CN102203082B - 黑皮质素受体调节剂、制备它们的方法及其在人用药物和化妆品中的用途 - Google Patents
黑皮质素受体调节剂、制备它们的方法及其在人用药物和化妆品中的用途 Download PDFInfo
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- CN102203082B CN102203082B CN200980144700.5A CN200980144700A CN102203082B CN 102203082 B CN102203082 B CN 102203082B CN 200980144700 A CN200980144700 A CN 200980144700A CN 102203082 B CN102203082 B CN 102203082B
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- ethyl
- imidazol
- methoxy
- urea
- phenyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Abstract
本发明涉及新的通式(I)黑皮质素受体调节剂、含它们的组合物、制备它们的方法和它们在药用组合物或化妆品组合物中的用途。
Description
本发明涉及新化合物作为调节一种或多种黑皮质素受体的产物。本发明还涉及制备它们的方法和它们的治疗用途。
黑皮质素形成调节肽家族,该家族肽通过激素阿黑皮素原(POMC-长131氨基酸)的翻译后过程合成。POMC导致3类激素产生:黑皮质素、激素促肾上腺皮质激素和各种内啡肽,例如lignotropin(Cone等,Recent Prog.Horm.Res.,51:287-317,(1996);Cone等Ann.N.Y.Acad.Sc.,31:342-363,(1993)。
黑皮质素受体(MCR)形成具有7个跨膜域的GPCR超家族的一部分。迄今为止,在哺乳动物中鉴定出5种受体亚型MC1-5R。一组内源性肽与MCR结合,产生激动剂或拮抗剂作用,例如促黑激素(MSH)、促肾上腺皮质激素(ACTH)和Agouti蛋白质及其衍生物。但MC2R受体是例外,该受体仅与ACTH结合(ACTH受体与其它黑皮质素受体的主要药理学区别(Major pharmacological distinction of the ACTHreceptor from other melanocortin receptors),Schioth等,Life Sciences(1996),59(10),797-801)。
各种MCR具有不同生理作用。MC1R在皮肤中调节黑素形成,且具有调节免疫系统的作用。MC2R在肾上腺中调节皮质类固醇的产生。受体MC3R和MC4R在控制食物摄取和性行为中起作用。MC5R参于调节外分泌腺体(Wikberg,Jarl E.S.,黑皮质素受体:用于新药的前景(Melanocortin receptors:perspectives for novel drugs).EuropeanJournal of Pharmacology(1999),375(1-3),295-310.Wikberg,Jarl E.S.,黑皮质素受体:药物发现的新机会(Melanocortin receptors:newopportunities in drug discovery).Expert Opinion on Therapeutic Patents(2001),11(1),61-76)。
MCR作为治疗主要疾病(major pathologies)例如肥胖症、糖尿病、炎性病症和性功能障碍的药物的靶标的潜在用途引起对显示对特定亚型有高特异性的化合物的需要。但是,设计对于略微不同受体亚型具有选择性药物的任务难度很大,可根据有关配体-受体相互作用的决定子的详细知识将该任务简化。
申请人现惊讶和预料之外地发现,下文中定义的新的通式(I)化合物显示对黑皮质素受体具有极佳活性,尤其是某些化合物对MC1-R有活性,且具有适合局部给药的物理化学性质。
尤其已证实,MC1-R是在黑素细胞中调节黑素合成的关键蛋白之一。
MC1-R在黑素细胞中表达,涉及动物的皮肤色素沉着、软毛着色和黑素细胞的功能。因此,黑皮质素可用于治疗色素减退和着色过度病症。MC1-R基因的多晶数据与生姜毛发(ginger hair)表型和恶性及非恶性皮肤癌有关(Xu X.等Nat.Genet.1996;14:384;Van Der VeldenP.A.等Am.J.Hum.Genet.2001;69;774-779;Valverde P.等Hum.Mol.Genet.1996;5;1663-1666;Schioth H.B.,Biochem.Biophys.Res.Commun.1999;260:488-491;Scott M.C.等J.Cell Sci.2002;115;2349-2355)。因此,MC1-R与黑素瘤之间存在关联,因此MC1-R在预防和治疗某些形式的皮肤癌中可能很重要(Stockfleth E.等RecentResults in Cancer Res.2002;160;259-268;Stander等Exp.Dermatol.2002;11:42-51)。MC1-R还在以下细胞中表达:巨噬细胞和单核细胞(Star等Proc.Natl.Acad.Sci.USA 92;8016-8020;Hartmeyer等J.Immunol.159;1930-1937)、嗜中性粒细胞(Catania等Peptides 17;675-679)、内皮细胞(Hartmeyer等J.Immunol.159;1930-1937)、神经胶质细胞(gliomal cells)和星形胶质细胞(Wong等Neuroimmunomodulation 4,37-41)、成纤维细胞(Boston and Cone,Endocrinology 137,2043-2050)和角质细胞(Luger等J.Invest.Dermatol.Symp.Proc.2,87-93)。MC1-R在这些细胞中的定位与MSH-基肽抑制炎性过程的能力有关。尤其是,α-MSH在肠炎、关节炎、局部缺血、接触性过敏反应和皮炎的慢性模型中显示强抑制,它还可诱发对haptenes的耐受性(Ceriana等Neuroimmunomodulation,1,28-32;Chiao等Clin.Invest.99,1165-1172;Huh and Lipton,Neurosurgery,40,132-139;Luger等J.Invest.Dermatol.Symp.Proc.2,87-93;Rajora等Peptides 18,381-385;J.Neurosci.17,2181-2196;Lipton等Neuroimmunomodulation,5,178-183)。因此,黑皮质素可用于治疗炎症和免疫疾病。由此提示,MC1-R信号途径在疼痛感觉中起作用,MC1-R的功能变化与对疼痛的高耐受力有关(Mogil等J.Med.Genet.2005 Jul;42(7):583-7)。
人毛发的色泽与MC1-R的变体存在高度相关性(Valverde等Nat.Genet.1995Nov;11(3):328-30)。MC1-R的功能变化与生姜毛发颜色有关。
还已知,皮脂腺表达MC1-R(Ganceviciene等Exp.Dermatol.2007Jul;16(7):547-52)和MC5-R(Zhang等Peptides,2006 Feb;27(2):413-20)。也有报道称,在痤疮情况下,MC1-R在皮脂腺中过度表达。
因此,在人用药物,尤其是在皮肤科和在化妆品领域中,本发明化合物发现了应用。
专利WO 96/35713、WO 96/38471和WO 99/58501公开了某些二肽和它们刺激生长激素合成的用途。
在Journal of Medicinal Chemistry(2003),46,1123-1126中发表的论文描述了“具有抗炎性质的MC1-R受体的小、高效和选择性的基于酪氨酸激动剂的分子发现”(″discovery of small,powerful and selectivetyrosine-based agonist molecules of the MC1-R receptor that haveanti-inflammatory properties″)。
专利WO 02/070 511、WO 02/079 146和WO 02/069 905要求保护作为黑皮质素受体,更尤其是MC1-R和MC4-R的调节剂的化合物的用途。
在专利WO 05/047 253中描述了化合物和它们作为黑皮质素受体激动剂的用途。
申请人现惊讶并预料之外地发现,作为本发明主题的某些结构(I)化合物为一种或多种黑皮质素受体的调节剂,尤其是某些化合物对MC1-R有活性,并具有适合局部给药的物理化学性质。
尤其是,本发明化合物有利地具有它们的物理化学性质赋予的几个优点,允许局部给药,尤其是使以下情况成为可能:其快速并按定向的方式接近靶标、减少在靶标上产生活性所需要的活性剂的量、减少全身暴露并且也具有较少的副作用。
因此,本发明涉及以下通式(I)化合物及其相应的盐和对映体:
其中:
R1代表氢原子、芳基、取代的芳基、烷基、环烷基、环烷基烷基或环烷基烷基烷基,
R2代表氢原子、羟基、低级烷基、取代的低级烷基、高级烷基、取代的高级烷基、环烷基、环烷基烷基、低级烷氧基、取代的低级烷氧基、高级烷氧基、取代的高级烷氧基、环烷基烷氧基、酰氧基、酰基、烷氧基羰基、甲酰胺基、羧基(carboxylic acid)、氰基,或被酰基和芳基或烷基二取代的氨基,
R3代表芳烷基或取代的芳烷基,
R4代表杂芳烷基或取代的杂芳烷基,
R5代表氢原子或烷基,
X代表氧原子或硫原子,
n、m可等于1或2。
在通式(I)化合物的药学上可接受的酸加成盐中,可提及优选的有机酸或无机酸的盐。
合适的无机酸为例如氢卤酸例如盐酸或氢溴酸;硫酸和硝酸。
合适的有机酸为例如苦味酸、甲磺酸、乙磺酸、对-甲苯磺酸、草酸和酒石酸。
通式(I)化合物也可存在含水的水合物或含溶剂的溶剂合物形式。
形成溶剂合物或水合物的合适溶剂为例如醇,例如乙醇或异丙醇或水。
按照本发明,术语“芳基”表示未取代的苯基或萘基。
按照本发明,术语“取代的芳基”表示被一个或多个原子团取代的苯基或萘基,所述原子团选自烷基、烷氧基、卤素、羟基、氰基、三氟甲基和硝基。
按照本发明,术语“环烷基”表示含3-7个碳原子的饱和环烃基链。
按照本发明,术语“羟基”表示OH基团。
按照本发明,术语“氨基”表示NH2基团。
按照本发明,术语“氰基”表示CN基团。
按照本发明,术语“羧基(carboxylic acid)”表示CO2H基团。
按照本发明,术语“酰基”表示被烷基、环烷基或环烷基烷基取代的甲酰基或羰基。
按照本发明,术语“烷基”表示取代或未取代的低级烷基或高级烷基。
按照本发明,术语“低级烷基”表示含1-4个碳原子的直链或支链,饱和或不饱和烃基链或含2-4个碳原子的不饱和链,尤其是例如甲基、乙基、丙基、异丙基和丁基。
按照本发明,术语“取代的低级烷基”表示含1-4个碳原子且被一个或多个卤素原子或羟基取代的直链或支链、饱和或不饱和烃基链,或含2-4个碳原子且被一个或多个卤素原子或羟基取代的不饱和烃基链。
按照本发明,术语“高级烷基”表示含5-10个碳原子的直链或支链、饱和或不饱和烃基链。
按照本发明,术语“取代的高级烷基”表示含5-10个碳原子且被一个或多个卤素原子或羟基取代的直链或支链、饱和或不饱和烃基链。
按照本发明,术语“卤素原子”表示氯、氟、碘和溴原子。
按照本发明,术语“环烷基烷基”表示被环烷基取代的烷基。
按照本发明,术语“低级烷氧基”表示被低级烷基取代的氧原子,尤其是例如甲氧基、乙氧基、丙氧基、异丙氧基或丁氧基。
按照本发明,术语“取代的低级烷氧基”表示被取代的低级烷基取代的氧原子。
按照本发明,术语“高级烷氧基”表示被高级烷基取代的氧原子。
按照本发明,术语“取代的高级烷氧基”表示被取代的高级烷基取代的氧原子。
按照本发明,术语“环烷基烷氧基”表示被环烷基烷基取代的氧原子。
按照本发明,术语“酰氧基”表示被酰基取代的氧原子。
按照本发明,术语“烷氧基羰基”表示被烷氧基、环烷氧基或环烷基烷氧基取代的羰基。
按照本发明,术语“甲酰胺基”表示被一烷基氨基或二烷基氨基取代的羰基。
按照本发明,术语“芳烷基”表示被芳基取代的烷基。
按照本发明,术语“取代的芳烷基”表示被取代的芳基取代的烷基。
按照本发明,术语“杂环”表示饱和或不饱和的环状或双环烃基链,含选自O、S和N的一个或多个杂原子。
按照本发明,术语“取代的杂环”表示饱和或不饱和的环状或双环烃基链,含被一个或多个烷基取代的一个或多个杂原子,所述杂原子选自O、S和N。
按照本发明,术语“杂芳基”表示芳族杂环。
按照本发明,术语“取代的杂芳基”表示被一个或多个烷基取代的芳族杂环。
按照本发明,术语“杂芳烷基”表示被杂芳基取代的烷基。
按照本发明,术语“取代的杂芳烷基”表示被取代的杂芳基取代的烷基。
在包括在本发明文中的通式(I)化合物中,尤其可提及以下化合物:
1)1-[(S)-2-(4-丁酰基-4-苯基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
2)1-[2-(1H-咪唑-4-基)乙基]-3-[1-(4-甲氧基苄基)-2-氧代-2-(4-氧代-1-苯基-1,3,8-三氮杂螺[4.5]癸-8-基)乙基]脲
3)1-[2-(4-氰基-4-苯基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
4)1-[2-(1H-咪唑-4-基)乙基]-3-[1-(4-甲氧基苄基)-2-氧代-2-(4-苯基哌啶-1-基)乙基]脲
5)1-[2-(1H-咪唑-4-基)乙基]-3-[1-(4-甲氧基苄基)-2-氧代-2-哌啶-1-基-乙基]脲
6)4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
7)N-{1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-基}-N-苯基丙酰胺
8)丁酸1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]-3-苯基-氮杂环丁烷-3-基酯
9)1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-甲酸乙酯
10)1-[2-(1H-咪唑-4-基)乙基]-3-{1-(4-甲氧基苄基)-2-[4-(2-甲氧基苯基)-哌啶-1-基]-2-氧代乙基}脲
11)1-[2-(3-丁氧基-3-苯基氮杂环丁烷-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
12)N-甲基-4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酰胺
13)1-[2-(3-环己基羰基氮杂环丁烷-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
14)4-环己基-1-[2-{3-乙基-3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
15)N-环丙基-N-{1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-基}丙酰胺
16)4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸乙酯
17)1-[2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3H-咪唑-4-基)乙基]脲
18)1-[2-(4-丁氧基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
19)4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-2-苯基乙酰基)-哌啶-4-甲酸乙酯
20)4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸甲酯
21)1-[2-(4-环己基-4-乙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
22)1-[2-(4-乙酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
23)4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-2-苯基乙酰基)-哌啶-4-甲酸甲酯
24)4-乙基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
25)1-[2-(4-环己基-4-丙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
26)4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸
27)1-[2-(1H-咪唑-4-基)乙基]-3-{1-(4-甲氧基苄基)-2-[3-(2-甲基环己基)-3-丙氧基氮杂环丁烷-1-基]-2-氧代乙基}脲
28)4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸丙酯
29)1-[2-(1H-咪唑-4-基)乙基]-3-[1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基-氮杂环丁烷-1-基)乙基]脲
30)1-((R)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
31)1-((S)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
32)1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
33)1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基甲基)脲
34)4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
35)4-环丙基甲基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
36)4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸丙酯
37)4-环戊基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸乙酯
38)4-环戊基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
39)4-环己基-1-[(S)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
40)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
41)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氟苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
42)1-[(R)-1-苄基-2-(4-丁酰基-4-环己基哌啶-1-基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
43)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲
44)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氯苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
45)4-环己基-1-((R)-3-(3,4-二氯苯基)-2-{3-[3-(1H-咪唑-4-基)丙基]-脲基}丙酰基)哌啶-4-甲酸乙酯
46)4-环己基-1-((R)-3-(4-甲氧基苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲基}丙酰基)哌啶-4-甲酸乙酯
47)4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]硫脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
48)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]硫脲
49)1-[(R)-2-(4-环己基-4-丙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]硫脲
50)1-[(R)-1-苄基-2-(4-环己基-4-丙氧基哌啶-1-基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]硫脲
51)1-[(R)-1-苄基-2-(4-环己基-4-丙氧基哌啶-1-基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
52)4-环己基-1-((R)-3-(4-甲氧基苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]硫脲基}丙酰基)哌啶-4-甲酸乙酯
53)4-环己基-1-((R)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲基}-3-苯基-丙酰基)哌啶-4-甲酸乙酯
