300mg，1.22mmol)、1-(环丁基甲基)-3-(2-氟-4-(哌嗪-1-羰基)苯基)脲(391mg，1.22mmol)和碳酸钾(505mg，3.66mmol)，在乙腈中搅拌18小时。减压浓缩该反应混合物。将得到的残余物溶于二氯甲烷，用水洗涤，用硫酸钠干燥，真空浓缩，得到标题化合物(407mg)。
MS(ESI)m/z 470.5[M+H]+
C：6-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)吡
啶甲酸钠
合并6-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)吡啶甲酸甲酯(400mg，0.852mmol)和氢氧化钠(35mg，0.852mmol)，在甲醇中加热至回流18小时。减压浓缩该反应混合物，得到标题化合物(323mg)。
MS(ESI)m/z 456.5[M+H]+
D：N-叔丁基-6-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)
甲基)吡啶酰胺
合并6-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)吡啶甲酸钠(100mg，0.209mmol)、三乙胺(66mg，0.693mmol，0.091mL)和叔-丁基胺(32mg，0.435mmol)，在室温在二氯甲烷中搅拌。滴加1-丙烷膦酸环酐(208mg，0.326mmol，0.194mL，50％的乙酸乙酯溶液)，将该反应体系搅拌1小时。减压浓缩该反应混合物，将得到的残余物溶于乙酸乙酯，用饱和碳酸氢钠溶液洗涤。用硫酸钠干燥有机相，真空浓缩，得到标题化合物(24mg)。MS(ESI)m/z 511.6[M+H]+
使用类似方法制备下列化合物：
9B：N-叔丁基-6-((4-(3-氟-4-(3-新戊基脲基)苯甲酰基)哌嗪-1- 基)甲基)吡啶酰胺
MS(ESI)m/z 527.0[M+H]+
9C：N-叔丁基-6-((4-(3-氟-4-(3-异戊基脲基)苯甲酰基)哌嗪-1-
基)甲基)吡啶酰胺
MS(ESI)m/z 527.0[M+H]+
9D：N-叔丁基-6-((4-(4-(3-(环丙基甲基)脲基)-3-氟苯甲酰基)哌
嗪-1-基)甲基)吡啶酰胺
MS(ESI)m/z 511.3[M+H]+
实施例10
N-叔丁基-2-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)
甲基)异烟酰胺
A：2-((甲基磺酰氧基)甲基)异烟酸甲酯
将2-(羟基甲基)异烟酸甲酯(3.17mmol，0.530g)和三乙胺(9.51mmol，1.322mL，0.963g)在二氯甲烷(20mL)中在0℃搅拌。滴加甲磺酰氯(4.76mmol，0.368mL，0.545g)，将该反应体系在室温搅拌1小时。用水洗涤该反应混合物，用硫酸钠干燥，真空浓缩，得到标题化合物(686mg)。MS(ESI)m/z 246.4[M+H]+
B：2-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)异
烟酸甲酯
合并2-(甲基磺酰基基)异烟酸甲酯(2.99mmol，0.686g)、1-环丁基-3-(2-氟-4-(哌嗪-1-羰基)苯基)脲(2.99mmol，0.959g)和碳酸钾(8.98mmol，1.241g)，在乙腈(20mL)中加热至40℃2小时。减压浓缩该反应混合物，将残余物溶于二氯甲烷。用硫酸钠干燥有机相，真空浓缩。通过硅胶色谱法纯化残余物(用二氯甲烷至6％甲醇/二氯甲烷的溶剂梯度洗脱)，得到标题化合物(822mg)。MS(ESI)m/z 470.5[M+H]+
C：2-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)异 烟酸钠
将2-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)异烟酸甲酯(1.746mmol，0.82g)和氢氧化钠(1.746mmol，0.070g)在甲醇中(20mL)加热至回流18小时。减压浓缩该反应混合物，得到标题化合物(798mg)。
MS(ESI)m/z 456.5[M+H]+
D：N-叔丁基-2-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)
甲基)异烟酰胺
