CN104903290A - 具有抑制11β-HSD1酶活性的新型化合物或其药学上可接受的盐及其制备方法,以及包含其作为活性成分的药物组合物 - Google Patents
具有抑制11β-HSD1酶活性的新型化合物或其药学上可接受的盐及其制备方法,以及包含其作为活性成分的药物组合物 Download PDFInfo
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- CN104903290A CN104903290A CN201380044468.4A CN201380044468A CN104903290A CN 104903290 A CN104903290 A CN 104903290A CN 201380044468 A CN201380044468 A CN 201380044468A CN 104903290 A CN104903290 A CN 104903290A
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Classifications
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/08—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms with acylated ring nitrogen atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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- C07D239/42—One nitrogen atom
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
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Abstract
本发明涉及一种抑制11β-HSD1酶活性的新型化合物或其药学上可接受的盐,一种该化合物的制备方法,以及一种含有该化合物作为活性成分的药物组合物。由于本发明化合物选择性地抑制11β-HSD1(11β-羟基类固醇脱氢酶1型)的活性,因此,本发明的化合物可以有效地用作治疗由11β-HSD1过度活化引起的疾病的治疗剂,诸如非胰岛素依赖型II型糖尿病、胰岛素耐受、肥胖、血脂异常、代谢综合征,以及其它糖皮质激素过度活跃介导的疾病。
Description
技术领域
本发明涉及一种抑制人11β-HSD1的新型化合物或其药学上可接受的盐及其制备方法,以及一种包含所述化合物作为活性成分的药物组合物。
背景技术
代谢综合征是一类尤其在发达国家、亚洲和发展中国家增长迅速的疾病。这种疾病以肥胖、II型糖尿病、高血脂、高血压、动脉硬化、冠心病和慢性肾衰竭为特征(C.T.Montague等人(2000),Diabetes,49,883-888)。
与糖皮质激素受体结合的糖皮质激素(人体中为皮质醇,大鼠和小鼠中为皮质酮)是在几乎每一种脊椎动物中都有发现的一种类固醇激素(Dallman MF,Strack AM,Akana SF等人,1993;Front Neuroendocrinol 14,303-347)。
这种激素调节参与糖异生的肝酶的表达,以使得甘油从脂肪细胞中释放,并使得氨基酸从肌肉中释放,致使底物补充物的增加。有报道称糖皮质激素在脂肪细胞前体分化为能够储存甘油三酸酯的成熟脂肪细胞中发挥着重要作用(Bujalska IJ等人,1999;Endocrinology 140,3188-3196)。这意味着在由“应激”诱导的糖皮质激素与腹型肥胖引起的疾病是深度相关的,其中,腹型肥胖是引发II型糖尿病、高血压和冠状动脉疾病的主要风险因素(Bjorntorp P和Rosmond R 2000;Int.J.Obesity 24,S80-S85)。