54)1-[(R)-2-(4-环己基-4-丙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲
55)1-((R)-3-(4-氯苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲基}-丙酰基)-4-环己基哌啶-4-甲酸乙酯
56)4-环己基-1-((R)-3-(4-氟苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]-脲基}丙酰基)哌啶-4-甲酸乙酯
57)4-环己基-1-((R)-3-(4-氟苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-丙酰基)哌啶-4-甲酸乙酯
58)4-环己基-1-((R)-3-(4-氟苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]硫脲基}丙酰基)哌啶-4-甲酸乙酯
59)1-((R)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]硫脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
60)1-((R)-3-(4-氯苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]硫脲基}-丙酰基)-4-环己基哌啶-4-甲酸乙酯
61)1-[(R)-2-(4-环己基-4-丙氧基哌啶-1-基)-1-(4-氟苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
62)1-[(R)-1-(4-氯苄基)-2-(4-环己基-4-丙氧基哌啶-1-基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
及其各自的盐和对映体。
按图1中提供的通用反应流程制备通式(I)化合物。
使用反应流程1(图1):
按照流程1,可在标准的肽偶合条件下(Han,S.,Kim,Y.Tetrahedron,2004,60,2447-2467;Albericio,F.Current Opinion inChemical Biology,2004,8,211-221;Humphrey,J.,Chamberlin,R.Chem.Rev.,1997,97,2243-2266),用例如作为偶联剂的1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐、羟基苯并三唑或TBTU,和作为碱的三乙胺或二异丙基乙胺,在溶剂例如二氯甲烷或二甲基甲酰胺中,通过使式(II)中间体与其胺官能团用Pg保护基(例如Boc、CBz或Fmoc基团)保护的式(III)氨基酸偶合,制备式(IV)化合物。
通式(IV)氨基酸有市售或可通过文献(Williams,R.M.,旋光性α-氨基酸的合成(Synthesis of optically active α-amino acids),PergamonPress,Oxford,1989)中所述方法制备。
通过选自本领域技术人员已知那些方法的方法将式(IV)化合物的胺官能团脱保护,得到式(V)化合物。其中,它们包括例如在被Boc基团保护的情况下,使用三氟乙酸或盐酸的二氯甲烷或乙酸乙酯溶液;例如在被CBz基团保护的情况下,用合适的金属在四氢呋喃或甲醇中氢化;例如在被Fmoc基团保护的情况下,使用哌啶的乙腈溶液。
在最后步骤中,例如,可通过将式(VI)胺加入由化合物(V)得到的异氰酸酯或异硫氰酸酯的二氯甲烷或二甲基甲酰胺的溶液制备式(I)化合物。例如,可在光气、双光气或三光气的存在下,由胺(V)制备异氰酸酯。例如,在硫光气的存在下,由胺(V)(Nowick J.S.等JOC(1996)3929-3934)或由硫代碳酸二(2-吡啶)酯(bis(2-pyridyl)thionocarbonate)(WO 2008/008 954)制备异硫氰酸酯。例如,也可通过将式(VI)胺加入由胺(V)得到的活化氨基甲酸酯的二氯甲烷或二甲基甲酰胺溶液合成式(I)化合物。术语“活化氨基甲酸酯”表示例如氨基甲酸对-硝基苯基酯基(Igarashi,T.,Synlett(2007)1436),该基团可通过在碱的存在下将氯甲酸对-硝基苯基酯加入胺(V)得到,碱可为例如三乙胺的二氯甲烷或二甲基甲酰胺溶液。
式(II)化合物有市售,或可按文献中所述或本领域技术人员已知方法,按照取代基R1和R2性质的函数做相应改变来制备。以下流程1-9显示式(II)化合物的制备实例。
例如,当R2含酰氧基或甲酰胺链时,可按流程1制备化合物(II,n,m=2):
流程1:
-当X为氧时,例如通过用文献中所述方法将化合物(VII)的羧酸官能团酯化,或
-当X为氮时,例如通过用选自本领域技术人员已知那些方法的方法,加入胺或由羧酸(VII)得到的酰氯。尤其可用溶于溶剂例如二氯甲烷或二甲基甲酰胺的草酰氯或亚硫酰氯溶液,
得到式(VIII)化合物。
通过选自本领域技术人员已知那些方法的方法将式(VIII)化合物的胺官能团脱保护,得到式(II)化合物。其中它们包括例如在被Boc基团保护的情况下,使用三氟乙酸或盐酸的二氯甲烷或乙酸乙酯溶液;例如在被CBz基团保护的情况下,用合适的金属在四氢呋喃或甲醇中氢化;和例如在被Fmoc基团保护的情况下,使用哌啶的乙腈溶液。
例如,当R1含烷基、环烷基或环烷基烷基,R2含酰氧基链时,可按流程2制备化合物(II,n,m=2):
流程2:
例如,可通过在碱例如二异丙基氨基化锂或六甲基二硅基胺基锂(lithium hexamethyldisilazide)的存在下,在溶剂例如二氯甲烷或四氢呋喃中,将化合物(IX)的酯官能团α脱保护,引入R1基团。通过选自本领域技术人员已知那些方法的方法将式(X)化合物的胺官能团脱保护,得到式(II)化合物。其中它们包括例如在被Boc基团保护的情况下,使用三氟乙酸或盐酸的二氯甲烷或乙酸乙酯溶液;例如在被CBz基团保护的情况下,用合适的金属在四氢呋喃或甲醇中氢化。
例如,当R2含烷氧基或烷氧基羰基链时,可按流程3制备化合物(II,n,m=1):
流程3:
例如,通过将由R1衍生的卤化镁加成到N-Boc-氮杂环丁烷酮(XI),然后按文献中所述常规方法将叔醇烷基化或酰化,得到式(XII)化合物,以得到化合物(XIII)。通过例如在三氟乙酸或盐酸的存在下,在二氯甲烷或乙酸乙酯中,将式(XIII)化合物的胺官能团脱保护,得到式(II)化合物。
例如,当R2含酰基时,可按流程4制备化合物(II,n=m=1):
流程4:
可在肽偶联条件下,用例如作为偶联剂的1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐、羟基苯并三唑或TBTU,和作为碱的三乙胺或二异丙基乙胺,在溶剂例如二氯甲烷或二甲基甲酰胺中,使羧酸(XIV)化合物与Weinreb胺之间进行偶联,得到式(XV)化合物。例如,通过将由R1衍生的卤化镁加成到Weinreb酰胺(XV)的衍生物,得到式(XVI)化合物。通过选自本领域技术人员已知那些方法的方法,将式(X)化合物的胺官能团脱保护,得到式(II)化合物。其中,它们包括例如在Boc基团脱保护的情况下,使用三氟乙酸或盐酸的二氯甲烷或乙酸乙酯溶液;例如在被CBz基团保护的情况下,用合适的金属在四氢呋喃或甲醇中氢化。
例如,当R2含二取代的胺时,可按流程5制备化合物(II,n=m=2):
流程5:
例如,可在还原性氨化条件下,在硼氢化钠或氰基硼氢化钠的存在下,使市售酮(XVII)与胺之间进行还原性氨化,得到式(XVIII)化合物。然后,例如在碱例如三乙胺和酰氯的存在下,可将仲胺(XVIII)酰化,得到化合物(XIX)。通过选自本领域技术人员已知那些方法的方法,将式(VIII)化合物的胺官能团脱保护,得到式(II)化合物。其中,它们包括例如在被Boc基团保护的情况下,使用三氟乙酸或盐酸的二氯甲烷或乙酸乙酯溶液;例如在被CBz基团保护的情况下,用合适的金属在四氢呋喃或甲醇中氢化,和例如在被Fmoc基团保护的情况下,使用哌啶的乙腈溶液。
例如,当R1含环己基,R2含酰基时,可按流程6制备化合物(II,n=m=2):
流程6:
例如,通过在碱例如三乙胺的存在下,在二氯甲烷中,与甲苯磺酰氯反应,将市售胺(XX)用甲苯磺酸酯基保护后,得到化合物(XXI)。例如通过在甲苯中,将由烷基衍生的卤化镁加成到衍生物(XXI)的腈官能团,然后将中间体亚胺在可为盐酸的酸性介质中水解,得到式(XXII)化合物。通过在酸性介质中将胺官能团脱保护,得到式(XXIII)化合物,在甲苯磺酸酯基的情况下,酸性介质可为硫酸。例如通过在催化剂的存在下将化合物(X)氢化,得到化合物(II),催化剂例如可为铑/氧化铝或氧化铂/二
烷。
例如,当R1含环己基,R2含烷氧基时,可按流程7制备化合物(II,n=m=2):
流程7:
例如,通过将由苯基衍生的卤化镁加成到市售酮(XVII),然后按文献中通常所述方法将叔醇烷基化,得到化合物(XXV),得到式(XXIV)化合物。例如通过在催化剂的存在下,将化合物(XXV)氢化,得到化合物(XXVI),催化剂例如可为铑/氧化铝或氧化铂/二
烷。通过例如在三氟乙酸或盐酸的存在下,在二氯甲烷或乙酸乙酯中,将式(XXVI)化合物的胺官能团脱保护,得到式(II)化合物。
例如,当R1为芳基,R2含烷基链时,可按流程8制备化合物(II,n=m=1):
流程8:
例如通过在由R2衍生的卤化衍生物的存在下,将碱例如氢化钠加入市售腈衍生物(XXVII),可得到式(XXVIII)化合物。可在碱例如氢化钠和低聚甲醛的存在下,由腈衍生物(XXVIII)合成伯醇(XXIX)。可例如在可为三乙胺的碱和甲苯磺酰氯的存在下,将化合物(XXIX)的伯醇官能团转化为磺酸酯。可通过例如在氢化铝锂的存在下,将腈官能团还原后得到的胺官能团和甲苯磺酸酯官能团之间进行分子内环化,合成氮杂环丁烷化合物(II)。
式(VI)化合物有市售,或可按文献中所述或本领域技术人员已知的方法,按照取代基R4和R5的性质函数做适当调整进行制备。以下流程9-11提供了式(VI)化合物的制备实例。
例如,当R5为烷基,R4含杂芳烷基时,可例如按文献中所述方案(Durant G.J.,Emmet J.C,Ganellin C.R.,Roe A.M.,(1973)Br.Pat.1341 375)制备化合物(VI),如流程9所述:
流程9:
例如,当R4含1,2,3-三唑杂环时,可按流程10制备化合物(VI):
流程10:
可通过文献(Loren J.C,Synlett,2005,2847-2850)中所述方法制备式(XXXIV)化合物,然后在碱性介质中,例如在氢氧化钠的存在下解离,得到化合物(VI)。
例如,当R4含杂芳烷基时,可按流程11制备化合物(VI):
流程11:
可通过文献(Wolin R.,BOMCL,1998,2157)中所述方法,通过使杂芳基取代的醛与市售叶立德之间进行Wittig反应,形成烯(XXXV),然后将双键氢化,将苯邻二甲酰亚胺肼解,得到化合物(VI),制备式(VI)化合物。
按照本发明,尤其优选的通式(I)化合物是以下那些化合物及其相应的盐和对映体,其中:
R1代表氢原子、芳基、取代的芳基、烷基、环烷基或环烷基烷基,
R2代表氢原子、低级烷基、取代的低级烷基、高级烷基、取代的高级烷基、环烷基、环烷基烷基、低级烷氧基、取代的低级烷氧基、高级烷氧基、取代的高级烷氧基、环烷基烷氧基、酰氧基、酰基、烷氧基羰基、甲酰胺基或氰基,
R3代表芳烷基或取代的芳烷基,
R4代表杂芳烷基或取代的杂芳烷基,
R5代表氢原子,
X代表氧原子或硫原子,
n、m可等于1或2。
在本发明范围内的通式(I)化合物中,尤其可提及以下化合物:
1)1-[(S)-2-(4-丁酰基-4-苯基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
2)1-[2-(4-氰基-4-苯基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
3)1-[2-(1H-咪唑-4-基)乙基]-3-[1-(4-甲氧基苄基)-2-氧代-2-(4-苯基哌啶-1-基)乙基]脲
4)4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
5)1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]-哌啶-4-甲酸乙酯
6)1-[2-(1H-咪唑-4-基)乙基]-3-{1-(4-甲氧基苄基)-2-[4-(2-甲氧基苯基)-哌啶-1-基]-2-氧代乙基}脲
7)1-[2-(3-丁氧基-3-苯基氮杂环丁烷-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
8)N-甲基-4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酰胺
9)1-[2-(3-环己基羰基氮杂环丁烷-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
10)4-环己基-1-[2-{3-乙基-3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
11)4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸乙酯
12)1-[2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3H-咪唑-4-基)乙基]脲
13)1-[2-(4-丁氧基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
14)4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-2-苯基乙酰基)-哌啶-4-甲酸乙酯
15)4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸甲酯
16)1-[2-(4-环己基-4-乙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
17)1-[2-(4-乙酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
18)4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-2-苯基乙酰基)-哌啶-4-甲酸甲酯
19)4-乙基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
20)1-[2-(4-环己基-4-丙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
21)1-[2-(1H-咪唑-4-基)乙基]-3-{1-(4-甲氧基苄基)-2-[3-(2-甲基环己基)-3-丙氧基氮杂环丁烷-1-基]-2-氧代乙基}脲
22)4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸丙酯
23)1-[2-(1H-咪唑-4-基)乙基]-3-[1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基-氮杂环丁烷-1-基)乙基]脲
24)1-((R)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
25)1-((S)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
26)1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
27)1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基甲基)脲
28)4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
29)4-环丙基甲基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
30)4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸丙酯
31)4-环戊基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸乙酯
32)4-环戊基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
33)4-环己基-1-[(S)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
34)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
35)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氟苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
36)1-[(R)-1-苄基-2-(4-丁酰基-4-环己基哌啶-1-基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
37)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲
38)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氯苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
39)4-环己基-1-((R)-3-(3,4-二氯苯基)-2-{3-[3-(1H-咪唑-4-基)丙基]-脲基}丙酰基)哌啶-4-甲酸乙酯
40)4-环己基-1-((R)-3-(4-甲氧基苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲基}丙酰基)哌啶-4-甲酸乙酯
41)4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]硫脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
及其各自的盐和对映体。
按照本发明,尤其优选的通式(I)化合物为以下那些化合物及其相应的盐和对映体,其中:
R1代表环烷基或环烷基烷基,
R2代表低级烷氧基、环烷基烷氧基、酰基、烷氧基羰基或氰基,
R3代表芳烷基或取代的芳烷基,
R4代表杂芳烷基或取代的杂芳烷基,
R5代表氢原子,
X代表氧原子或硫原子,
n、m等于2。
优选的化合物为:
1)4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
2)4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸乙酯
3)1-[2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3H-咪唑-4-基)乙基]脲
4)1-[2-(4-丁氧基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
5)4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸甲酯
6)1-[2-(4-环己基-4-乙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
7)1-[2-(4-乙酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
8)4-乙基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
9)1-[2-(4-环己基-4-丙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
10)4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸丙酯
11)1-((R)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
12)1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
13)1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基甲基)脲
14)4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
15)4-环丙基甲基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
16)4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸丙酯
17)4-环戊基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
18)4-环己基-1-[(S)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
19)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
20)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氟苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