将2-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)异烟酸钠(0.209mmol，0.1g)、叔-丁基胺(0.419mmol，0.088mL，0.061g)和三乙胺(0.628mmol，0.087mL，0.064g)在二氯甲烷(10mL)中搅拌。加入1-丙烷膦酸环酐(0.209mmol，0.062mL，0.067g，50％的乙酸乙酯溶液)，将该反应体系在室温搅拌1小时。减压浓缩该反应混合物。将残余物溶于乙酸乙酯，用饱和碳酸氢钠溶液洗涤。用硫酸钠干燥有机相，真空浓缩。通过反相酸性制备型HPLC纯化得到的残余物，得到标题化合物(35mg)。MS(ESI)m/z 511.6[M+H]+
实施例11
使用重组人LXRα或LXRβ蛋白的放射性配体竞争结合闪烁迫近
测定法(SpA)
这些测定用它们与激动剂放射性配体[3H]T0901317的结合竞争的能力来评价化合物的效力。这些测定使用与谷胱甘肽-S-转移酶(GST)标记的蛋白融合的肝X受体α(LXRα)或肝X受体β(LXRβ)的纯化的配体结合域(LBD)(LXRα-LBD-GST和LXRβ-LBD-GST)和闪烁迫近测定法(SpA)技术，以测定化合物在人核激素受体LXRα或LXRβ的配体结合域(LBD)处的结合亲和力(pKi)。
重组人LXRα和LXRβ的制备
在大肠杆菌中将人LXRα和LXRβ表达为GST-融合蛋白。通过PCR，扩增LXRα或LXRβ的LBD，并亚克隆进原核表达载体pGEX-4T-1(GEHealthcare)。来自pGEX-4T-1质粒的LXRα或LXRβ在大肠杆菌中的表达，导致重组谷胱甘肽-S-转移酶(GST)LXRα-LBD或LXRβ-LBD融合蛋白的产生。
培养含有LXRα或LXRβ pGEX-4T-1质粒的大肠杆菌，诱导，并通过离心进行收获。将细菌沉淀物重新悬浮于裂解缓冲液中，所述缓冲液含有50mM三(羟甲基)氨基甲烷(TRIS)-pH 8.0、100mM氯化钠(NaCl)、1mM乙二胺四乙酸(EDTA)和1片完整的蛋白酶抑制剂混合剂/不含EDTA(Roche)(每50ml缓冲液)。用Branson超声波仪，在冰上超声处理混合物。将悬浮液离心，并将二硫苏糖醇(DTT)加入上清液，以得到25mM的终浓度。通过glutathione-Sepharose Fast flow(Amersham)上的亲和色谱法，从得到的上清液纯化重组人LXRα-LBD-GST或LXRβ-LBD-GST蛋白，并用含有谷胱甘肽的缓冲液(50mMtris pH 8.0，2mM DTT，10mM谷胱甘肽)洗脱蛋白。在-80℃在20mMN-2-羟乙基哌嗪-N′-2-乙磺酸(HEPES)、含有10％甘油的2mM DTT中储存蛋白。
与LXRα或LXRβ LBD结合
对于LXRα或LXRβ测定，将重组人LXRα-LBD-GST或LXRβ-LBD-GST蛋白的等分部分稀释至0.5μg/mL，并在终体积为100μL的SpA缓冲液(10mM无水磷酸氢钾[K2HPO4]、10mM磷酸二氢钾[KH2PO4]、2mM EDTA pH 7.1、50mM NaCl、1mM DTT、2mM 3-[(3-胆酰胺基丙基)二甲铵基]-1-丙烷磺酸盐(CHAPS))中温育，所述SpA缓冲液含有终浓度为1mg/mL的蛋白-A偶联的闪烁剂填充的YtSi SpA珠子(GEHealthcare)和终浓度为5μg/ml的山羊抗-GST抗体(GEHealthcare)。在每个测定中，使用T0901317(Kd＝10nM)作为参照。向测定混合物中，加入50nM[3H]T0901317(50Ci/mmol)±实验化合物，并在平板振荡器上在15℃温育混合物2小时。温育后，在PackardTopCount上读出测定平板。在LXRα和LXRβ结合测定中的T0901317pKi值是：pKi＝8.4±0.2。浓度为5μM的T0901317用作最大结合对照。在这些测定中，活性化合物对LXRα和/或LXRβ表现出pKi值＞5.5，且优选的化合物对LXRα和/或LXRβ表现出pKi值＞7。
LXRα和LXRβ反式激活测定
使用重组中国仓鼠卵巢K1(CHO.K1)细胞，体外测量了对LXRα和LXRβ的细胞内激动剂活性，所述细胞稳定地表达含有天然雌激素效应元件(ERE)的萤光素酶报道基因构建体和人雌激素受体α(ERα)/LXRα或ERα/LXRβ嵌合受体蛋白，它们分别来自真核表达构建体。ERα/LXRα和ERα/LXRβ嵌合受体蛋白含有与人ERα受体DNA结合域(DBD)融合的人LXRα或人LXRβ受体LBD。在这些测定中，可以结合人LXRα或LXRβ受体的LBD的化合物能细胞内地激活嵌合受体蛋白。在活化后，通过在大鼠催产素启动子萤光素酶构建体(pROLUC)中存在的天然ERE，ERα DBD可以诱导ERE-介导的萤光素酶表达。使用该系统，产生了LXRα和LXRβ激动剂-诱导的萤光素酶测定，使用T0901317作为激动剂对照。
构建体