实验证明糖皮质激素的活性可以在组织水平上进行调控,不仅受皮质醇分泌的控制,而且受由11β-HSD1(11β-羟基类固醇脱氢酶1型) 和11β-HSD2(11β-羟基类固醇脱氢酶2型)介导的有活性皮质醇和无活性皮质醇的细胞内互变所控制(Sandeep TC和Walker BR 2001Trends in Endocrinol&Metab.12,446-453)。
糖皮质激素和11β-HSD1被认为是脂肪细胞分化的重要因素。肥胖患者内脏脂肪组织中的11β-HSD1的mRNA水平较之其皮下组织中有所升高。转基因小鼠脂肪组织中11β-HSD1的过度表达与脂肪组织中的皮质酮上调、内脏型肥胖、胰岛素敏感、II型糖尿病、高血脂和饮食过量相关(H.Masuzaki等人(2001),Science,294,2166-2170)。因此,可以说11β-HSD1主要参与内脏型肥胖和代谢综合征。
此时,11β-HSD1将无活性的糖皮质激素转化为有活性的形式,这表明11β-HSD1在激活靶组织糖皮质激素受体以及调节其中糖皮质激素浓度方面发挥着重要的作用。
已经证实,上述机理可被很好地应用于糖尿病和肥胖的治疗。尤其是,其治疗效果在使用能抑制11β-HSD1和11β-HSD2二者的抗溃疡剂生胃酮治疗时被证实。该治疗提高了胰岛素敏感性,并且被抑制的11β-HSD1降低了细胞内皮质醇水平,这表明胰岛素的作用可以被控制(Walker BR等人.1995;J.Clin.Endocrinol.Metab.80,3155-3159)。11β-HSD1基因敲除的小鼠中11β-HSD1的抑制弱化了糖异生酶诱导糖皮质激素的活性,并降低了血浆葡萄糖响应应激或肥胖的水平(Kotelevtsev Y.等人,Proc Natl Acad Sci USA.1997Dec 23;94(26):14924-14929),这表明抑制11βHSD1在降低II型糖尿病中血浆葡萄糖和肝葡萄糖水平中是有效的。11β-HSD1的抑制不仅缓解了典型的糖尿病相关症状,而且没有带来任何严重的副作用。
在使用非特异性抑制剂生胃酮的研究过程中,当11β-HSD2被抑制时,观察到副作用如血压升高。因此,有必要开发一种对11β-HSD1具有选择性的的抑制剂。
骨骼发育和骨功能也受糖皮质激素的调节。11β-HSD1存在于人破骨细胞和成骨细胞中。当用生胃酮治疗健康的志愿者时,显示骨形成指标不变,但是骨吸收指标下降(Cooper MS等人,2000;Bone 27,375- 381)。骨中11β-HSD1活性的抑制可以作为骨质疏松症治疗中的保护机制。
此外,糖皮质激素也参与如青光眼的眼病。已知11β-HSD1会影响人的眼内压,因此预计11β-HSD1的抑制能缓解与青光眼相关的眼内压升高(Rauz S等人.2001;Investigative Ophthalmology&Visual Science 42,2037-2042)。
在研究制备可选择性抑制11β-HSD1的化合物的过程中,本发明的发明人成功地合成了显示出优异的抑制11β-HSD1的活性、并且具有剂量依赖性的降血浆葡萄糖作用的新型化合物,这已由动物体内研究所确认。本发明的发明人通过确认其合成的新型化合物可有效地用于治疗以下疾病或状况而完成了本发明:非胰岛素依赖型II型糖尿病、胰岛素耐受、肥胖、血脂异常、代谢综合征,以及其它由糖皮质激素过度活跃介导的疾病。
发明概述
本发明的一个目的是提供一种具有抑制11β-HSD1酶活性的化合物或其药学上可接受的盐。
本发明的另一个目的是提供一种制备所述化合物的方法。
本发明的再一个目的是提供一种包含所述化合物或其药学上可接受的盐作为活性成分的药物组合物。
为了实现以上目的,本发明提供了一种式1所示的、具有抑制11β-HSD1酶活性的化合物或其在药学上可接受的盐:
[式1]
在式1中,
X为羰基或磺酰基;
R1为C1-4直链或支链烷基、C3-7环烷基、C5-12芳基、C5-12芳基胺、5-8元单环或8-12元二环杂环烷基、或5-8元单环或8-12元二环杂环芳基;
R2和R3独立地为氢、C1-4直链或支链烷基、C5-8环烷基、C5-8二环烷基、C5-8芳基、1-金刚烷基或2-金刚烷基,其中,所述1-金刚烷基或2-金刚烷基是未被取代的或被选自羟基、氨基、醛基、羟基C1-4直链或支链烷基、羟基羰基、氨基羰基、N-羟氨羰基、腈基、羟基羰基C1-4直链或支链烷基、氨基羰基C1-4直链或支链烷基、 的一个或多个取代基所取代;
R4为氢、C1-4直链或支链烷基、羟基C1-4直链或支链烷基或钠;
A为 其中,Y是未被取代的或卤素;
其中,所述R1-R3、芳基是未被取代的或被选自羟基、卤素、氨基、C1-4直链或支链烷基、C1-4直链或支链卤代烷基、C1-4直链或支链卤代烷氧基、C1-4直链或支链烷氧基、-O-Z1-NZ2Z3、-O-NZ2Z3和-Z1-NZ2Z3的一个或多个取代基所取代,其中,Z1为C1-4直链或支链烷基,并且Z2和Z3独立地为氢或C1-4直链或支链烷基;
其中,所述R1-R3、杂环烷基或杂芳基是含有一个或多个选自氧、氮、硫的杂原子的单环或二环,其中,杂环烷基或杂芳基是未被取代的或者被选自三氟C1-4直链或支链烷基、嘧啶基、C1-4直链或支链烷基和C1-4直链或支链烷氧羰基的一个或多个取代基所取代,并且杂环烷基也 可以是与C5-12芳基或杂芳基稠合成的二环,杂芳基也可以是与C3-7环烷基或杂环烷基稠合成的二环;
其中,R1和R4可与连接在R1和R4上的X和N形成5-8元单环或8-12元二环杂环烷基;
其中,R4可与连接在R4上的N和A形成5-8元单环杂环烷基。
本发明还提供了一种式1所示的化合物的制备方法,该制备方法包含将式2所示化合物与式3所示化合物反应以制备式1所示化合物的步骤,如下述反应式1所示。
[反应式1]
在反应式1中,
R1-R4、X和A如式1中所定义。
此外,本发明提供了一种用于预防或治疗由11β-HSD1酶过度活化引发的疾病的药物组合物,该药物组合物包含式1所示化合物或其药学上可接受的盐作为活性成分。
有益效果
如前文所述,本发明的化合物可以有效地用作一种治疗剂,其通过选择性抑制11β-HSD1活性(11β-羟基类固醇脱氢酶1型),用于治疗11β-HSD1过度活化所介导的疾病或状况,如非胰岛素依赖型II型糖尿病、胰岛素耐受、肥胖、血脂异常、代谢综合征,以及其它由糖皮质激素过度活跃介导的疾病。
具体实施方式
下文将详细的描述本发明。
本发明提供了一种具有抑制11β-HSD1酶活性的式1所示的化合物或其药学上可接受的盐。
[式1]
在式1中,
X为羰基或磺酰基;
R1为C1-4直链或支链烷基、C3-7环烷基、C5-12芳基、C5-12芳基胺、5-8元单环或8-12元二环杂环烷基、或5-8元单环或8-12元二环杂芳基;
R2和R3独立地为氢、C1-4直链或支链烷基,C5-8环烷基、C5-8二环烷基、C5-8芳基、1-金刚烷基或2-金刚烷基,其中,所述1-金刚烷基或2-金刚烷基是未被取代的或被选自羟基、氨基、醛基、羟基C1-4直链或支链烷基、羟基羰基、氨基羰基、N-羟氨羰基、腈基、羟基羰基C1-4直链或支链烷基、氨基羰基C1-4直链或支链烷基、 的一个或多个取代基所取代;
R4为氢、C1-4直链或支链烷基、羟基C1-4直链或支链烷基或钠;
A为 其中Y是未被取代的或卤素;
其中,所述R1-R3、芳基是未被取代的或被选自羟基、卤素、氨基、C1-4直链或支链烷基、C1-4直链或支链卤代烷基、C1-4直链或支链卤代烷氧基、C1-4直链或支链烷氧基、-O-Z1-NZ2Z3、-O-NZ2Z3和-Z1- NZ2Z3的一个或多个取代基所取代,其中Z1为C1-4直链或支链烷基,Z2和Z3独立地为氢或C1-4直链或支链烷基;