21)1-[(R)-1-苄基-2-(4-丁酰基-4-环己基哌啶-1-基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
22)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲
23)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-[1,2,3]三唑-4-基)乙基]脲
24)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氯苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
25)4-环己基-1-((R)-3-(3,4-二氯苯基)-2-{3-[3-(1H-咪唑-4-基)丙基]-脲基}丙酰基)哌啶-4-甲酸乙酯
26)4-环己基-1-((R)-3-(4-甲氧基苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲基}丙酰基)哌啶-4-甲酸乙酯
27)4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]硫脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
及其各自的盐和对映体。
按照本发明,尤其优选的通式(I)化合物为以下那些化合物及其相应的盐和对映体,其中:
R1代表环烷基,
R2代表低级烷氧基、酰基或烷氧基羰基,
R3代表芳烷基或取代的芳烷基,
R4代表杂芳烷基,
R5代表氢原子,
X代表氧原子或硫原子,
n、m等于2。
尤其优选的化合物为:
1)4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
2)4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸乙酯
3)1-[2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3H-咪唑-4-基)乙基]脲
4)1-[2-(4-丁氧基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
5)4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸甲酯
6)1-[2-(4-环己基-4-乙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
7)1-[2-(4-乙酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
8)1-[2-(4-环己基-4-丙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
9)4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸丙酯
10)1-((R)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
11)1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
12)4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
13)4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸丙酯
14)4-环戊基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
15)4-环己基-1-[(S)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
16)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
17)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氟苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
18)1-[(R)-1-苄基-2-(4-丁酰基-4-环己基哌啶-1-基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
19)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲
20)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氯苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
21)4-环己基-1-((R)-3-(4-甲氧基苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲基}丙酰基)哌啶-4-甲酸乙酯
22)4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]硫脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
及其各自的盐和对映体。
按照本发明,尤其优选的通式(I)化合物为以下那些化合物及其相应的盐和对映体,其中:
R1代表环烷基,
R2代表酰基或烷氧基羰基,
R3代表芳烷基或取代的芳烷基,
R4代表取代的或未取代的咪唑,
R5代表氢原子,
X代表氧原子或硫原子,
n、m等于2。
尤其优选的化合物为:
1)4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
2)4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸乙酯
3)1-[2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3H-咪唑-4-基)乙基]脲
4)4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸甲酯
5)1-[2-(4-乙酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
6)4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸丙酯
7)1-((R)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
8)1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
9)4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
10)4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸丙酯
11)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
12)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氟苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
13)1-[(R)-1-苄基-2-(4-丁酰基-4-环己基哌啶-1-基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
14)1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氯苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
15)4-环己基-1-((R)-3-(4-甲氧基苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲基}丙酰基)哌啶-4-甲酸乙酯
16)4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]硫脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
及其各自的盐和对映体。
本发明化合物对黑皮质素受体具有调节性质。表述“对黑皮质素受体的调节性质”表示对黑皮质素受体的激动剂或拮抗剂性质。按实施例10中所述,通过反式激活试验测量对MCR受体的该活性,由50%有效浓度(EC 50)定量。
优选,化合物至少为MCR受体的调节剂,且具有适合局部给药的性质,即它们在人微粒体中的半衰期小于或等于10分钟,它们在pH 6.5下的log D大于或等于3,它们在体内模型中具有局部活性。
最好,本发明化合物对于MC1受体的50%有效浓度(EC50)小于或等于10μM,更尤其是小于或等于1μM。
因此,本发明涉及至少一种以上定义的通式(I)化合物在制备药用组合物或化妆品组合物中的用途,其中所述化合物对一种或多种黑皮质素受体,尤其是对亚型1、3、4和5具有调节活性。
在本发明的一种具体模式中,某些本发明式(I)化合物对MC1R受体有活性,尤其可用于治疗色素病症和炎症及免疫病症。某些本发明化合物对MC4R受体有活性,尤其可用于治疗饮食行为障碍和代谢障碍,也可用于治疗神经变性病症。
本发明还涉及治疗或美容处理方法,该方法包括给予药用组合物或化妆品组合物,所述组合物含所述化合物作为一种或多种黑皮质素受体,尤其是亚型1、3、4和5的调节剂。在一种具体模式中,本发明还涉及治疗或美容方法,该方法包括给予含所述化合物的药用组合物或化妆品组合物,用于治疗色素病症和炎症及免疫病症。在本发明的一种具体模式中,化合物为亚型1的调节剂,具有适合局部给药的性质。
本发明还涉及以上定义的通式(I)化合物及其相应的盐和对映体在制备用于治疗与MC1R受体功能障碍有关的病症的药物中的用途。
最后,按本发明使用的化合物尤其适合治疗和/或预防病症和/或疾病例如以下炎性疾病:
-消化器官,尤其包括肠的炎性疾病(尤其是在肠易激综合征、溃疡-出血性直肠结肠炎或节段性回肠炎的情况下的结肠):胰腺炎、肝炎(急性和慢性)、炎性膀胱病和胃炎;
-运动器官的炎性疾病,包括类风湿性关节炎、骨关节炎、骨质疏松症、创伤性关节炎、感染后关节炎、肌肉变性和皮肌炎;
-泌尿生殖器官的炎性疾病,尤其是肾小球肾炎;
-心脏器官的炎性疾病,尤其是心包炎和心肌炎,及包括炎症为潜在因素的那些疾病的疾病。这些疾病包括但不限于动脉粥样硬化、移植所致动脉粥样硬化、外周血管病、炎性血管病、间歇性跛行或跛行、再狭窄、中风、一过性缺血发作、心肌缺血和心肌梗塞。这些化合物也可用于治疗高血压、高脂血症、冠状动脉疾病、不稳定性心绞痛(或心绞痛)、血栓形成、凝血酶引起的血小板凝集和/或血栓形成后遗症(consequence)和/或动脉粥样化斑块形成的后遗症;
-呼吸和ORL器官的炎性疾病,尤其包括哮喘、急性呼吸窘迫综合征、枯草热、过敏性鼻炎和慢性阻塞性肺部疾病。本发明化合物也可用于治疗变态反应疾病;
-中枢神经系统的炎性疾病,尤其是早老性痴呆症和任何其它形式的痴呆症、帕金森病、克罗伊茨费尔特-雅各布病、多发性硬化和脑膜炎;
-皮肤炎性疾病,尤其是荨麻疹、硬皮病、接触性皮炎、特应性皮炎、银屑病、鱼鳞病、痤疮和其它形式的毛囊炎、红色痤疮和脱发;
-及免疫疾病,尤其是红斑狼疮、甲状腺疾病、肾上腺的自身免疫疾病和自身免疫性胃炎、白斑和斑秃;
-伴随细菌、病毒或真菌感染的炎症,尤其是肺结核、败血症、发烧、HIV、位置无关的感染、疱疹、巨细胞病毒,和甲型、乙型和丙型肝炎;
-移植或移植物排斥,例如肾脏、肝脏、心脏、肺、胰腺、骨髓、角膜、肠或皮肤的排斥(皮肤同种异体移植物、同种移植物或异种移植物等)。
另外,这些化合物可用于治疗疼痛、起源无关的疼痛:术后疼痛、神经肌肉疼痛、头痛、癌症相关疼痛、牙痛、骨关节疼痛。
这些化合物可用于调节色素沉着,因此可用于:
-治疗具有色素沉着障碍的疾病,尤其是良性皮肤病例如白斑、白化病、黑斑病、着色斑、雀斑、皮肤黑素细胞增生病和所有炎症后色素沉着;和着色肿瘤例如黑素瘤和它们的局部(渗透分子)、区域或全身转移;
-防日晒保护,用于以下的预防目的:
-日光的有害作用,例如光化性红斑、皮肤老化、皮肤癌(棘细胞瘤、基底细胞瘤和黑素瘤),尤其是加速其发生的疾病(着色性干皮病、基底细胞痣综合征和家族性黑素瘤);
-由外源性光敏剂造成的光照性皮肤病,尤其是由接触性光敏剂(例如呋喃并香豆素、卤化水杨苯胺和衍生物,和局部磺酰胺和衍生物)造成的那些皮肤病或由全身性光敏剂造成的那些皮肤病(例如补骨脂素、四环素类、磺酰胺、吩噻嗪、萘啶酸和三环类抗抑郁药);
-光过敏性皮肤病发作,尤其是
-由日光加剧的皮肤病(例如红斑狼疮、疱疹复发、先天性皮肤异色病或光过敏性毛细管扩张病(布卢姆综合征、科克因综合征或罗-汤综合征)、光化性扁平苔藓、光化性肉芽肿、表浅性播散性光化性角化病、红色痤疮、青少年痤疮、大疱性皮肤病、毛囊角化病、淋巴瘤皮肤、银屑病、特应性皮炎、接触性湿疹、毛囊皮脂腺粘蛋白沉积症、多形红斑、固定性药疹、皮肤淋巴细胞瘤、网状红斑粘蛋白沉积症和黑斑病);
-保护系统缺乏所致光过敏性皮肤病,黑素形成或分布异常(例如眼皮白化病、苯丙酮尿症、垂体功能减退、白斑和花斑),DNA修复系统缺乏(例如着色性干皮病和科克因综合征),
-通过代谢异常的光过敏性皮肤病,例如皮肤卟啉症(例如迟发性皮肤卟啉症、混合型卟啉症、红细胞肝性原卟啉症、先天性红细胞生成性原卟啉症(京塞病)和红细胞生成性粪卟啉尿)、糙皮病或类糙皮病红斑(例如糙皮病、类糙皮病红斑和色氨酸代谢症);
-自发性光照性皮肤病,尤其是PMLE发作(多态光疹)、良性夏季光疹、光化性痒疹、持续性感光过敏(光化性网状细胞增多症、残余光敏性(remanent photosensitization)和光过敏性湿疹)、日光荨麻疹、牛痘样水疱病、青少年春季发疹和日光瘙痒);
-改变皮肤或头发和体毛的颜色,尤其是通过增加黑素合成将皮肤晒成褐色或通过干扰黑素合成将其漂白,还通过阻止头发或体毛漂白或变灰白(例如白发和花斑);
-在美容体征中,改变头发和体毛的颜色。
这些化合物可用于调节皮脂分泌功能,用于:
-治疗皮脂溢过多(hyperseborrhoea)病,尤其是痤疮、脂溢性皮炎、多油脂性皮肤和多油脂性头发、帕金森病中的皮脂溢过多和癫痫和雄激素过多症;
-治疗皮脂分泌减少的疾病,尤其是干燥病和所有形式的干燥皮肤;
-调节皮脂腺细胞和皮脂腺的良性或恶性增生;
-治疗毛囊皮脂腺的炎症,尤其是痤疮、疖、痈和毛囊炎。
本发明还涉及以上定义的通式(I)化合物在制备药物中的用途,所述药物用于治疗与MC4R受体功能障碍有关的病症。
本发明化合物也可用于治疗神经变性病症,此类病症包括抑郁症、焦虑症、强迫症(例如强迫观念与行为障碍)、神经功能病、精神病、失眠症和睡眠障碍、睡眠呼吸暂停和药物滥用。
这些化合物可用于治疗男性或女性性功能障碍。男性性功能障碍包括但不限于阳痿、性欲丧失和勃起功能障碍。
女性性功能障碍包括但不限于性刺激障碍或性欲相关障碍;性感受性、性欲高潮和主要的性功能点障碍。女性性功能障碍也可包括疼痛、早产、痛经、月经过多和子宫内膜异位。
本发明化合物也可用于治疗与体重有关的病症但不限于肥胖症和厌食(例如食欲、脾代谢的改变或减少,或无限制摄取(vocableirreproachable taking)脂肪或碳水化合物):糖尿病(由葡萄糖耐量和/或胰岛素耐受减少所致)。
所述化合物也可用于治疗癌症,尤其是肺癌、前列腺癌、肠癌、乳腺癌、卵巢癌、骨癌或包括实体瘤形成或生长在内的血管增生病症。
本发明主题还为尤其打算用于治疗上述疾病的药用组合物,该组合物的特征在于其在与为其选择的给药模式相容的药学上可接受的载体中包含通式(I)化合物的互变异构体之一,或其药学上可接受的酸的盐。
术语“药学上可接受的载体”表示与皮肤、粘膜和外皮相容的介质。
可通过口服、肠、肠胃外、局部或眼给予本发明组合物。优选,按适合局部施用的形式将药用组合物包装。
通过口腔途径,组合物可为片剂、凝胶胶囊剂、包衣片剂、糖浆、混悬液、溶液、散剂、颗粒剂、乳液、混悬液的形式,或允许控释的微球、纳米球或脂质或聚合物微囊。通过肠胃外途径,组合物可为用于灌注或注射的溶液或混悬液的形式。
通常按日剂量约0.01mg/kg-100mg/kg体重,按一个或多个剂量摄取,给予本发明化合物。
化合物全身使用的浓度相对于组合物重量通常为0.001%-10%重量,优选0.01%-5%重量。
通过局部途径,本发明药用组合物更尤其用于治疗皮肤和粘膜,可为液体、糊或固体形式,更尤其为软膏、霜剂、乳、润发油、粉末、浸渍垫、合成洗涤剂、溶液、凝胶、喷雾剂、摩丝、混悬液、棒状物、洗发精或主要洗涤成分的形式。它们也可为允许控释的微球或纳米球或脂质或聚合物微囊的混悬液形式,或聚合物或胶凝贴剂的形式。
用于局部施用的组合物含本发明化合物的浓度相对于组合物总重量通常为0.001%-10%重量,优选0.01%-5%重量。
本发明通式(I)化合物还在化妆品领域中发现应用,尤其在防止日光的有害方面,防止和/或抵挡光诱发的或岁月所致皮肤和外皮老化。
因此,本发明主题还为组合物,该组合物在化妆品可接受的载体中包含至少一种通式(I)化合物。术语“化妆品可接受的介质”表示与皮肤、粘膜和外皮相容的介质。
本发明主题还为用于防止和/或治疗皮肤老化体征的组合物化妆品用途,该组合物含至少一种通式(I)化合物。
本发明主题还为用于身体或头发卫生的组合物化妆品用途,该组合物含至少一种通式(I)化合物。
在化妆品可接受的载体中含通式(I)化合物或其互变异构体或其药学上可接受酸的盐的本发明化妆品组合物尤其可为以下的形式:面霜、乳、凝胶、微球或纳米球或脂质或聚合物微囊的混悬液、浸渍垫、溶液、喷雾剂、摩丝、棒状物、肥皂、主要洗涤成分或洗发精。
通式(I)化合物在化妆品组合物中的浓度相对于组合物总重量优选为0.001%-10%重量。
前述药用和化妆品组合物也可含惰性添加剂或甚至与药用组合物有关的药效活性添加剂,或这些添加剂的组合,且尤其是:
-润湿剂;
-香味增强剂;
-防腐剂例如对-羟基苯甲酸酯:
-稳定剂:
-湿度调节剂;
-pH调节剂;
-渗透压调节剂;
-乳化剂;
-UV-A和UV-B掩蔽剂;
-抗氧化剂,例如α-生育酚、丁基羟基苯甲醚或丁基羟基甲苯、过氧化物岐化酶或泛醌醇;
-润肤剂;
-增湿剂例如甘油、PEG-400、硫代吗啉酮(thiamorpholinone)及其衍生物,或脲:
-抗脂溢或抗痤疮剂,例如S-羧基甲基半胱氨酸、S-苄基胱胺、其盐或其衍生物,或过氧化苯甲酰。
毫无疑问,本领域技术人员会小心选择待加入这些组合物中的任选的化合物,以使与本发明内在性质有关的有利的性质不受或基本上不受设计加入的物质的不利影响。
现给出本发明通式(I)化合物的一些制备实施例和这些化合物的生物活性结果,它们用于举例说明目的,不具有任何限制性质。
以下实施例描述某些本发明化合物的制备。这些实施例为非限制性,仅用于举例说明本发明。提供的化合物的编号是指下文表中给出的那些编号,所述表阐述了许多本发明化合物的化学结构和物理性质。
使用以下缩写:
-DMAP:二甲基氨基吡啶
-EDC:1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐
-HOBt:1-羟基-1,2,3-苯并三唑
-TBTU:N,N,N′,N′-四甲基-O-(苯并三唑-1-基)脲
四氟硼酸盐
-Fmoc:6-芴基甲氧基羰基
-DBU:1,5-二氮杂双环(5,4,0)十一碳-5-烯
-NaBH3CN:氰基硼氢化钠
-LiAlH4:氢化铝锂
-Rh/Al2O3:铑/氧化铝
-NaHCO3:碳酸氢钠
-NH4Cl:氯化铵
-NaCl:氯化钠
-MgSO4:硫酸镁
-Na2SO4:硫酸钠
-CuSO4:硫酸铜
-NaOH:氢氧化钠
-EtOAc:乙酸乙酯
-DCM:二氯甲烷
-DMF:二甲基甲酰胺
-MeOH:甲醇
-THF:四氢呋喃
-TLC:薄层层析
材料和方法:
制备HPLC法:
Modulo-cart策略C18 100x21.2mm,5μm柱
UV检测器:210-400nm
流速:17mL/min
溶剂A:H2O+0.05TFA
溶剂B:CH3CN+0.05TFA
梯度:
HPLC法:
方法A1
Atlantis C18 150x2.1mm,3μm柱
UV检测器:190-450nm
流速:0.3mL/min
溶剂A:CH3CN+0.1TFA
溶剂B:H2O+0.1TFA
梯度:
时间 组成
0.0min A=10%,B=90%
25.0min A=90%,B=10%
30.0min A=90%,B=10%
方法A
Gemini 150x3mm,3μm柱
UV检测器:190-450nm
流速:0.5mL/min
溶剂A:CH3CN+0.05TFA
溶剂B:H2O+0.05TFA
梯度:
方法B
Gemini 150x3mm,3μm柱
UV检测器:190-450nm
流速:0.5mL/min
溶剂A:CH3CN+0.05TFA
溶剂B:H2O+0.05TFA
梯度:
时间 组成
0.0min A=5%,B=95%
20.0min A=90%,B=10%
30.0min A=90%,B=10%
方法C
Gemini 150x3mm,3μm柱
UV检测器:190-450nm
流速:0.5mL/min
溶剂A:CH3CN
溶剂B:H2O+0.02TFA
梯度:
时间 组成
0.0min A=5%,B=95%
20.0min A=90%,B=10%
30.0min A=90%,B=10%
方法D
Gemini 150x3mm,3μm柱
UV检测器:190-450nm
流速:0.5mL/min
溶剂A:CH3CN
溶剂B:H2O+0.02TFA
梯度:
时间 组成
0.0min A=10%,B=90%
15.0min A=95%,B=5%
30.0min A=95%,B=5%
方法E
柱?