如下制备表达构建体：通过将人LXRα或人LXRβ cDNA的配体结合域(LBD)插入到人ERα转录因子DNA结合域(DBD)附近，建立pNGV1.ERαDBD-LXRαLBD和pNGV1.ERαDBD-LXRβLBD。pNGV1哺乳动物表达构建体(EMBL核苷酸序列数据库文件ASPNGV1，登记号X99274)携带新霉素(G418)选择标记。使用大鼠催产素启动子(RO)的ERα效应元件，产生启动子构建体pROLUC，其含有置于萤光素酶报告基因附近的ERα效应元件(ERE)的几个拷贝。启动子构建体的构建是基于RO启动子区(位置-363/+16)，将其作为HindIII/MboI限制性酶片段切离，并连接到编码萤火虫萤光素酶的序列上(参见Ivell和Richter.，ProcNatl Acad Sci USA.7：2006-2010(1984))。在转染并使用新霉素选择阳性表达克隆后，制备表达与pROLUC组合的pNGV1.ERαDBD-LXRαLBD或pNGV1.ERαDBD-LXRβLBD的稳定CHO.K1细胞系。基于响应3μM T0901317的激动剂窗和高达20代的响应稳定性，选择最好的细胞系(CHO.K1 LXRα和CHO.K1 LXRβ)。
实验化合物在LXRα和LXRβ反式激活测定中的激动剂活性
对于LXRα和LXRβ反式激活测定，分别将CHO.K1LXRα或CHO.K1LXRβ细胞以25000细胞/孔的密度接种到在37℃在5％CO2控湿气氛下的96孔平板内的200μl Dulbecco氏改良的伊格尔培养基(不含酚红)中，所述培养基含有5％炭处理过的小牛血清。接种后6小时，通过在一定的浓度范围内温育细胞16小时，表征化合物。在每个测定中，将浓度为3μM的T0901317用作最大激动剂对照。使用萤光素酶测定试剂盒(Perkin Elmer)，测定萤光素酶活性。通过将裂解缓冲液加入每个孔中，并使用Packard Topcount读数器测量光发射，开始萤光素酶活性的测定。T0901317在LXRα和LXRβ反式激活测定中的pEC50值分别是：pEC50＝7.3±0.2和7.4±0.2。将实验化合物的激动剂活性与最大激动剂对照进行对比。使用这些测定方法证实了本发明的优选化合物具有LXRα和/或LXRβ激动剂活性。
Claims (8)
1.具有通式I的1-(4-脲基苯甲酰基)哌嗪衍生物，
其中
R1为(C1-8)烷基，(C3-8)环烷基或(C3-8)环烷基(C1-3)烷基，其每一个可以被羟基，氰基或卤素取代；
R2表示1或2个任选的卤素；
R3为(C1-6)烷基，(C3-6)环烷基或(C3-6)环烷基(C1-3)烷基，其每一个可以被一个或多个卤素取代；
A表示杂芳基环系统，包含1-3选自N，O和S的杂原子，该环系统当X为C时为5-或6-元的，并且当X为N时为5元的；n为1或2；
或者其药学可接受的盐。
2.权利要求1的1-(4-脲基苯甲酰基)哌嗪衍生物，其中A表示呋喃-2，5，二基或吡啶-2，6-二基。
3.权利要求1或2的1-(4-脲基苯甲酰基)哌嗪衍生物，其中R2表示选自F和Cl的1或2个卤素。
4.权利要求1-3任一项的1-(4-脲基苯甲酰基)哌嗪衍生物，其中R3为叔丁基。
5.权利要求1的1-(4-脲基苯甲酰基)哌嗪衍生物，其选自：
-N-叔丁基-5-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(3-氟-4-(3-异丁基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(4-(3-(环丙基甲基)脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(3-氟-4-(3-新戊基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(3-氟-4-(3-异戊基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(4-(3-丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺盐酸盐；