UV检测器:190-450nm
流速:0.5mL/min
溶剂A:MeOH+0.1TFA
溶剂B:H2O+0.02TFA
梯度:
时间 组成
0.0min A=10%,B=90%
15.0min A=95%,B=5%
30.0min A=95%,B=5%
方法F
Xbridge苯基250*4.6mm 5μm柱
UV检测器:190-450nm
流速:0.6mL/min
溶剂A:MeOH+25mM NH4OAc
溶剂B:H2O+25mM NH4OAc
梯度:
时间 组成
0.0min A=50%,B=50%
15.0min A=95%,B=5%
30.0min A=95%,B=5%
方法G
Xbridge苯基 150*2.1mm 3.5μm柱
UV检测器:190-450nm
流速:1.0mL/min
溶剂A:MeOH 95%+H2O 5%+25mM NH4OAc
溶剂B:H2O+25mM NH4OAc
梯度:
时间 组成
0.0min A=5%,B=95%
20.0min A=98%,B=2%
30.0min A=98%,B=2%
方法I
Gemini 150x3mm,3μm柱
UV检测器:190-450nm
流速:0.5mL/min
溶剂A:CH3CN+0.02TFA
溶剂B:H2O+0.02TFA
梯度:
时间 组成
0.0min A=10%,B=90%
15.0min A=90%,B=10%
30.0min A=90%,B=10%
方法J
Atlantis dC 18 250x4.6mm,5μm柱
UV检测器:190-450nm
流速:1.0mL/min
溶剂A:CH3CN+0.02TFA
溶剂B:H2O+0.02TFA
梯度:
方法K
Gemini C18 150x3mm,3μm柱
UV检测器:190-450nm
流速:0.3mL/min
溶剂A:MeOH 94%+H2O 6%+10mM(NH4)2CO3
溶剂B:H2O+10mM(NH4)2CO3
梯度:
时间 组成
0.0min A=20%,B=80%
15.0min A=95%,B=5%
30.0min A=95%,B=5%
方法L
Gemini C18 150x3mm,3μm柱
UV检测器:190-450nm
流速:0.3rnL/min
溶剂A:MeOH 94%+H2O 6%+10mM(NH4)2CO3
溶剂B:H2O+10mM(NH4)2CO3
梯度:
时间 组成
0.0min A=5%,B=95%
10.0min A=95%,B=5%
30.0min A=95%,B=5%
方法M
Gemini C18 150x3mm,3μm柱
UV检测器:190-450nm
流速:0.5mL/min
溶剂A:CH3CN+0.05TFA
溶剂B:H2O+0.05TFA
梯度:
时间 组成
0.0min A=10%,B=90%
15.0min A=90%,B=10%
30.0min A=90%,B=10%
方法N
Gemini C18 150x3mm,3μm柱
UV检测器:190-450nm
流速:0.5mL/min
溶剂A:CH3CN+0.1%HCOOH
溶剂B:H2O+0.1%HCOOH
梯度:
时间 组成
0.0min A=5%,B=95%
20.0min A=95%,B=5%
30.0min A=95%,B=5%
方法O
Gemini C18 150x3mm,3μm柱
UV检测器:190-450nm
流速:0.3mL/min
溶剂A:CH3CN+0.05TFA
溶剂B:H2O+0.05TFA
梯度:
方法P
Phenomenex Gemini C6-苯基 150x3mm,3μm柱
UV检测器:190-450nm
流速:0.5mL/min
溶剂A:H2O+0.05TFA
溶剂B:CH3CN+0.05TFA
梯度:
时间 组成
0.0min A=95%,B=5%
20.0min A=5%,B=95%
30.0min A=5%,B=95%
方法Q
Gemini C18 150x3mm,3μm柱
UV检测器:190-450nm
流速:0.5mL/min
溶剂A:CH3CN+0.1%HCOOH
溶剂B:H2O+0.1%HCOOH
梯度:
时间 组成
0.0min A=5%,B=95%
10.0min A=5%,B=95%
30.0min A=70%,B=30%
方法R
Thermohypersil Hypurity C18 150x4.6mm,5μm柱
UV检测器:190-450nm
流速:0.5mL/min
溶剂A:H2O+0.05TFA
溶剂B:CH3CN+0.05TFA
梯度:
时间 组成
0.0min A=95%,B=5%
20.0min A=5%,B=95%
30.0min A=5%,B=95%
方法S
Atlantis T3 150x4.6mm,5μm柱
UV检测器:190-450nm
流速:0.3mL/min
溶剂A:H2O+0.05TFA
溶剂B:CH3CN+0.05TFA
梯度:
时间 组成
0.0min A=95%,B=5%
20.0min A=5%,B=95%
30.0min A=5%,B=95%
方法U
Atlantis T3 C18 150x2.1mm,3μm柱
UV检测器:190-900nm
流速:0.3mL/min
溶剂A:CH3CN+0.02TFA
溶剂B:H2O+0.02TFA
梯度:
时间 组成
0.0min A=5%,B=95%
20.0min A=98%,B=2%
30.0min A=98%,B=2%
实施例1:1-[(S)-2-(4-丁酰基-4-苯基哌啶-1-基)-1-(4-甲氧基-苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲(化合物1)
1-1
1-{1-[(S)-2-氨基-3-(4-甲氧基苯基)丙酰基]-4-苯基哌啶-4-基}丁-1-酮
向含溶于120mL二氯甲烷和10mL二甲基甲酰胺的11.9g(28.5mmol)(S)-2-Fmoc-氨基-3-(4-甲氧基-苯基)丙酸的溶液中加入5.51g(38.9mmol)EDC和5.25g(38.9mmol)HOBt。在室温下搅拌30分钟后,加入6.95g(26.1mmol)1-(4-苯基哌啶-4-基)-丁-1-酮盐酸盐和18mL三乙胺的150mL二氯甲烷溶液。将反应介质搅拌2小时,然后加入饱和碳酸氢钠水溶液。将有机化合物用二氯甲烷萃取。有机相经硫酸镁干燥,然后过滤,将溶剂蒸去。粗产物经硅胶层析(洗脱液:9/1二氯甲烷/甲醇)纯化。得到橙色油状形式的4.7g 1-{1-[(S)-2-氨基-3-(4-甲氧基苯基)-丙酰基]-4-苯基哌啶-4-基}丁-1-酮,收率44%。
1-2
1-[(S)-2-(4-丁酰基-4-苯基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
向含100mg(0.245mmol)1-{1-[(S)-2-氨基-3-(4-甲氧基-苯基)丙酰基]-4-苯基哌啶-4-基}丁-1-酮的10mL二氯甲烷溶液中依次加入64μL二异丙基乙胺、74mg(0.368mmol)氯甲酸4-硝基苯基酯。将介质在室温下搅拌1小时30分钟。将含90mg(0.489mmol)组胺二盐酸盐和0.15mL二异丙基乙胺的5mL二氯甲烷和2mL二甲基甲酰胺溶液加入该混合物。
在室温下搅拌3小时后,将溶剂蒸去,得到的粗产物经制备HPLC(参见38页的条件)纯化。得到白色粉末形式的37mg 1-[(S)-2-(4-丁酰基-4-苯基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲三氟乙酸盐,收率37%。
HPLC:(方法A1);保留时间:15.87min,98%,M+H:545
实施例2:1-[2-(4-氰基-4-苯基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲(化合物3)
2-1
(S)-2-氨基-3-(4-甲氧基苯基)丙酸甲酯
向10g(33.8mmol)(S)-2-叔-丁氧基羰基氨基-3-(4-甲氧基苯基)丙酸中加入75mL甲醇,然后用30分钟滴加10mL硫酸。30小时后,通过依次加入10N氢氧化钠水溶液、饱和碳酸氢钠溶液将反应介质碱化至pH 8-9。将有机产物用二氯甲烷萃取。有机层经硫酸镁干燥,然后过滤,将溶剂蒸去。得到褐色油状物形式的6.36g(S)-2-氨基-3-(4-甲氧基苯基)丙酸甲酯,收率90%。
2-2
(S)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酸甲酯
向5.08g(24.3mmol)(S)-2-氨基-3-(4-甲氧基苯基)丙酸甲酯中加入15ml二氯甲烷。将反应介质浸入冷水浴。依次加入7.34g(36.4mmol)氯甲酸4-硝基苯基酯、6.33mL二异丙基乙胺。升温至室温后,将反应介质搅拌2小时。通过加入水将反应终止,然后用二氯甲烷萃取。有机相经硫酸镁干燥,过滤,在旋转蒸发仪中浓缩。得到12g黄色油状物。向12g这些油状物中加入10mL二甲基甲酰胺,然后将混合物加热至80℃。加入8.95g(48.6mmol)组胺二盐酸盐,然后滴加14.8mL(85.1mmol)二异丙基乙胺。冷却至室温后,将溶剂蒸去,粗产物经硅胶层析(洗脱液:85/15 二氯甲烷/甲醇)纯化。得到黄色油状物形式的5.6g(S)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酸甲酯,收率67%。
2-3
2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酸
向500mg(1.44mmol)(S)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酸甲酯中加入500mg氢氧化锂、7mL四氢呋喃和2mL水。将反应介质放入微波反应器中,在100℃下搅拌10分钟。进行另外7个相同试验。将各试验产物合并,浓缩至干。得到的粗产物通过硅胶垫过滤(洗脱液:1/1 二氯甲烷/甲醇)纯化。得到浅黄色粉末形式的2.73g 2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酸,收率70%。
2-4
1-[2-(4-氰基-4-苯基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
向溶于3.5ml二氯甲烷和1.5ml二甲基甲酰胺的300mg(0.90mmol)2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酸中加入0.46ml(2.7mmol)二异丙基乙胺、318mg(0.99mmol)TBTU和220mg(0.99mmol)4-氰基-4-苯基哌啶盐酸盐。16小时后,将溶液用饱和碳酸氢钠溶液洗涤,将有机产物用二氯甲烷萃取。有机相经硫酸镁干燥,过滤,浓缩。得到的粗产物通过硅胶垫过滤(洗脱液:7/3 二氯甲烷/甲醇)纯化。得到白色粉末形式的75mg 1-[2-(4-氰基-4-苯基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲,收率17%。
1H NMR/DMSOD6 100℃:δ=1.92-2.13(m,2H);2.62(t,J=7.2Hz,2H);2.72-2.99(m,8H);3.26(bq,J=5.6-7.2Hz,2H);3.67(s,3H);4.87(bq,J=8.4Hz,1H);5.95(bt,1H);6.10(d,J=8.4Hz,1H);6.74(s,1H);6.83(d,J=8.8Hz,2H);7.11-7.14(m,2H);7.34-7.53(m,7H).
实施例3:4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-甲酸乙酯三氟乙酸盐(化合物6)
3-1-1
哌啶-1-叔-丁氧基羰基-4-环己基-4′-甲酸乙酯
将2.00g(6.42mmol)哌啶-1-叔-丁氧基羰基-4-环己基-4′-甲酸的10mL甲苯溶液加入1.92mL(12.8mmol)DBU和1.04ml(12.8mmol)碘乙烷。在120℃下,将介质在微波反应器中搅拌10分钟。将二氯甲烷加入反应介质,将有机相用饱和NaHCO3水溶液洗涤。有机相经MgSO4干燥,过滤,浓缩。得到的粗产物经硅胶层析(洗脱液:9/1 庚烷/乙酸乙酯)纯化。得到1.92g无色油状物形式的哌啶-1-叔丁氧基羰基-4-环己基-4′-甲酸乙酯,收率88%。
3-1-2
哌啶-4-环己基-4′-甲酸乙酯
在0℃下,向溶于8ml二氯甲烷的1.90g(5.60mmol)溶液中加入6ml三氟乙酸。4小时后,将溶剂蒸去,将反应介质溶于EtOAc,然后用1N氢氧化钠洗涤。有机相经MgSO4干燥,过滤,蒸发。得到白色粉末形式的1.21g哌啶-4-环己基-4′-甲酸乙酯,收率90%。
3-2
4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯三氟乙酸盐
向溶于90ml二甲基甲酰胺的2.0g(6.02mmol)2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酸(参见制备2-3)中加入1.93g(6.02mmol)TBTU、2.1ml(12.0mmol)二异丙基乙胺和2.05g(5.80mmol)哌啶-4-环己基-4’-甲酸乙酯。6小时后,将溶液用1N氢氧化钠溶液洗涤,将有机产物用二氯甲烷萃取。有机相经硫酸镁干燥,过滤,浓缩。得到的粗产物经制备HPLC(条件参见第74页)纯化。得到白色粉末形式的530mg 1-[2-(4-氰基-4-苯基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]-脲三氟乙酸盐,收率14%。
1H NMR/DMSOD6 100℃:δ=0.87-0.90(m,2H);1.07-1.37(m,13H);1.57-1.64(m,3H);1.72-1.75(m,2H),1.92-1.96(m,2H);2.66-2.82(m,4H);3.29-3.35(m,2H);3.74(s,3H);4.13(q,J=6.8-7.2Hz,2H);4.80(m,1H);6.00-6.10(m,2H);6.82(d,J=8.4Hz,2H);7.07(d,J=8.4Hz,2H);7.30(s,1H);8.80(s,1H).
实施例4:丁酸1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酰基]-3-苯基氮杂环丁烷-3-基酯(化合物8)
4-1-1
3-羟基-3-苯基氮杂环丁烷-1-叔-丁氧基羰基
将含500mg(2.92mmol)3-氧代-氮杂环丁烷-1-叔-丁氧基羰基的10mL THF溶液浸入-50℃浴中,向其中滴加3.9ml(11.7mmol)3M苯基溴化镁的乙醚溶液。将介质在-50℃下搅拌1小时,通过加入饱和氯化铵溶液进行水解。升温至室温后,加入1N盐酸溶液,然后用乙酸乙酯萃取。将有机相干燥,蒸发至干。得到的粗产物经硅胶层析(洗脱液:7/3 庚烷/乙酸乙酯)纯化。得到253mg白色粉末,收率35%。
4-1-2
3-丁酰氧基-3-苯基氮杂环丁烷-1-叔-丁氧基羰基
向含200mg(0.80mmol)3-羟基-3-苯基氮杂环丁烷-1-叔-丁氧基羰基的4ml二氯甲烷溶液中加入98mg(0.80mmol)DMAP和0.13ml吡啶。在室温下搅拌10分钟后,加入0.26ml丁酸酐。4小时后,加入饱和氯化铵溶液,然后用二氯甲烷萃取。将有机相干燥,蒸发至干。得到的粗产物经硅胶层析(洗脱液:7/3 庚烷/乙酸乙酯)纯化。得到186mg油状物,收率73%。
4-1-3
丁酸3-苯基氮杂环丁烷-3-基酯三氟乙酸盐
向含溶于8ml二氯甲烷的183mg(0.57mmol)3-丁酰氧基-3-苯基氮杂环丁烷-1-叔-丁氧基羰基的溶液中加入2ml三氟乙酸。将反应介质在室温下搅拌1小时,然后浓缩。得到的粗产物经硅胶层析(洗脱液:90/10 二氯甲烷/甲醇)纯化。得到88mg浅黄色油状物,收率46%。
4-2
丁酸1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]-3-苯基氮杂环丁烷-3-基酯
向溶于2.75ml二氯甲烷和1.25mL二甲基甲酰胺的80mg(0.24mmol)2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酸(参见制备2-3)中加入0.08m L(0.48mmol)二异丙基乙胺、84mg(0.26mmol)TBTU和88mg(0.26mmol)丁酸3-苯基氮杂环丁烷-3-基酯三氟乙酸盐。2小时后,将溶液用1N氢氧化钠溶液洗涤,将有机产物用二氯甲烷萃取。有机相经硫酸镁干燥,过滤,浓缩。得到的粗产物经制备TLC(洗脱液:9/1 二氯甲烷/甲醇)纯化。得到5.4mg丁酸1-[2-{3-[2-(1H-咪唑-4-基)乙基]-脲基}-3-(4-甲氧基苯基)丙酰基]-3-苯基氮杂环丁烷-3-基酯,收率2%。
HPLC:(方法B);保留时间:12.15min,86%,M+H:534.
实施例51-[2-(3-丁氧基-3-苯基氮杂环丁烷-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲(化合物11)
5-1-1
3-羟基-3-苯基氮杂环丁烷-1-叔-丁氧基羰基
将含500mg(2.92mmol)3-氧代-氮杂环丁烷-1-叔-丁氧基羰基的10mL THF溶液浸入-50℃浴中,向其中滴加3.9mL(11.7mmol)3M苯基溴化镁的乙醚溶液。将介质在-50℃下搅拌1小时,加入饱和氯化铵溶液进行水解。升温至室温后,加入1N盐酸溶液,然后用乙酸乙酯萃取。将有机相干燥,蒸发至干。得到的粗产物经硅胶层析(洗脱液:7/3 庚烷/乙酸乙酯)纯化。得到253mg白色粉末,收率35%。
5-1-2
3-丁氧基-3-苯基氮杂环丁烷-1-叔-丁氧基羰基
将300mg 60%NaH的3mL DMF悬浮液浸入0℃浴中,向其中滴加溶于5mL DMF的1g(4.0mmol)3-羟基-3-苯基氮杂环丁烷-1-叔-丁氧基羰基溶液。滴加2.5mL正-丁基碘。将反应介质在0℃下搅拌15分钟,然后在室温下搅拌72小时。通过加入饱和氯化铵溶液将介质水解,然后用乙酸乙酯萃取。将有机相干燥,蒸发至干。得到的粗产物经硅胶层析(洗脱液:7/3 庚烷/乙酸乙酯)纯化。得到500mg浅黄色油状物,收率41%。
5-1-3
3-丁氧基-3-苯基氮杂环丁烷三氟乙酸盐
向含溶于5ml二氯甲烷的500mg(1.64mmol)3-丁氧基-3-苯基氮杂环丁烷-1-叔-丁氧基羰基的溶液中加入1ml三氟乙酸。将反应介质在室温下搅拌3小时,然后浓缩。得到的粗产物经硅胶层析(洗脱液:90/10 二氯甲烷/甲醇)纯化。得到400mg浅黄色粉末,收率76%。
5-2
1-[2-(3-丁氧基-3-苯基氮杂环丁烷-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
向溶于4ml二氯甲烷和1.5ml二甲基甲酰胺的57mg(0.17mmol)2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酸(参见制备2-3)中加入0.12ml(0.68mmol)二异丙基乙胺、61mg(0.19mmol)TBTU和55mg(0.17mmol)3-丁氧基-3-苯基氮杂环丁烷三氟乙酸盐。3小时后,将溶液用1N氢氧化钠溶液洗涤,将有机产物用二氯甲烷萃取。有机相经硫酸镁干燥,过滤,浓缩。得到的粗产物经制备TLC(洗脱液:9/1 二氯甲烷/甲醇)纯化。得到3mg 1-[2-(3-丁氧基-3-苯基氮杂环丁烷-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲,收率3%。
HPLC:(方法C);保留时间:11.6min,93%,M+H:520.
实施例6:N-甲基-4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-甲酰胺(化合物12)
6-1
4-甲基氨基甲酰基-4-环己基哌啶
在0℃下,向溶于2ml二氯甲烷的70mg(0.22mmol)哌啶-1-叔-丁氧基羰基-4-环己基-4′-甲基氨基甲酰基中加入1ml三氟乙酸。1小时后,将溶剂蒸去,将反应介质溶于二氯甲烷,用1N氢氧化钠洗涤。有机相经MgSO4干燥,过滤,蒸发。得到黄色油状物形式的44mg 4-甲基氨基甲酰基-4-环己基哌啶,收率90%。
6-2
N-甲基-4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酰胺
向溶于2ml二氯甲烷和0.5mL二甲基甲酰胺的66mg(0.20mmol)2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酸(参见制备2-3)中加入0.06ml(0.40mmol)二异丙基乙胺、71mg(0.22mmol)TBTU和44mg(0.20mmol)4-甲基氨基甲酰基4-环己基哌啶。2小时后,将溶液用1N氢氧化钠溶液洗涤,将有机产物用二氯甲烷萃取。有机相经硫酸镁干燥,过滤,浓缩。得到的粗产物经制备TLC(洗脱液:8/2 二氯甲烷/甲醇)纯化。得到白色粉末形式的11mg N-甲基-4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酰胺,收率10%。
HPLC:(方法D);保留时间:11.82min,97%,M+H:539.
实施例7:1-[2-(3-环己基羰基氮杂环丁烷-1-基)-1-(4-甲氧基-苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲(化合物13):
7-1-1
3-(甲氧基甲基氨基甲酰基)氮杂环丁烷-1-叔-丁氧基羰基
将2g(9.94mmol)1-叔-丁氧基羰基-3-氮杂环丁烷羧酸溶于8mL二氯甲烷,加入3.19g(9.94mmol)TBTU,然后加入4mL二甲基甲酰胺。加入0.97g(9.94mmol)N,O-二甲基羟胺的10mL二氯甲烷和5.17mL(29.8mmol)二异丙基乙胺溶液。搅拌2小时后,加入二氯甲烷,将介质依次用饱和NaHCO3溶液、5%柠檬酸溶液洗涤。有机相经MgSO4干燥,过滤,在旋转蒸发仪上浓缩。得到的粗产物经硅胶层析(洗脱液:7/3 庚烷/乙酸乙酯)纯化。得到1.9g无色油状物,收率78%。
7-1-2
3-环己烷羰基氮杂环丁烷-1-叔-丁氧基羰基
在0℃下,向301mg(1.23mmol)3-(甲氧基甲基氨基甲酰基)氮杂环丁烷-1-叔-丁氧基羰基的5mL THF溶液中加入1.48ml(1.48mmol)1M环己基溴化镁的THF溶液。必需再加入3.35mL(3.35mmol)镁试剂以使原料消失。加入二氯甲烷,将有机相依次用饱和NH4Cl溶液、饱和NaCl溶液洗涤,然后经MgSO4干燥,过滤,浓缩。得到的粗产物经硅胶层析(洗脱液:7/3 庚烷/乙酸乙酯)纯化。得到205mg无色油状物,收率62%。
7-1-3
3-环己基羰基氮杂环丁烷
向含溶于8mL二氯甲烷的192mg(0.72mmol)3-环己基羰基氮杂环丁烷-1-叔-丁氧基羰基的溶液中加入2mL三氟乙酸。将反应介质在室温下搅拌2小时,然后浓缩。在1N氢氧化钠溶液的存在下,将反应介质用二氯甲烷萃取。有机相经MgSO4干燥,过滤,浓缩。得到95mg白色粉末,收率79%。
7-2
1-[2-(3-环己基羰基氮杂环丁烷-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
向溶于3.5mL二氯甲烷和1.0mL二甲基甲酰胺的189mg(0.57mmol)2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酸(参见制备2-3)中加入0.2mL(1.14mmol)二异丙基乙胺、202mg(0.63mmol)TBTU和95mg(0.57mmol)3-环己基羰基氮杂环丁烷。5小时后,将溶液用1N氢氧化钠溶液洗涤,将有机产物用二氯甲烷萃取。有机相经硫酸镁干燥,过滤,浓缩。得到的粗产物经制备TLC(9/1 二氯甲烷/甲醇)纯化。得到8.5mg 1-[2-(3-环己基羰基氮杂环丁烷-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲,收率3%。
HPLC:(方法E);保留时间:12.36min,86%,M+H:482.
实施例8:4-环己基-1-[2-{3-乙基-3-[2-(1H-咪唑-4-基)乙基]-脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-甲酸乙酯(化合物14):
8-1-1
2,6,7,8-四氢咪唑并[1,5-c]嘧啶-5-酮
向含500mg(4.5mmol)组胺的5mL乙腈悬浮液中加入730mg(4.5mmol)N,N′-羰基二咪唑,将混合物在80℃下加热16小时。冷却至室温后,将溶剂蒸去,加入2.5mL乙醇。将产物沉淀,并在0℃下搅拌1小时。将产物滤出,用冰冷乙醇冲洗,在真空干燥箱中干燥过夜。得到370mg 2,6,7,8-四氢咪唑并[1,5-c]嘧啶-5-酮,收率60%。
8-1-2
6-乙基-7,8-二氢-6H-咪唑并[1,5-c]嘧啶-5-酮
在室温下,向溶于5mL DMF的500mg(3.6mmol)5,6,7,8-四氢-5-氧代咪唑并[1,5-c]嘧啶小心加入173mg(4.32mmol)氢化钠。将反应介质在室温下搅拌1小时,然后滴加0.35mL(4.32mmol)碘乙烷。将反应介质在室温下搅拌2小时,然后将溶剂蒸去。将残余物用1N NaHCO3溶液处理,用氯仿萃取。合并的有机相经MgSO4干燥,过滤,蒸发。得到的油状物直接用于下一步。
8-1-3
乙基[2-(1H-咪唑-4-基)乙基]胺盐酸盐
向前一步得到的粗产物加入氢氧化钾水溶液(173mg(6.16mmol)的5ml水溶液),将介质回流1小时。冷却至室温后,加入浓盐酸溶液至pH 1。将水蒸去,将残余物溶于乙醇。将乙醇溶液加热至80℃,趁热过滤。将滤液蒸发。然后使得到的固体在1/1的乙醚/乙醇混合物中沉淀,然后在氮气氛下滤出。得到160mg乙基[2-(1H-咪唑-4-基)乙基]胺盐酸盐,最后两步合计收率21%。
8-2
(S)-3-(4-甲氧基苯基)-2-(4-硝基苯氧基羰基氨基)丙酸甲酯
将1g(4.8mmol)(S)-2-氨基-3-(4-甲氧基苯基)丙酸甲酯(参见制备2-1)在30ml二氯甲烷中稀释。将溶液在冷水浴中冷却,然后加入1.4g(7.2mmol)氯甲酸4-硝基苯基酯和1.2ml(7.2mmol)二异丙基乙胺。升温至室温后,将反应介质搅拌2小时。将溶液倾入水中,然后用二氯甲烷萃取。将有机相干燥,然后蒸发。得到的粗产物用于下一步,无需进一步纯化。
8-3
(S)-2-{3-乙基-3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酸甲酯
将0.14g(0.38mmol)(S)-3-(4-甲氧基苯基)-2-(4-硝基苯氧基羰基-氨基)丙酸甲酯在2ml DMF中稀释。将溶液加热至80℃,然后加入0.16g(0.76mmol)乙基[2-(1H-咪唑-4-基)乙基]胺盐酸盐和0.13mL(1.3mmol)二异丙基乙胺。5分钟后,将反应介质冷却至室温,搅拌15分钟。加入甲苯,将溶剂蒸去。得到的粗产物经硅胶层析(洗脱液:8/2二氯甲烷/甲醇)纯化。得到无色油状物形式的0.15g(S)-2-{3-乙基-3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酸甲酯,收率100%。
8-4
2-{3-乙基-3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酸
将150mg(0.4mmol)(S)-2-{3-乙基-3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酸甲酯在4mL THF和1mL水中稀释,加入150mg(6mmol)氢氧化锂。在微波反应器中,将混合物在100℃下加热10分钟。将溶剂蒸去,残余物然后经硅胶垫纯化(洗脱液:1/1 二氯甲烷/甲醇)。得到浅黄色粉末形式的100mg 2-{3-乙基-3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酸,收率69%。
8-5
4-环己基哌啶-4-甲酸乙酯三氟乙酸盐
将0.34g(1mmol)哌啶-1-叔-丁氧基羰基-4-环己基-4′-甲酸乙酯(参见制备3-1-1)溶于4ml 80/20的二氯甲烷/三氟乙酸混合物。将溶液在室温下搅拌2小时,然后在氮气下蒸发。得到0.5g无色油状物,用于下一步,无需进一步纯化。
8-6
4-环己基-1-[2-{3-乙基-3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
将66mg(0.19mmol)4-环己基哌啶-4-甲酸乙酯三氟乙酸盐在3ml二氯甲烷和3ml二甲基甲酰胺中稀释,加入67mg(0.21mmol)TBTU和75mg(0.21mmol)2-{3-乙基-3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酸和0.06ml(0.38mmol)二异丙基乙胺。在室温下搅拌2小时后,加入1N NaOH水溶液,将有机产物用二氯甲烷萃取。将有机相干燥,然后蒸发。得到的粗产物经硅胶层析(洗脱液:95/5 二氯甲烷/甲醇)纯化。得到黄色油状物形式的34mg 4-环己基-1-[2-{3-乙基-3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-甲酸乙酯,收率30%。
HPLC:(方法F);保留时间:20.72min,91%,M+H:582.
实施例9:N-环丙基-N-{1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-基}丙酰胺(化合物15)
9-1-1
4-环丙基氨基哌啶-1-甲酸叔丁酯
将1g(5mmol)4-氧代哌啶-1-甲酸叔丁酯溶于含10%乙酸的40mL乙醇。加入0.28ml(4.2mmol)环丙胺。30分钟后,加入0.53g(36mmol)NaBH3CN,将反应介质在室温下搅拌1小时。通过加入氨水溶液将反应终止,然后将有机产物用乙酸乙酯萃取。将有机相干燥,然后蒸发。得到的粗产物经硅胶层析(洗脱液:55/45 庚烷/乙酸乙酯)纯化。得到无色油状物形式的0.8g 4-环丙基氨基-哌啶-1-甲酸叔丁酯,收率79%。
9-1-2
4-(环丙基丙酰基氨基)哌啶-1-甲酸叔丁酯
将0.8g(3.3mmol)4-环丙基氨基哌啶-1-甲酸叔丁酯、0.48ml(3.3mmol)三乙胺和0.56ml(3.3mmol)丙酰氯溶于50ml THF。将反应介质在室温下搅拌2小时。通过加入水将反应终止,然后将有机产物用二氯甲烷萃取。将有机相干燥,然后蒸发。得到的粗产物经硅胶层析(洗脱液:6/4 庚烷/乙酸乙酯)纯化。得到无色油状物形式的0.87g 4-(环丙基丙酰基氨基)哌啶-1-甲酸叔丁酯,收率89%。
9-1-3
N-环丙基-N-哌啶-4-基丙酰胺
将0.87g(2.9mmol)4-(环丙基丙酰基氨基)哌啶-1-甲酸叔丁酯溶于8ml 80/20的DCM/MeOH混合物。将溶液在室温下搅拌2小时,然后倾入1N NaOH溶液,用二氯甲烷萃取。有机相经硫酸镁干燥,然后蒸发。得到290mg粗产物,用于下一步,无需进一步纯化。
9-2
N-环丙基-N-{1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-基}丙酰胺
在氮气下,将100mg(0.51mmol)N-环丙基-N-哌啶-4-基丙酰胺、170mg(0.51mmol)2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酸(参见制备2-3)、108mg(0.56mmol)EDC和76mg(0.56mmol)HOBT溶于5ml DMF。将混合物在室温下搅拌过夜,然后将溶液用5%柠檬酸水溶液洗涤,用乙酸乙酯萃取。将有机相用1N NaOH水溶液洗涤,然后干燥,蒸发。得到的粗产物经制备HPLC(条件参见第38页)纯化。得到2mg N-环丙基-N-{1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-基}-丙酰胺,收率8%。
HPLC:(方法G);保留时间:12.46min,92%,M+H:511.
实施例10:1-[-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基-苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲三氟乙酸盐(化合物17):
10-1-1
4-苯基-1-(甲苯-4-磺酰基)哌啶-4-甲腈
将溶于150mL二氯甲烷的17.2g(89.8mmol)4-甲基苯磺酰氯加入20g(89.8mmol)4-苯基哌啶-4-甲腈和28mL三乙胺的200mL二氯甲烷溶液。将反应混合物在室温下搅拌1小时。通过加入200mL水将反应终止,然后用二氯甲烷萃取。将有机相合并,经硫酸钠干燥。将溶剂蒸去,将残余物溶于乙醚,滤出。得到白色粉末形式的30.3g 4-苯基-1-(甲苯-4-磺酰基)哌啶-4-甲腈,收率99%。
10-1-2
1-[4-苯基-1-(甲苯-4-磺酰基)哌啶-4-基]-丁-1-酮
将88mL(176mmol)正丙基氯化镁加入30g(88mmol)4-苯基-1-(甲苯-4-磺酰基)哌啶-4-甲腈的500mL甲苯溶液。将反应混合物在65-70℃下搅拌6小时,然后在室温下搅拌过夜。通过加入100mL四氢呋喃将反应终止,然后用1N盐酸溶液水解,用乙酸乙酯萃取。将有机相合并,经硫酸钠干燥。将溶剂蒸去,将残余物溶于乙醚,滤出。将1.38g原料回收。将滤液浓缩至干,然后经硅胶层析(洗脱液:80/20庚烷/乙酸乙酯)纯化。得到白色粉末形式的17.8g 1-[4-苯基-1-(甲苯-4-磺酰基)哌啶-4-基]-丁-1-酮,收率50%。
10-1-3
4-丁酰基-4-苯基哌啶盐酸盐
将10g(26mmol)1-[4-苯基-1-(甲苯-4-磺酰基)哌啶-4-基]-丁-1-酮悬浮于64ml硫酸和32ml水。将反应混合物搅拌回流48小时。通过HPLC监测反应。加入50ml乙醇,使反应介质均化,然后加入40ml硫酸,继续加热24小时。通过加入冰将反应终止,用氢氧化钠溶液碱化,然后用乙酸乙酯萃取。将有机相合并,经硫酸钠干燥。将溶剂蒸去,然后将残余物溶于乙醚,用4N氯化氢的乙酸乙酯溶液沉淀。得到白色粉末形式的3.8g 4-丁酰基-4-苯基哌啶盐酸盐,收率55%。
10-1-4
1-(4-环己基哌啶-4-基)丁-1-酮
在帕尔高压反应器中,在6巴氢气压下,将100mg铑/氧化铝和0.2ml乙酸加入100mg(0.5mmol)4-丁酰基-4-苯基哌啶盐酸盐的10ml二
烷溶液。将反应介质在80℃下加热12小时。将反应终止,然后通过硅藻土过滤,用二氯甲烷洗涤。将溶剂蒸去,将残余物溶于水,用1N氢氧化钠溶液碱化,用乙酸乙酯萃取。有机相经硫酸钠干燥。将溶剂蒸去,残余物经硅胶层析(洗脱液:9/1 二氯甲烷/甲醇)纯化。得到白色粉末形式的51.2mg 1-(4-环己基哌啶-4-基)-丁-1-酮,收率61%。
10-2
1-[2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲三氟乙酸盐
将29mg(0.22mmol)HOBt和41mg(0.22mmol)EDC加入62.5mg(0.19mmol)2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酸(参见制备2-3)和43.7mg(0.19mmol)1-(4-环己基哌啶-4-基)丁-1-酮的2mL二甲基甲酰胺溶液。将反应混合物在室温下搅拌16小时。通过加入10mL水将反应终止,然后用乙酸乙酯萃取。将有机相合并,经硫酸钠干燥。将溶剂蒸去,残余物经制备HPLC(条件参见第38页)纯化。得到白色泡沫形式的63.7mg 1-[2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲三氟乙酸盐,收率59%。
HPLC:(方法J);保留时间:21.49min,97%,M+H:552.
实施例11:1-[2-(4-丁氧基-4-环己基哌啶-1-基)-1-(4-甲氧基-苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲(化合物18):
11-1-1
4-羟基-4-苯基哌啶-1-叔-丁氧基羰基
将2.5g(12.5mmol)4-氧代哌啶-1-甲酸叔丁酯溶于100mL THF,浸入-50℃浴中。加入40mL(40mmol)苯基溴化镁溶液。搅拌1小时30分钟后,加入饱和NH4Cl溶液,然后将反应介质用乙酸乙酯萃取。将有机相用5%柠檬酸洗涤,然后经MgSO4干燥,过滤,浓缩。粗产物经硅胶层析(洗脱液:7/3 庚烷/乙酸乙酯)得到。得到1.84g白色粉末,收率53%。
11-1-2
4-丁氧基-4-苯基哌啶-1-叔-丁氧基羰基
将溶于7.5mL DMF的500mg(1.80mmol)4-羟基-4-苯基哌啶-1-叔-丁氧基羰基溶液浸入0℃浴,向其中依次加入196mg(4.90mmol)60%NaH、1mL(8.7mmol)正丁基碘。搅拌3小时后,再加入206mg60%NaH和1mL正丁基碘。5天后,将反应介质用乙酸乙酯萃取,用饱和NH4Cl溶液洗涤。有机相经MgSO4干燥,过滤,浓缩。得到的粗产物经硅胶层析(洗脱液:9/1 庚烷/乙酸乙酯)纯化。得到233mg无色油状物,收率39%。
11-1-3
4-丁氧基-4-环己基哌啶-1-叔-丁氧基羰基
将含178mg 5%Rh/Al2O3、0.35ml乙酸和220mg(0.66mmol)4-丁氧基-4-苯基哌啶-1-叔-丁氧基羰基的18ml二
烷溶液置于6巴氢气下,在80℃下保持18小时。将反应介质过滤,用二氯甲烷洗涤,浓缩。得到的粗产物经硅胶层析(洗脱液:95/5 庚烷/EtOAc)纯化。得到139mg无色油状物,收率62%。
11-1-4
4-丁氧基-4-环己基哌啶三氟乙酸盐
向含溶于8ml二氯甲烷的139mg(0.41mmol)4-丁氧基-4-环己基哌啶-1-叔-丁氧基羰基的溶液中加入2ml三氟乙酸。将反应介质在室温下搅拌2小时,然后浓缩。得到241mg无色油状物,用于下一步,无需进一步纯化。
11-2
1-[2-(4-丁氧基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
向溶于2ml DMF的69mg(0.21mmol)2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酸(参见制备2-3)中加入71mg(0.20mmol)4-丁氧基-4-环己基哌啶三氟乙酸盐的1.5ml DMF溶液、44mg(0.23mmol)EDC和33mg(0.24mmol)HOBt。2小时30分钟后,将反应介质用2%柠檬酸水溶液水解,然后用二氯甲烷萃取。然后将有机相用1N氢氧化钠水溶液洗涤。有机相经MgSO4干燥,过滤,浓缩。该油状物经硅胶层析(洗脱液:8/2 DCM/MeOH)纯化。得到25mg1-[2-(4-丁氧基-4-环己基哌啶-1-基)-1-(4-甲氧基-苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲,收率22%。
1H NMR/DMSOD6 100℃:δ=0.87-0.94(m,4H);1.06-1.23(m,5H);1.33-1.68(m,12H);1.72-1.80(m,3H);2.63(t,J=7.6Hz,2H);2.71-2.83(m,4H);2.91-3.09(m,2H);3.19-3.28(m,4H);3.73(s,3H);4.84(bq,J=6.4-8.4Hz,1H);5.96-6.02(m,2H);6.79(d,J=5.6Hz,2H);6.82(s,1H);7.08(d,J=8.0Hz,2H);7.58(s,1H).
实施例12:4-乙基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-甲酸乙酯(化合物24):
12-1-1
4-乙基-4-乙氧基羰基哌啶-1-甲酸叔丁酯
在-10℃下,将0.2g(0.78mmol)4-乙氧基羰基哌啶-1-甲酸叔丁酯溶于4ml THF。滴加0.8ml(1.56mmol)二异丙基氨基化锂。15分钟后,加入0.09mL(1.2mmol)碘乙烷,让混合物升温至室温。搅拌30分钟,然后倾入饱和氯化铵溶液,用乙酸乙酯萃取。将有机相干燥,然后浓缩至干。得到的油状物经硅胶层析(洗脱液:95/5 庚烷/乙酸乙酯)纯化。得到黄色油状物形式的183mg 4-乙基-4-乙氧基羰基哌啶-1-甲酸叔丁酯,收率82%。
12-1-2
4-乙氧基羰基-4-乙基哌啶三氟乙酸盐
将183mg(0.64mmol)4-乙基-4-乙氧基羰基哌啶-1-甲酸叔丁酯在4mL 8/2的二氯甲烷/三氟乙酸混合物中稀释。将溶液在室温下搅拌1小时,然后将溶剂蒸去。得到油状物形式的140mg 4-乙氧基羰基-4-乙基哌啶三氟乙酸盐,收率73%。
12-2
4-乙基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
将0.194g(0.59mmol)2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酸(参见制备2-3)、140mg(0.47mmol)4-乙氧基羰基-4-乙基哌啶三氟乙酸盐、124mg(0.65mmol)EDC和88mg(0.65mmol)HOBt溶于4mL DMF。将混合物在室温下搅拌72小时。将反应介质用1N NaOH水溶液洗涤,然后用二氯甲烷萃取。将有机相干燥,蒸发。
得到的油状物经硅胶层析(洗脱液:90/10 DCM/MeOH)纯化。得到无色油状物形式的89mg 4-乙基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯,收率30%。
HPLC:(方法M);保留时间:9.32min,93%,M+H:500.
实施例13:环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-甲酸三氟乙酸盐(化合物26)
13-1
4-环己基哌啶-4-甲酸三氟乙酸盐
在室温下,向含溶于3ml二氯甲烷的480mg(1.54mmol)哌啶-1-叔-丁氧基羰基-4-环己基-4′-甲酸的溶液中加入1ml三氟乙酸。蒸去溶剂后,得到的油状物用于下一步。
13-2
环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸三氟乙酸盐
向含93mg(0.28mmol)2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酸和100mg(0.31mmol)4-环己基-哌啶-4-甲酸三氟乙酸盐的0.8ml二甲基甲酰胺溶液中加入0.16ml二异丙基乙胺和90mg(0.28mmol)TBTU。将反应介质在室温下搅拌18小时。通过加入水将反应终止,将有机化合物用二氯甲烷萃取。将有机相干燥,蒸发。得到的油状物经制备HPLC(条件参见第38页)纯化。得到35mg环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-甲酸三氟乙酸盐,收率19%。
HPLC:(方法L);保留时间:14.75min,96%,M+H:526.