-N-叔丁基-5-((4-(3-氯-4-(3-新戊基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(3-氯-4-(3-异丁基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(3-氯-4-(3-(环丙基甲基)脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(3-氯-4-(3-环丁基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(3-氯-4-(3-异戊基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(4-(3-丁基脲基)-3-氯苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(4-(3-(环丙基甲基)脲基)-2，3-二氟苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(2，3-二氟-4-(3-新戊基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(2，3-二氟-4-(3-异丁基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(4-(3-环丁基脲基)-2，3-二氟苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(4-(3-丁基脲基)-2，3-二氟苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-5-((4-(2，3-二氟-4-(3-异戊基脲基)苯甲酰基)哌嗪-1-基)甲基)呋喃-2-甲酰胺；
-N-叔丁基-6-((4-(4-(3-环丁基脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)吡啶酰胺；
-N-叔丁基-6-((4-(3-氟-4-(3-新戊基脲基)苯甲酰基)哌嗪-1-基)甲基)吡啶酰胺；
-N-叔丁基-6-((4-(3-氟-4-(3-异戊基脲基)苯甲酰基)哌嗪-1-基)甲基)吡啶酰胺；
-N-叔丁基-6-((4-(4-(3-(环丙基甲基)脲基)-3-氟苯甲酰基)哌嗪-1-基)甲基)吡啶酰胺；
或其药学可接受的盐。
6.药物组合物，包含权利要求1-5任一项的1-(4-脲基苯甲酰基)哌嗪衍生物以及药学上可接受的辅剂。
7.权利要求1-5任一项的1-(4-脲基苯甲酰基)哌嗪衍生物，用于治疗。
8.权利要求1-5任一项的1-(4-脲基苯甲酰基)哌嗪衍生物在制备用于治疗或者预防动脉粥样硬化和与胆固醇和胆汁酸运输和代谢有关的相关病症的药物中的用途。
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| US9246908P | 2008-08-28 | 2008-08-28 | |
| US61/092,469 | 2008-08-28 | ||
| PCT/US2009/055035 WO2010025179A1 (en) | 2008-08-28 | 2009-08-26 | 1-(4-ureidobenzoyl)piperazine derivatives |
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| US10669296B2 (en) | 2014-01-10 | 2020-06-02 | Rgenix, Inc. | LXR agonists and uses thereof |
| WO2015153498A1 (en) * | 2014-03-31 | 2015-10-08 | Epitherapeutics, Aps | Inhibitors of histone demethylases |
| JP6571077B2 (ja) | 2014-06-13 | 2019-09-04 | 武田薬品工業株式会社 | 含窒素複素環化合物 |
| CN109069461A (zh) | 2016-01-11 | 2018-12-21 | 洛克菲勒大学 | 与髓源性抑制细胞相关的病症的治疗方法 |
| US11214536B2 (en) | 2017-11-21 | 2022-01-04 | Inspirna, Inc. | Polymorphs and uses thereof |
| WO2020092395A1 (en) | 2018-10-29 | 2020-05-07 | Forma Therapeutics, Inc. | SOLID FORMS OF (4-(2-FLUORO-4-(1-METHYL-1 H-BENZO[d]IMIDAZOL-5-YL)BENZOYL) PIPERAZIN-1-YL)(1-HYDROXYCYCLOPROPYL)METHANONE |
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