实施例14:1-[2-(1H-咪唑-4-基)乙基]-3-{1-(4-甲氧基苄基)-2-[3-(2-甲基环己基)-3-丙氧基氮杂环丁烷-1-基]-2-氧代乙基}脲三氟乙酸盐(化合物27)
14-1-1
3-(2-甲基环己基)-3-丙氧基氮杂环丁烷-1-甲酸叔丁酯
将按实施例6-1-2中所述制备的170mg(0.56mmol)3-(2-甲基环己基)-3-丙氧基氮杂环丁烷-1-甲酸叔丁酯、48mg 5%铑/氧化铝、5ml甲醇和0.6ml乙酸加入帕尔高压反应器。在90℃下,将介质在4巴氢气压下搅拌7天。将反应介质过滤,用二氯甲烷冲洗,然后浓缩至干。粗产物经硅胶层析(洗脱液:95/5 庚烷/乙酸乙酯)纯化。得到无色油状物形式的96mg 3-(2-甲基环己基)-3-丙氧基-氮杂环丁烷-1-甲酸叔丁酯,收率55%。
14-1-2
3-(2-甲基环己基)-3-丙氧基氮杂环丁烷三氟乙酸盐
将91mg(0.29mmol)3-(2-甲基环己基)-3-丙氧基氮杂环丁烷-1-甲酸叔丁酯溶于8ml二氯甲烷。将反应介质浸入冰浴中。加入2ml三氟乙酸。1小时后,将溶剂蒸去。113mg褐色油状物用于下一步,无需进一步纯化。
14-2
1-[2-(1H-咪唑-4-基)乙基]-3-{1-(4-甲氧基苄基)-2-[3-(2-甲基环己基)-3-丙氧基氮杂环丁烷-1-基]-2-氧代乙基}脲三氟乙酸盐
向溶于2ml DMF的97mg(0.29mmol)2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酸(参见制备2-3)溶液中加入94mg(0.29mmol)3-(2-甲基环己基)-3-丙氧基氮杂环丁烷三氟乙酸盐、70mg(0.37mmol)EDC和45mg(0.33mmol)HOBt。3小时后,将反应介质用1N氢氧化钠水溶液水解,然后用二氯甲烷萃取。有机相经MgSO4干燥,过滤,浓缩。得到的粗产物经制备HPLC纯化。得到33mg 1-[2-(1H-咪唑-4-基)乙基]-3-{1-(4-甲氧基苄基)-2-[3-(2-甲基环己基)-3-丙氧基氮杂环丁烷-1-基]-2-氧代乙基}脲三氟乙酸盐,收率18%。
1H NMR/DMSOD6 100℃:δ=0.79-0.86(m,3H);0.88-0.95(m,3H);1.10-1.30(m,2H);1.40-1.50(m,8H);1.63-1.73(m,2H);1.98-2.05(m,1H);2.78(bq,J=6.8-8.8Hz,5H);3.22-3.38(m,2H);3.56-3.70(m,3H);3.75(s,3H);3.80-4.20(m,1H);4.34(bt,J=7.2Hz,1H);5.90-6.20(m,2H);6.85(bd,2H);7.10(d,J=8.0Hz,2H);7.31(s,1H);8.82(s,1H).
实施例15:1-[2-(1H-咪唑-4-基)乙基]-3-[1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基氮杂环丁烷-1-基)乙基]脲(化合物29)
15-1-1
2-苯基庚腈
将2g 60%NaH的50ml DMF悬浮液冷却至0℃,向其中滴加5g(42.7mmol)苯乙腈。在0℃下搅拌30分钟后,滴加5.32mL(42.7mmol)溴戊烷。将反应介质在室温下搅拌16小时,然后用冰处理,用乙醚萃取。将有机相用饱和碳酸氢钠水溶液洗涤,经硫酸钠干燥,过滤,减压蒸发。得到橙色-黄色油状物,并经减压分馏(在70-75℃下,在1×10-1mbar下)纯化。得到5.14g橙色油状物,收率64%。
15-1-2
2-羟基甲基-2-苯基庚腈
将1.34g 60%NaH的50mL DMF悬浮液冷却至0℃,向其中加入5.14g(27.4mmol)2-苯基庚腈。搅拌30分钟后,分批加入7.6g(220mmol)低聚甲醛。将反应介质在室温下搅拌6小时,然后用冰水解,用乙醚萃取。将有机相用饱和碳酸氢钠水溶液洗涤,经硫酸钠干燥,过滤,减压蒸发。得到的粗产物经硅胶层析(洗脱液:8/2 庚烷/乙酸乙酯)纯化。得到4.24g浅黄色油状物,收率71%。
15-1-3
甲苯-4-磺酸2-氰基-2-苯基庚酯
向含4.24g(19.5mmol)2-羟基甲基-2-苯基-庚腈的25m L二氯甲烷溶液中加入4.1g(21.5mmol)对-甲苯磺酰氯和6ml三乙胺。将反应介质在室温下搅拌15小时,然后用1N盐酸溶液处理。用二氯甲烷萃取。有机相经硫酸钠干燥,过滤,减压蒸发。得到黄色油状物,在9/1的庚烷/异丙醚混合物中沉淀。将形成的沉淀滤出,用异丙醚冲洗。得到5.26g浅褐色粉末,收率72%。
15-1-4
3-戊基-3-苯基氮杂环丁烷
在氮气下,向含5.26g(14.1mmol)甲苯-4-磺酸2-氰基-2-苯基庚酯的25ml THF溶液中小心加入600mg(15.5mmol)LiAlH4粉末。将反应介质在室温下搅拌1小时,然后用硫酸钠糊(热水+Na2SO4)处理。在室温下搅拌30分钟后,将形成的盐滤除,将滤液减压蒸发。将残余物溶于二氯甲烷,用1N氢氧化钠水溶液洗涤。有机相经硫酸钠干燥,过滤,减压蒸发。得到2.90g无色油状物,用于下一步,无需进一步纯化。
15-2
1-[2-(1H-咪唑-4-基)乙基]-3-[1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基-氮杂环丁烷-1-基)乙基]脲
将170mg(0.837mmol)3-戊基-3-苯基氮杂环丁烷溶于含50mg2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酸(参见制备2-3)的2ml DMF。向该溶液中依次加入177mg(0.920mmol)EDC、125mg(0.920mmol)HOBt。将反应介质搅拌4小时,然后用1N氢氧化钠处理,用二氯甲烷萃取。合并的有机相经Na2SO4干燥,过滤,蒸发。粗产物经硅胶层析(洗脱液:90/10 DCM/甲醇)得到。得到白色粉末形式的180mg 1-[2-(1H-咪唑-4-基)乙基]-3-[1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基氮杂环丁烷-1-基)乙基]脲,收率41%。
1H NMR/DMSOD6 100℃:δ=7.45(s,1H);7.30(m,3H);7.22(m,1H);7.19(m,4H);6.82(m,2H);6.72(s,1H);5.99(d,J=9.2Hz,1H);5.90(m,1H);4.38(q,J=7.2Hz,1H);3.73(m,4H);3.23(m,2H);2.93(m,3H);2.75(d,J=6Hz,2H);2.61(t,J=6.80Hz,2H);1.18(m,4H);0.98(m,2H);0.78(t,J=6.4Hz,3H).
实施例16:1-((R)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯(化合物30):
16-1
1-[(R)-2-叔-丁氧基羰基氨基-3-(4-氯苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯
将3.1g(10mmol)(R)-2-叔丁氧基羰基氨基-3-(4-氯苯基)丙酸、1.9g(11mmol)EDC、1.5g(11mmol)HOBt和1.7mL(20mmol)二异丙基乙胺溶于80mL DMF。将混合物在室温下搅拌15分钟,然后加入稀释在20mL DMF的2.6g(10mmol)哌啶-4-环己基-4′-甲酸乙酯(参见制备9-2)。搅拌2小时后,再加入1.7mL(20mmol)二异丙基乙胺。通过加入5%柠檬酸水溶液将反应终止。将有机产物用乙酸乙酯萃取,将有机相用1N NaOH水溶液洗涤。将有机相干燥,蒸发。得到无色油状物形式的5.2g 1-[(R)-2-叔-丁氧基羰基氨基-3-(4-氯苯基)丙酰基]-4-环己基-哌啶-4-甲酸乙酯,收率75%。
16-2
1-[(R)-2-氨基-3-(4-氯苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯
将0.26g(0.5mmol)1-[(R)-2-叔-丁氧基羰基氨基-3-(4-氯苯基)-丙酰基]-4-环己基哌啶-4-甲酸乙酯在4mL DCM和1mL三氟乙酸中稀释,在室温下将溶液搅拌2小时,然后通过加入1N NaOH水溶液猝灭,用二氯甲烷萃取。将有机相干燥,然后蒸发。得到无色油状物形式的200mg 1-[(R)-2-氨基-3-(4-氯苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯,收率95%。
16-3
1-((R)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
将200mg(0.48mmol)1-[(R)-2-氨基-3-(4-氯苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯和105mg(0.52mmol)氯甲酸对-硝基苯基酯溶于5ml二氯甲烷。将混合物在室温下搅拌2小时,然后将溶液倾入20%NH4OH水溶液,用二氯甲烷萃取。将有机相用水洗涤,然后经硫酸钠干燥,蒸发。将得到的无色油状物在5ml DMF中稀释,将混合物加热至80℃,然后加入58mg(0.52mmol)组胺,将溶液在80℃下搅拌5分钟,然后在室温下搅拌10分钟。通过加入5%柠檬酸水溶液将反应终止,将有机产物用DCM萃取。将有机相依次用1N NaOH水溶液、水洗涤。经硫酸钠干燥后,蒸发,得到的粗产物经硅胶层析(洗脱液:80/20 DCM/MeOH)纯化。得到无色油状物形式的40mg 1-((R)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯,收率15%。
HPLC:(方法N);保留时间:11.01min,96%,M+H:558.
实施例17:1-[2-(4-乙酰基-4-环己基哌啶-1-基)-1-(4-甲氧基-苄基)-2-氧代乙基]-3-(1H-咪唑-4-基甲基)脲三氟乙酸盐(化合物32):
17-1-1
1-[4-苯基-1-(甲苯-4-磺酰基)哌啶-4-基]丙-1-酮
将3.9ml(2.94mmol)3M乙基溴化镁溶液加入2g(5.9mmol)4-苯基-1-(甲苯-4-磺酰基)哌啶-4-甲腈的40ml甲苯溶液。将反应混合物在65-70℃下搅拌过夜。将反应终止,用1N盐酸溶液水解,然后用乙酸乙酯萃取。将有机相合并,用硫酸钠干燥。将溶剂蒸去,然后将残余物溶于乙酸乙酯,向其中加入1N盐酸溶液,将混合物在室温下搅拌72小时。得到黄色油状物形式的2.16g 1-[4-苯基-1-(甲苯-4-磺酰基)-哌啶-4-基]丙-1-酮,收率99%。
17-1-2
1-(4-苯基哌啶-4-基)丙-1-酮盐酸盐
将2.1g(5.6mmol)1-[4-苯基-1-(甲苯-4-磺酰基)哌啶-4-基]丙-1-酮悬浮于14ml硫酸和7ml水。将反应混合物搅拌回流72小时。通过加入冰将反应终止,用氢氧化钠溶液碱化,然后用乙酸乙酯萃取。将有机相合并,经硫酸钠干燥。将溶剂蒸去,将残余物溶于乙醚,用4N氯化氢的乙酸乙酯溶液沉淀。得到浅褐色粉末形式的1.04g 1-(4-苯基哌啶-4-基)丙-1-酮盐酸盐,收率73%。
17-1-3
4-苯基-4-丙酰基哌啶-1-甲酸叔丁酯
将溶于5ml二氯甲烷的470mg(2.17mmol)二碳酸二叔丁酯溶液加入500mg(1.97mmol)1-(4-苯基哌啶-4-基)丙-1-酮盐酸盐和0.7ml(4.93mmol)三乙胺的5ml二氯甲烷溶液。将反应混合物在室温下搅拌2小时。通过加入10ml水将反应终止。有机相经硫酸钠干燥。将溶剂蒸去,残余物然后经硅胶层析(洗脱液:80/20 庚烷/乙酸乙酯)纯化。得到白色粉末形式的582mg 4-苯基-4-丙酰基哌啶-1-甲酸叔丁酯,收率93%。
17-1-4
4-环己基-4-丙酰基哌啶-1-甲酸叔丁酯
将以下反应物加入帕尔高压反应器:582mg(1.83mmol)4-苯基-4-丙酰基哌啶-1-甲酸叔丁酯、300mg铑/氧化铝和0.5ml乙酸的15mL二
烷溶液。将反应混合物置于6巴氢气压下,在80℃下搅拌16小时。将反应终止,通过硅藻土过滤,用二氯甲烷洗涤。将溶剂蒸去,然后残余物经硅胶层析(洗脱液:95/5 庚烷/乙酸乙酯)纯化。得到无色油状物形式的549mg 4-环己基-4-丙酰基哌啶-1-甲酸叔丁酯,收率93%。
17-1-5
4-环己基-4-丙酰基哌啶盐酸盐
将549mg(1.7mmol)4-环己基-4-丙酰基哌啶-1-甲酸叔丁酯溶于2mL(17mmol)4N氯化氢的乙酸乙酯溶液。将反应混合物在室温下搅拌6小时。将溶剂蒸去。将残余物溶于乙醚,滤出。得到白色粉末形式的395mg 4-环己基-4-丙酰基哌啶盐酸盐,收率90%。
17-2
1-[2-(4-乙酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基甲基)脲三氟乙酸盐
依次将58mg(0.42mmol)HOBt和81mg(0.42mmol)EDC、0.2mL(1.15mmol)二异丙基乙胺加入128mg(0.38mmol)2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酸(参见制备2-3)和62.9mg(0.38mmol)4-环己基-4-丙酰基哌啶盐酸盐的5mL二甲基甲酰胺溶液。将反应混合物在室温下搅拌过夜。通过加入10mL水将反应终止,然后用乙酸乙酯萃取。将有机相合并,经硫酸钠干燥。将溶剂蒸去,然后残余物经制备HPLC(条件参见第38页)纯化。得到白色粉末形式的98.5mg 1-[2-(4-乙酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基甲基)-脲三氟乙酸盐,收率48%。
HPLC:(方法N);保留时间:9.98min,97%,M+H:538.
实施例18:1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基-苄基)-2-氧代乙基]-3-(1H-咪唑-4-基甲基)脲三氟乙酸盐(化合物33):
18-1-1
1-三苯甲基-1H-咪唑-4-甲醛:
向含悬浮于28ml乙腈的1g(10.4mmol)1H-咪唑-4-甲醛和3.18g(11.4mmol)三苯甲基氯溶液中滴加2.5ml(17.7mmol)三乙胺。在室温下搅拌2小时后,加入30ml水,将粗反应产物过滤。得到3.2g浅褐色粉末,用于下一步,无需进一步纯化。
18-1-2
哌啶-1-基-(1-三苯甲基-1H-咪唑-4-基-亚甲基)胺:
向含342mg(1.01mmol)1-三苯甲基-1H-咪唑-4-甲醛和100mg(1.0mmol)哌啶-1-基胺的溶液中加入3.5mL乙醇和1.5mL二氯甲烷。将反应介质在80℃下加热1小时。将溶剂蒸去,得到450mg粉末,用于下一步,无需进一步纯化。
18-1-3
C-(1H-咪唑-4-基)甲基胺二盐酸盐
向含450mg哌啶-1-基-(1-三苯甲基-1H-咪唑-4-基-亚甲基)胺的3.5mL 3N氯化氢的乙酸乙酯溶液中加入90mg 10%Pd/C、0.5mLTHF和0.9mL乙醇。将反应介质置于6巴氢气压下,在80℃下加热3小时。滤除催化剂后,将溶剂蒸去,得到的粗产物经硅胶层析(洗脱液:6/4 DCM/MeOH)纯化。得到白色粉末形式的50mg C-(1H-咪唑-4-基)甲胺二盐酸盐,收率29%。
18-2
(S)-2-[3-(1H-咪唑-4-基-甲基)脲基]-3-(4-甲氧基苯基)-丙酸甲酯
在80℃下,将1.1g(0.37mmol)(S)-3-(4-甲氧基苯基)-2-(4-硝基苯氧基羰基-氨基)丙酸甲酯(参见制备2-2)和0.7mL(0.37mmol)二异丙基-乙胺的5mL二甲基甲酰胺溶液加入500mg(0.37mmol)C-(1H-咪唑-4-基)甲胺二盐酸盐的15mL二甲基甲酰胺溶液。将反应混合物在80℃下搅拌2小时。通过加入30ml水将反应终止,然后用乙酸乙酯萃取。将有机相合并,经硫酸钠干燥。将溶剂蒸去,然后残余物经硅胶层析(洗脱液:80/20 二氯甲烷/甲醇)纯化。得到黄色油状物形式的279mg(S)-2-[3-(1H-咪唑-4-基-甲基)-脲基]-3-(4-甲氧基苯基)丙酸甲酯,收率63%。
18-3
2-[3-(1H-咪唑-4-基甲基)脲基]-3-(4-甲氧基苯基)丙酸
将351mg(84mmol)氢氧化锂一水合物加入278mg(8.4mmol)(S)-2-[3-(1H-咪唑-4-基甲基)脲基]-3-(4-甲氧基-苯基)丙酸甲酯的5ml四氢呋喃和1ml水溶液。在微波反应器中,将反应混合物在100℃下加热10分钟。通过加入2ml水和0.5ml乙酸将反应终止,然后用乙酸乙酯萃取。将水相浓缩至干,残余物然后经硅胶层析(洗脱液:7/3二氯甲烷/甲醇)纯化。得到白色泡沫状形式的261mg 2-[3-(1H-咪唑-4-基甲基)脲基]-3-(4-甲氧基苯基)丙酸,收率98%。
18-4
1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基甲基)脲三氟乙酸盐
依次将70mg(0.52mmol)HOBt和99.4mg(0.52mmol)EDC、0.25mL(1.4mmol)二异丙基乙胺加入150mg(0.47mmol)2-[3-(1H-咪唑-4-基甲基)脲基]-3-(4-甲氧基苯基)丙酸和123mg(0.47mmol)1-(4-环己基哌啶-4-基)丙-1-酮的5mL二甲基甲酰胺溶液。将反应混合物在室温下搅拌16小时。通过加入10mL水将反应终止,然后用乙酸乙酯萃取。将有机相合并,经硫酸钠干燥。将溶剂蒸去,残余物然后经制备HPLC(条件参见第38页)纯化。得到无色油状物形式的8.5mg 1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基甲基)脲三氟乙酸盐,收率4%。
HPLC:(方法N);保留时间:9.93min,98%,M+H:524.
实施例19:4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]-脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-甲酸乙酯(化合物34):
19-1
1-[(R)-2-叔-丁氧基羰基氨基-3-(4-甲氧基苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯
向溶于20ml DMF的3.22g(10.9mmol)(R)-2-叔-丁氧基羰基氨基-3-(4-甲氧基苯基)-丙酸中加入2.29g(12.0mmol)EDC、1.62g(12.0mmol)HOBt、2.62g(10.9mmol)4-环己基哌啶-4-甲酸乙酯(参见制备3-1-2)和4.6ml(32.7mmol)三乙胺。搅拌2小时30分钟后,通过加入1N氢氧化钠水溶液将反应终止,将有机产物用二氯甲烷萃取。有机相经MgSO4干燥,过滤,蒸发。得到的粗产物经硅胶层析(洗脱液:7/3庚烷/EtOAc)纯化。得到白色粉末形式的3.70g 1-[(R)-2-叔-丁氧基羰基氨基-3-(4-甲氧基苯基)丙酰基]-4-环己基-哌啶-4-甲酸乙酯,收率66%。
19-2
1-[(R)-2-氨基-3-(4-甲氧基苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯
将溶于30ml DCM的3.7g(7.16mmol)1-[(R)-2-叔-丁氧基羰基氨基-3-(4-甲氧基-苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯溶液浸入0℃浴中,向其中加入10ml三氟乙酸。搅拌1小时30分钟后,将溶剂蒸去。将反应介质用1N氢氧化钠水溶液洗涤,用DCM萃取。然后将有机相用水洗涤,然后经MgSO4干燥,过滤,浓缩。得到白色粉末形式的2.74g 1-[(R)-2-氨基-3-(4-甲氧基苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯,收率92%。
19-3
4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
将溶于25ml DCM的2.35g(5.64mmol)1-[(R)-2-氨基-3-(4-甲氧基苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯溶液浸入冷水浴中,向其中加入1.25g(6.21mmol)氯甲酸4-硝基苯基酯。升温至室温后,将反应介质搅拌1小时。通过加入NH4OH水溶液将反应终止,将有机化合物用DCM萃取。然后将有机相用水洗涤,然后经MgSO4干燥,过滤,浓缩。将得到的粗产物在80℃下溶于25ml DMF,然后加入0.70g(6.3mmol)组胺。15分钟后,通过加入1N氢氧化钠水溶液将反应终止,将有机化合物用DCM萃取。有机相经MgSO4干燥,过滤,浓缩。得到的粗产物经硅胶层析(洗脱液:86/14 DCM/MeOH)纯化。得到白色粉末形式的1.48g 4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-甲酸乙酯,收率47%。
1H NMR/DMSOD6 100℃:δ=0.87-1.28(m,10H);1.50-1.70(m,3H);1.71-1.74(m,2H);1.80-2.00(m,2H);2.54-2.63(m,2H);2.71-2.83(m,2H);3.24(bq,J=6.4-6.8Hz,1H);3.74(s,3H);3.75-4.05(m,4H);4.12(bq,J=6.8-7.2Hz,2H);4.81(bq,J=6.8-8.0Hz,1H);5.93(bt,J=4.8-5.6Hz,1H);6.01(bd,J=8.0Hz,1H);6.73(s,1H);6.82(bd,J=8.4Hz,2H);7.08(bd,J=7.6Hz,2H);7.44(s,1H);11.45(bs,1H).
实施例20:1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基-苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲(化合物40):
20-1
1-(4-环己基哌啶-4-基)丁-1-酮
将2.5g(7.4mmol)4-丁酰基-4-环己基哌啶-1-甲酸叔丁酯(参见制备17-1-4)在含40mL二氯甲烷和8ml三氟乙酸的混合物中稀释。将混合物在室温下搅拌2小时,然后通过加入1N NaOH水溶液将反应终止,将有机化合物用二氯甲烷萃取。将有机相干燥,然后浓缩。得到无色油状物形式的2.1g 1-(4-环己基哌啶-4-基)丁-1-酮,收率100%。
20-2
[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]氨基甲酸叔丁酯
将2.1g(8.9mmol)1-(4-环己基哌啶-4-基)丁-1-酮、2.6g(8.9mmol)(R)-2-叔-丁氧基羰基氨基-3-(4-甲氧基苯基)丙酸、1.88g(9.8mmol)EDC和1.2g(9.8mmol)HOBT溶于30ml DMF。将混合物在室温下搅拌2小时。将溶液用2.5%柠檬酸水溶液洗涤,用乙酸乙酯萃取。将有机相用10N NaOH水溶液洗涤,然后经硫酸钠干燥,过滤,浓缩。粗产物经硅胶层析(洗脱液:70/30 庚烷/乙酸乙酯)纯化。得到无色油状物形式的1.4g[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]氨基甲酸叔丁酯,收率31%。
20-3
1-{1-[(R)-2-氨基-3-(4-甲氧基苯基)丙酰基]-4-环己基哌啶-4-基}-丁-1-酮
将1.4g(2.7mmol)[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]氨基甲酸叔丁酯放入由40ml DCM和8ml三氟乙酸组成的混合物。将反应介质在室温下搅拌2小时,然后通过加入1N氢氧化钠水溶液将反应终止。用二氯甲烷萃取后,有机相经硫酸钠干燥,然后过滤,浓缩。得到无色油状物形式的1.24g 1-{1-[(R)-2-氨基-3-(4-甲氧基苯基)丙酰基]-4-环己基哌啶-4-基}丁-1-酮,收率100%。
20-4
1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
在0℃下,将1.24g(3mmol)1-{1-[(R)-2-氨基-3-(4-甲氧基苯基)丙酰基]-4-环己基-哌啶-4-基}丁-1-酮和660mg(3.3mmol)氯甲酸对-硝基苯基酯溶于40ml二氯甲烷。将反应混合物在室温下搅拌1小时,然后通过加入20%氨水溶液将反应终止,将有机产物用二氯甲烷萃取。将有机相用水洗涤,然后经硫酸钠干燥,过滤,浓缩。将得到的白色固体溶于20ml DMF,将混合物加热至80℃,然后加入0.367g(3.3mmol)组胺,将溶液在80℃下搅拌5分钟,然后在室温下搅拌10分钟。通过加入1N NaOH水溶液将反应终止,将反应介质用DCM萃取。将有机相用水洗涤,然后经硫酸钠干燥,过滤,浓缩。得到的粗产物经硅胶层析(洗脱液:80/20 DCM/MeOH)纯化。得到白色粉末形式的1.1g1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲,收率67%。
1H NMR/DMSOD6 100℃:δ=0.87-1.22(m,10H);1.38-1.54(m,5H);1.59-1.62(m,2H);1.70-1.73(m,2H);1.85-1.98(m,2H);2.40(t,J=7.2Hz,2H);2.61(t,J=7.2Hz,2H);2.70-2.94(m,2H);3.24(bq,J=6.4-6.8Hz,2H);3.73(s,3H);3.75-4.05(m,4H);4.79(bq,J=6.8-8.0Hz,1H);5.92(bt,J=4.8-5.6Hz,1H);5.99(bd,J=8.0Hz,1H);6.72(s,1H);6.81(bd,J=8.4Hz,2H);7.07(bd,J=7.6Hz,2H);7.44(s,1H);11.45(bs,1H).
实施例21:4-环己基-1-((R)-3-(3,4-二氯苯基)-2-{3-[3-(1H-咪唑-4-基)丙基]脲基}丙酰基)哌啶-4-甲酸乙酯(化合物45):
21-1
1-[(R)-2-叔-丁氧基羰基氨基-3-(3,4-二氯苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯
将0.5g(2.1mmol)哌啶-4-环己基-4′-甲酸乙酯(参见制备3-1-2)、0.7g(2.1mmol)Boc-3,4-二氯-D-苯基丙氨酸、0.31g(2.3mmol)HOBT、0.44g(2.3mmol)EDC和0.73ml(4.2mmol)二异丙基乙胺放入5ml二甲基甲酰胺。将混合物在室温下搅拌2小时,然后用5%柠檬酸水溶液洗涤,用乙酸乙酯萃取。将有机相依次用1N氢氧化钠水溶液、水洗涤,经硫酸钠干燥,过滤,最后浓缩至干。得到的油状物经层析(洗脱液:5/5 庚烷/乙酸乙酯)纯化。得到300mg 1-[(R)-2-叔-丁氧基羰基氨基-3-(3,4-二氯苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯,收率26%。
21-2
1-[(R)-2-氨基-3-(3,4-二氯苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯
将300mg(0.54mmol)1-[(R)-2-叔-丁氧基羰基氨基-3-(3,4-二氯-苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯在5mL 2/1的二氯甲烷/三氟乙酸溶液中稀释。2小时后,将混合物倾入1N氢氧化钠水溶液,然后用二氯甲烷萃取。有机相经硫酸钠干燥,然后过滤,浓缩至干。得到210mg 1-[(R)-2-氨基-3-(3,4-二氯苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯,收率86%。
21-3
4-(3-氨基丙基)-1H-咪唑-1-
二(三氟乙酸盐)
将0.5g(1.4mmol)3-(1-三苯甲基-1H-咪唑-4-基)丙胺溶于含2mL三氟乙酸的8mL二氯甲烷。2小时后,将介质浓缩。将得到的浅褐色固体溶于EtOAc和水,然后将水相浓缩至干。得到0.3g 4-(3-氨基丙基)-1H-咪唑-1-
二(三氟乙酸盐),收率61%。
21-4
4-环己基-1-((R)-3-(3,4-二氯苯基)-2-{3-[3-(1H-咪唑-4-基)-丙基]脲基}丙酰基)哌啶-4-甲酸乙酯
将0.07g(0.15mmol)1-[(R)-2-氨基-3-(3,4-二氯苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯和34mg(0.17mmol)氯甲酸对-硝基苯基酯溶于5mL二氯甲烷。将混合物在室温下搅拌2小时,然后将溶液倾入水中,用二氯甲烷萃取。有机相经硫酸钠干燥,过滤,浓缩至干。将得到的无色油状物在5mL二甲基甲酰胺中稀释,将混合物加热至80℃,加入57mg(0.16mmol)3-(1H-咪唑-4-基)丙胺二(三氟乙酸盐)和0.05mL(0.3mmol)二异丙胺。将溶液在80℃下搅拌5分钟,然后在室温下搅拌16小时。通过加入1N氢氧化钠水溶液将反应终止,然后用二氯甲烷萃取。将有机相用水洗涤,然后经硫酸钠干燥,过滤,蒸发至干。得到的油状物经层析(洗脱液:90/10 DCM/MeOH)纯化。得到无色油状物形式的40mg 4-环己基-1-((R)-3-(3,4-二氯苯基)-2-{3-[3-(1H-咪唑-4-基)丙基]脲基}-丙酰基)哌啶-4-甲酸乙酯,收率44%。
1H NMR/DMSOD6 100℃:δ=0.92-1.20(m,6H);1.22(t,3H,7.2Hz);1.27(m,2H);1.61(m,2H);1.72-1.84(m,3H);1.98(m,3H);2.82-3.22(m,6H);3.64(m,4H);3.93(t,2H,6.8Hz);4.14(quart.,2H,7.2Hz);4.87(quart.,1H,6.4Hz);6.01(m,2H);6.87(s,1H);7.07(s,1H);7.18(d,1H,6.8Hz);7.40(d,1H,2.4Hz);7.47(d,1H,8.4Hz);7.52(s,1H)
实施例22:4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]-硫脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-甲酸乙酯(化合物47):
22-1
1-[(R)-2-氨基-3-(4-甲氧基苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯三氟乙酸盐
在室温下,向10g(19.4mmol)1-[(R)-2-叔-丁氧基羰基氨基-3-(4-甲氧基苯基)-丙酰基]-4-环己基哌啶-4-甲酸乙酯(参见制备19-1)的80mL二氯甲烷溶液中加入20mL三氟乙酸。将反应介质搅拌2小时,然后将溶剂蒸去。将乙醚和几滴二氯甲烷加入得到的油状物,将得到的白色固体滤出,然后干燥。得到8g 1-[(R)-2-氨基-3-(4-甲氧基苯基)丙酰基]-环己基哌啶-4-甲酸乙酯三氟乙酸盐,收率78%。
22-2
4-环己基-1-[(R)-2-异硫氰酸酯基-3-(4-甲氧基苯基)丙酰基]-哌啶-4-甲酸乙酯
向溶于5mL CH2Cl2和0.5mL(2.8mmol)二异丙基乙胺的500mg(0.94mmol)1-[(R)-2-氨基-3-(4-甲氧基苯基)丙酰基]-4-环己基哌啶-4-甲酸乙酯三氟乙酸盐加入219mg(0.94mmol)硫代碳酸O,O-二(2-吡啶基)酯。将反应介质在室温下搅拌2小时后,将溶剂蒸去,粗产物经硅胶层析(洗脱液:6/4 庚烷/EtOAc)得到。得到无色油状物形式的421mg4-环己基-1-[(R)-2-异硫氰酸酯基-3-(4-甲氧基苯基)丙酰基]哌啶-4-甲酸乙酯,收率97%。
22-3
4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]硫脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-甲酸乙酯
向400mg(0.87mmol)4-环己基-1-[(R)-2-异硫氰酸酯基-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯的5mL DMF溶液中依次加入97mg(0.87mmol)组胺、0.130mL(0.87mmol)1,8-二氮杂双环[5.4.0]十一碳-7-烯。将反应介质搅拌2小时,然后通过加入5%柠檬酸水溶液水解。将有机化合物用二氯甲烷萃取。有机相经MgSO4干燥,过滤,浓缩。得到的粗产物经硅胶层析(洗脱液:80/20 CH2Cl2/MeOH)得到。得到浅黄色粉末形式的265mg 4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]硫脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-甲酸乙酯,收率53%。
HPLC:(方法U);保留时间:16.05min,95%,M+H:569.
表1举例说明本发明化合物的实施例。
在该表中:
-在“盐”列中,TFA代表三氟乙酸盐形式的化合物
-纯度(%)代表由HPLC图谱得到的产物纯度
-质量(M+H)代表质量+H,得自与预期产物的HPLC峰相关的质谱
表1:
实施例23:反式激活试验:
细胞:将HEK293细胞系用载体pCRE-Luc和hMC1R转染。在37℃和5%CO2下,将细胞在补充10%胎牛血清的DMEM培养基中培养。
试验原理:在激活剂(激动剂)的存在下,黑皮质素受体激活cAMP途径,该途径通过载体CRE-Luc导致荧光素酶的合成。加入含发光荧光素酶底物的溶胞缓冲液后,可测量与受体的激活或抑制程度成比例的荧光。
测试产物:以10mM将产物溶于DMSO。在最终0.1%DMSO反应剂量下测试它们。含10个点和0的浓度范围从10μM开始,按4倍稀释度依次稀释。为测试激动剂,单独测试产物。为测定拮抗剂的行为,在1nM NDP-MSH(参照激动剂)的存在下测试目的产物。按5000细胞/孔的比例(384孔板),将细胞接种在不含血清的DMEM培养基中,在37℃和5%CO2下温育过夜。
次日,加入产物和参照配体(NDP-MSH),将板在37℃和5%CO2下再温育6小时。加入含荧光素的溶胞缓冲液后,在Top-Count机器中读板。用100%(细胞+10nM NDP-MSH)和0%(单独细胞)对照将结果归一化为活性百分率。用XLFit软件计算各产物的EC50。按nM给出结果。
化合物编号 | EC50hMC1-R(nM) |
34 | 60 |
40 | 120 |
实施例24:在肝脏微粒体的存在下测试代谢稳定性:
肝脏微粒体:微粒体为从肝脏组织纯化后得到的细胞内质网泡状体。它们含涉及氧化代谢(I期)的细胞膜酶(细胞色素P450)。
试验原理:在37℃的缓冲反应介质中,在不同种的微粒体的存在下,温育试验产物。在不同时间抽取温育样品(动力学)。通过LC/MS/MS分析定量,使测量与I期肝脏代谢有关的母体产物的消失成为可能。
测试产物:以10mM将产物溶于DMSO。在微粒体(0.5mg/ml)的存在下,在10μM下,将它们温育。由100mM磷酸盐缓冲液pH 7.4、G6PDH(0.4U/ml)、0.01%Pluronic酸和辅因子MgCl2 5mM、NADP和G6P(分别为1.3mM和3.3mM)形成反应介质。在0、5、10、15、30和60分钟抽取反应介质样品。在各时间点,加入甲醇将酶反应终止。离心(3000rpm,30分钟)后,通过LC/MS/MS分析样品。将剩余母体产物的浓度随时间定量,以允许计算各产物的半衰期。
化合物编号 | t1/2(min) |
34 | 3-4min |
40 | 3-4min |
实施例25:通过HPLC-MS测定Log P和Log D
定义:
LogP又称为Log Kow,(辛醇/水分配系数)能够表征分子的亲油性质。
LogP=Log(C辛醇/C水)
与LogP形成对照,Log D为给定pH的测定值。
样品制备
将10-2M分子的DMSO溶液置于辛醇-水混合物(50/50 体积/体积)。
搅拌10小时后,将样品离心,将两相分离,以用于分析。将辛醇相在甲醇中稀释,然后分析。
通过LC/MS/MS分析测定存在于各相的试验分子的浓度。
LogP=Log(面积辛醇*稀释因子/面积水)
化合物编号 | LogD(pH 6.5) |
34 | 4 |
40 | 4.8 |
实施例26:小鼠脱毛后在体毛再生长期间调节色素沉着(图2的表中结果)
将雌性8周龄B6.Cg-Ay小鼠的毛剃除,然后在气体麻醉下用冷蜡脱毛,使所有毛囊在生长期(anagenic phase)开始同步。
脱毛后,将MC1R激动剂在乙醇中稀释至5%,将得到的溶液局部每日涂布在脱毛区域,持续11天。脱毛19天后,在再生长的区域上,通过色度计(chromametry)测量毛的色素沉着:按黑色到白色色度标尺,L值衡量颜色(L值越小,毛颜色越深)。
Claims (1)
1.通式(I)化合物及其相应的盐和对映体
其中:
R1代表含3 – 7个碳原子的环烷基,
R2代表酰基或烷氧基羰基,
R3代表用被烷氧基取代的苯基或萘基取代的烷基,
R4代表被含有1-4个碳原子或5-10个碳原子的基于直链或支链饱和或不饱和烃的链取代的咪唑,
R5代表氢原子,
X代表氧原子,
n、m等于2;
其中:
“酰基”表示被含有1-4个碳原子或5-10个碳原子的基于直链或支链饱和或不饱和烃的链取代的甲酰基或羰基;
“烷氧基羰基”表示被烷氧基取代的羰基;
“烷氧基”表示被含有1-4个碳原子或5-10个碳原子的基于直链或支链饱和或不饱和烃的链取代的氧原子。
2. 权利要求1的通式(I)化合物及其相应的盐和对映体,其中:
“烷基”表示低级烷基或高级烷基;
“低级烷基”表示含1 – 4个碳原子的直链或支链,饱和或不饱和烃基链;
“高级烷基”表示含5 -10个碳原子的直链或支链、饱和或不饱和烃基链。
3. 选自以下的化合物:
1) 1-[(S)-2-(4-丁酰基-4-苯基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
2) 1-[2-(1H-咪唑-4-基)乙基]-3-[1-(4-甲氧基苄基)-2-氧代-2-(4-氧代-1-苯基-1,3,8-三氮杂螺[4.5]癸-8-基)乙基]脲
3) 1-[2-(4-氰基-4-苯基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
4) 1-[2-(1H-咪唑-4-基)乙基]-3-[1-(4-甲氧基苄基)-2-氧代-2-(4-苯基哌啶-1-基)乙基]脲
5) 1-[2-(1H-咪唑-4-基)乙基]-3-[1-(4-甲氧基苄基)-2-氧代-2-哌啶-1-基-乙基]脲
6) 4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
7) N-{1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]哌啶-4-基}-N-苯基丙酰胺
8) 丁酸1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]-3-苯基-氮杂环丁烷-3-基酯
9) 1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]-哌啶-4-甲酸乙酯
10) 1-[2-(1H-咪唑-4-基)乙基]-3-{1-(4-甲氧基苄基)-2-[4-(2-甲氧基苯基)-哌啶-1-基]-2-氧代乙基}脲
11) 1-[2-(3-丁氧基-3-苯基氮杂环丁烷-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
12) N-甲基-4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酰铵
13) 1-[2-(3-环己基羰基氮杂环丁烷-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
14) 4-环己基-1-[2-{3-乙基-3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
15) N-环丙基-N-{1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-基}丙酰胺
16) 4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸乙酯
17) 1-[2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3H-咪唑-4-基)乙基]脲
18) 1-[2-(4-丁氧基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
19) 4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-2-苯基乙酰基)-哌啶-4-甲酸乙酯
20) 4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸甲酯
21) 1-[2-(4-环己基-4-乙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
22) 1-[2-(4-乙酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
23) 4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-2-苯基乙酰基)-哌啶-4-甲酸甲酯
24) 4-乙基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
25) 1-[2-(4-环己基-4-丙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
26) 4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸
27) 1-[2-(1H-咪唑-4-基)乙基]-3-{1-(4-甲氧基苄基)-2-[3-(2-甲基环己基)-3-丙氧基氮杂环丁烷-1-基]-2-氧代乙基}脲
28) 4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸丙酯
29) 1-[2-(1H-咪唑-4-基)乙基]-3-[1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基-氮杂环丁烷-1-基)乙基]脲
30) 1-((R)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
31) 1-((S)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
32) 1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
33) 1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基甲基)脲
34) 4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
35) 4-环丙基甲基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
36) 4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸丙酯
37) 4-环戊基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸乙酯
38) 4-环戊基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
39) 4-环己基-1-[(S)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
40) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
41) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氟苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
42) 1-[(R)-1-苄基-2-(4-丁酰基-4-环己基哌啶-1-基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
43) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲
44) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氯苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
45) 4-环己基-1-((R)-3-(3,4-二氯苯基)-2-{3-[3-(1H-咪唑-4-基)丙基]-脲基}丙酰基)哌啶-4-甲酸乙酯
46) 4-环己基-1-((R)-3-(4-甲氧基苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲基}丙酰基)哌啶-4-甲酸乙酯
47) 4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]硫脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
48) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]硫脲
49) 1-[(R)-2-(4-环己基-4-丙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]硫脲
50) 1-[(R)-1-苄基-2-(4-环己基-4-丙氧基哌啶-1-基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]硫脲
51) 1-[(R)-1-苄基-2-(4-环己基-4-丙氧基哌啶-1-基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
52) 4-环己基-1-((R)-3-(4-甲氧基苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)-乙基]硫脲基}丙酰基)哌啶-4-甲酸乙酯
53) 4-环己基-1-((R)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲基}-3-苯基-丙酰基)哌啶-4-甲酸乙酯
54) 1-[(R)-2-(4-环己基-4-丙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲
55) 1-((R)-3-(4-氯苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲基}-丙酰基)-4-环己基哌啶-4-甲酸乙酯
56) 4-环己基-1-((R)-3-(4-氟苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]-脲基}丙酰基)哌啶-4-甲酸乙酯
57) 4-环己基-1-((R)-3-(4-氟苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-丙酰基)哌啶-4-甲酸乙酯
58) 4-环己基-1-((R)-3-(4-氟苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]硫脲基}丙酰基)哌啶-4-甲酸乙酯
59) 1-((R)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]硫脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
60) 1-((R)-3-(4-氯苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]硫脲基}-丙酰基)-4-环己基哌啶-4-甲酸乙酯
61) 1-[(R)-2-(4-环己基-4-丙氧基哌啶-1-基)-1-(4-氟苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
62) 1-[(R)-1-(4-氯苄基)-2-(4-环己基-4-丙氧基哌啶-1-基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
及其各自的盐和对映体。
4. 选自以下的化合物:
1) 1-[(S)-2-(4-丁酰基-4-苯基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
2) 1-[2-(4-氰基-4-苯基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
3) 1-[2-(1H-咪唑-4-基)乙基]-3-[1-(4-甲氧基苄基)-2-氧代-2-(4-苯基哌啶-1-基)乙基]脲
4) 4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
5) 1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)丙酰基]-哌啶-4-甲酸乙酯
6) 1-[2-(1H-咪唑-4-基)乙基]-3-{1-(4-甲氧基苄基)-2-[4-(2-甲氧基苯基)-哌啶-1-基]-2-氧代乙基}脲
7) 1-[2-(3-丁氧基-3-苯基氮杂环丁烷-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
8) N-甲基-4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酰胺
9) 1-[2-(3-环己基羰基氮杂环丁烷-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
10) 4-环己基-1-[2-{3-乙基-3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
11) 4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸乙酯
12) 1-[2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3H-咪唑-4-基)乙基]脲
13) 1-[2-(4-丁氧基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
14) 4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-2-苯基乙酰基)-哌啶-4-甲酸乙酯
15) 4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸甲酯
16) 1-[2-(4-环己基-4-乙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
17) 1-[2-(4-乙酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
18) 4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-2-苯基乙酰基)-哌啶-4-甲酸甲酯
19) 4-乙基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
20) 1-[2-(4-环己基-4-丙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
21) 1-[2-(1H-咪唑-4-基)乙基]-3-{1-(4-甲氧基苄基)-2-[3-(2-甲基环己基)-3-丙氧基氮杂环丁烷-1-基]-2-氧代乙基}脲
22) 4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸丙酯
23) 1-[2-(1H-咪唑-4-基)乙基]-3-[1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基-氮杂环丁烷-1-基)乙基]脲
24) 1-((R)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
25) 1-((S)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
26) 1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
27) 1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基甲基)脲
28) 4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
29) 4-环丙基甲基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
30) 4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸丙酯
31) 4-环戊基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸乙酯
32) 4-环戊基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
33) 4-环己基-1-[(S)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
34) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
35) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氟苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
36) 1-[(R)-1-苄基-2-(4-丁酰基-4-环己基哌啶-1-基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
37) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲
38) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氯苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
39) 4-环己基-1-((R)-3-(3,4-二氯苯基)-2-{3-[3-(1H-咪唑-4-基)丙基]-脲基}丙酰基)哌啶-4-甲酸乙酯
40) 4-环己基-1-((R)-3-(4-甲氧基苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲基}丙酰基)哌啶-4-甲酸乙酯
41) 4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]硫脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
及其各自的盐和对映体。
5. 选自以下的化合物:
1) 4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
2) 4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸乙酯
3) 1-[2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3H-咪唑-4-基)乙基]脲
4) 1-[2-(4-丁氧基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
5) 4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸甲酯
6) 1-[2-(4-环己基-4-乙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
7) 1-[2-(4-乙酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
8) 4-乙基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
9) 1-[2-(4-环己基-4-丙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
10) 4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸丙酯
11) 1-((R)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
12) 1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
13) 1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基甲基)脲
14) 4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
15) 4-环丙基甲基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
16) 4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸丙酯
17) 4-环戊基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
18) 4-环己基-1-[(S)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
19) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
20) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氟苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
21) 1-[(R)-1-苄基-2-(4-丁酰基-4-环己基哌啶-1-基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
22) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲
23) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-[1.2.3]三唑-4-基)乙基]脲
24) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氯苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
25) 4-环己基-1-((R)-3-(3,4-二氯苯基)-2-{3-[3-(1H-咪唑-4-基)丙基]-脲基}丙酰基)哌啶-4-甲酸乙酯
26) 4-环己基-1-((R)-3-(4-甲氧基苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲基}丙酰基)哌啶-4-甲酸乙酯
27) 4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]硫脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
及其各自的盐和对映体。
6. 选自以下的化合物:
1) 4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
2) 4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸乙酯
3) 1-[2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3H-咪唑-4-基)乙基]脲
4) 1-[2-(4-丁氧基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
5) 4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸甲酯
6) 1-[2-(4-环己基-4-乙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
7) 1-[2-(4-乙酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
8) 1-[2-(4-环己基-4-丙氧基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
9) 4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸丙酯
10) 1-((R)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
11) 1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
12) 4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
13) 4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸丙酯
14) 4-环戊基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
15) 4-环己基-1-[(S)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
16) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
17) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氟苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
18) 1-[(R)-1-苄基-2-(4-丁酰基-4-环己基哌啶-1-基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
19) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲
20) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氯苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
21) 4-环己基-1-((R)-3-(4-甲氧基苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲基}丙酰基)哌啶-4-甲酸乙酯
22) 4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]硫脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
及其各自的盐和对映体。
7. 选自以下的化合物:
1) 4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
2) 4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸乙酯
3) 1-[2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(3H-咪唑-4-基)乙基]脲
4) 4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸甲酯
5) 1-[2-(4-乙酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
6) 4-环己基-1-[2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸丙酯
7) 1-((R)-3-(4-氯苯基)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}丙酰基)-4-环己基哌啶-4-甲酸乙酯
8) 1-[2-(4-环己基-4-丙酰基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
9) 4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-(4-甲氧基苯基)-丙酰基]哌啶-4-甲酸乙酯
10) 4-环己基-1-(2-{3-[2-(1H-咪唑-4-基)乙基]脲基}-3-苯基丙酰基)-哌啶-4-甲酸丙酯
11) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
12) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氟苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
13) 1-[(R)-1-苄基-2-(4-丁酰基-4-环己基哌啶-1-基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
14) 1-[(R)-2-(4-丁酰基-4-环己基哌啶-1-基)-1-(4-氯苄基)-2-氧代乙基]-3-[2-(1H-咪唑-4-基)乙基]脲
15) 4-环己基-1-((R)-3-(4-甲氧基苯基)-2-{3-[2-(3-甲基-3H-咪唑-4-基)乙基]脲基}丙酰基)哌啶-4-甲酸乙酯
16) 4-环己基-1-[(R)-2-{3-[2-(1H-咪唑-4-基)乙基]硫脲基}-3-(4-甲氧基-苯基)丙酰基]哌啶-4-甲酸乙酯
及其各自的盐和对映体。
8. 权利要求1-7中任一项的化合物在制备组合物中的用途,所述组合物用于治疗和/或预防选自以下的病症和/或疾病:
-消化器官的炎性疾病;
-运动器官的炎性疾病;
-泌尿生殖器官的炎性疾病;
-心脏器官的炎性疾病;
-呼吸和ORL器官的炎性疾病;
-中枢神经系统的炎性疾病;
-皮肤的炎性疾病;
-自身免疫疾病;
-伴随细菌、病毒或真菌感染的炎症;
-移植或移植物排斥;
-治疗与起源无关的疼痛;
-调节色素沉着,和治疗以下疾病:
-具有色素沉着障碍的疾病;
-防日晒保护,用于防止:
·日光的有害作用;
·由外源性光敏剂造成的光照性皮肤病;
·光过敏性皮肤病发作;
·自发性光照性皮肤病;
-改变皮肤或头发和体毛的颜色;
-改善皮脂分泌功能;
-神经变性疾病;
-男性或女性性功能障碍;
-与体重有关的病症;
-癌症。
9. 权利要求1-7中任一项的化合物在制备组合物中的用途,所述组合物用于治疗和/或预防选自以下的病症和/或疾病:
-皮肤病;
-自身免疫疾病;
-具有色素沉着障碍的疾病;
-防日晒保护,用于防止:
·日光的有害作用;
·由外源性光敏剂造成的光照性皮肤病;
·光过敏性皮肤病发作;
·自发性光照性皮肤病;
-改变皮肤或头发和体毛的颜色。
10. 权利要求1-7中任一项的化合物在制备组合物中的用途,所述组合物用于治疗选自以下的病症/疾病:
-皮脂溢过多病;
-皮脂分泌减少的疾病;
-调节皮脂腺细胞和皮脂腺的良性或恶性增生;
-毛囊皮脂腺的炎症。
11. 权利要求1-7中任一项的化合物在制备组合物中的用途,所述组合物用于治疗选自以下的病症/疾病
白斑、白化病、黑斑病、着色斑、雀斑、皮肤黑素细胞增生病和所有炎症后色素沉着;和着色肿瘤和它们的局部、区域或全身转移。
12. 权利要求1-7中任一项的化合物在制备组合物中的用途,所述组合物用于治疗和/或预防选自以下的病症和/或疾病:
-荨麻疹、硬皮病、接触性皮炎、特应性皮炎、银屑病、鱼鳞病、痤疮和其它形式的毛囊炎、红色痤疮和脱发。
13. 药用组合物,其特征在于其在生理上可接受的介质中包含至少一种权利要求1 -7中任一项定义的化合物。
14. 权利要求13的药用组合物,其特征在于化合物的浓度相对于所述组合物的总重量为0.001%-10%重量。
15. 权利要求13或14的药用组合物,其特征在于局部用化合物的浓度相对于所述组合物的总重量为0.01%- 5%重量。
16. 化妆品组合物,其特征在于其在化妆品可接受的载体中包含至少一种权利要求1 -7中任一项定义的化合物。
17. 权利要求16的化妆品组合物,其特征在于化合物的浓度相对于所述组合物的总重量为0.001%
-3%重量。
18. 权利要求16和17中任一项定义的化妆品组合物在制备化妆品中的用途,所述用途为预防和/或治疗皮肤老化体征。
19. 权利要求16和17中任一项定义的化妆品组合物在制备化妆品中的用途,所述用途为身体或毛发卫生。
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FR2981933B1 (fr) * | 2011-11-02 | 2013-11-15 | Galderma Res & Dev | Derives d'oxoazetidine, leur procede de preparation et leur utilisation en medecine humaine ainsi qu'en cosmetique |
FR2984167B1 (fr) * | 2011-12-16 | 2014-01-17 | Galderma Res & Dev | Association d'un agoniste des recepteurs des prostaglandines et d'un agoniste du recepteur mc1r pour le traitement et/ou la prevention de desordres de la pigmentation |
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2008
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Publication number | Priority date | Publication date | Assignee | Title |
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CN104860924A (zh) * | 2008-11-04 | 2015-08-26 | 盖尔德马研究及发展公司 | 黑皮质素受体调节剂、制备它们的方法及其在人用药物和化妆品中的用途 |
CN104860924B (zh) * | 2008-11-04 | 2018-10-09 | 盖尔德马研究及发展公司 | 黑皮质素受体调节剂、制备它们的方法及其在人用药物和化妆品中的用途 |
Also Published As
Publication number | Publication date |
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AU2009312820A1 (en) | 2010-05-14 |
EP2352728A1 (en) | 2011-08-10 |
FR2937973B1 (fr) | 2010-11-05 |
AU2009312820B2 (en) | 2015-01-22 |
US8877968B2 (en) | 2014-11-04 |
FR2937973A1 (fr) | 2010-05-07 |
DK2352728T3 (da) | 2014-08-18 |
CA2738584A1 (en) | 2010-05-14 |
KR20110088550A (ko) | 2011-08-03 |
KR101782776B1 (ko) | 2017-09-28 |
PL2352728T3 (pl) | 2014-11-28 |
MX2011004067A (es) | 2011-05-31 |
CN104860924A (zh) | 2015-08-26 |
CN104860924B (zh) | 2018-10-09 |
HRP20140788T1 (hr) | 2014-11-21 |
JP6157443B2 (ja) | 2017-07-05 |
JP2015078212A (ja) | 2015-04-23 |
CN102203082A (zh) | 2011-09-28 |
RU2589056C2 (ru) | 2016-07-10 |
JP2012507492A (ja) | 2012-03-29 |
RU2011122635A (ru) | 2012-12-20 |
KR20160130326A (ko) | 2016-11-10 |
SI2352728T1 (sl) | 2014-10-30 |
JP6113403B2 (ja) | 2017-04-12 |
KR101835257B1 (ko) | 2018-03-06 |
PT2352728E (pt) | 2014-09-02 |
ES2486316T3 (es) | 2014-08-18 |
AR074895A1 (es) | 2011-02-23 |
WO2010052255A1 (en) | 2010-05-14 |
EP2352728B1 (en) | 2014-05-21 |
US20110275657A1 (en) | 2011-11-10 |
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