其中,所述R1-R3、杂环烷基或杂芳基是含有一个或多个选自氧、氮和硫的杂原子的单环或二环,其中杂环烷基或杂芳基是未被取代的或被选自三氟C1-4直链或支链烷基、嘧啶基、C1-4直链或支链烷基和C1-4直链或支链烷氧羰基的一个或多个取代基所取代,并且杂环烷基也可以是与C5-12芳基或杂芳基稠合的二环,杂环芳基也可以是与C3-7环烷基或杂环烷基稠合的二环;
其中,R1和R4可与连接在R1和R4上的X和N形成5-8元单环或8-12元二环杂环烷基;
其中,R4可与连接在R4上的N和A形成5-8元单环杂环烷基。
优选地,
X为羰基或磺酰基;
R1为C1-4直链或支链烷基、C3-7环烷基、C5-6芳基、C5-6芳基胺、5-6元单环或9-10元二环杂环烷基、或5-6元单环或9-10元二环杂芳基;
R2和R3独立地为氢、甲基、乙基、丙基、C6-7环烷基、C6-8二环烷基、C5-6芳基、1-金刚烷基或2-金刚烷基,其中1-金刚烷基或2-金刚烷基是未被取代的或被选自羟基、氨基、醛基、羟甲基、羟乙基、羟基羰基、氨基羰基、N-羟氨羰基、腈基、羟基羰基甲基、羟基羰基乙基、氨基羰基甲基、氨基羰基乙基、 中的一个或多个取代基所取代;
R4为氢、甲基、乙基、丙基、羟甲基、羟乙基或钠;
A为 其中Y为Cl或F;
其中所述R1-R3、芳基是未被取代的或被选自卤素、三氟甲基、三氟乙基、三氟甲氧基、三氟乙氧基、甲氧基、乙氧基、丙氧基、甲基、乙基、1,1,1-三氟-2-醇-异丙基、-O(CH2)nNZ2Z3和-(CH2)nNZ2Z3的一个或多个取代基所取代,n为1或2,并且Z2和Z3独立地为氢、甲基或乙基;
其中所述R1-R3、杂环烷基或杂芳基含有一个或多个选自氧、氮、硫的杂原子,其中杂环烷基或杂芳基是未被取代的或者被选自三氟甲基、三氟乙基、嘧啶基、甲基、乙基和异丁氧羰基的一个或多个取代基所取代,并且杂环烷基也可以是与C5-12芳基或杂芳基稠合成的二环,杂芳基也可以是与C3-7环烷基或杂环烷基稠合成的二环;
其中,R1和R4可与连接在R1和R4上的X和N形成5-6元单环或8-9元二环杂环烷基;
R4可与连接在R4上的N和A形成5-6元单环杂环烷基。
更优选地,
X为羰基或磺酰基,
R1为
R2为-H或-(CH2)2CH3,
R3为
R4为-H、-CH3、-CH2CH3、-CH2CH2OH或-Na,
A为
更优选地,
X为磺酰基;
R1为苯基,其中苯基是未被取代的或被选自卤素和三氟甲基的一个或多个取代基取代,并且卤素可以被取代一个或多个;
R2为-H或-CH3;
R3为
R4为-H,
A为
更优选地,
X为磺酰基;
R1为苯基,其中苯基是未被取代的或被选自卤素和三氟甲基的一个或多个取代基所取代,并且卤素可以被取代一个或多个;
R2为-H;
R3为
R4为-H或-Na,
A为
更优选地,
X为磺酰基;
R1为苯基,其中苯基是未被取代的或被选自卤素和三氟甲基的一个或多个取代基所取代,并且卤素可以被取代一个或多个;
R2为-H;
R3为
R4为-H或-Na,
A为
本发明式1所示化合物的具体实例如下所示:
(1)N-(金刚烷-2-基)-1-[(3-氯-2-甲基苯磺酰胺基)甲基]环丙基甲酰胺;
(2)(1-[(2-氟-苯磺酰胺基)甲基]-N-(5-羟基金刚烷-2-基)环丙基甲酰胺;
(3)E-4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(4)Z-4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(5)E-4-[1-((3-氯-2-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(6)Z-4-[1-((3-氯-2-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(7)E-4-[1-((3-氯-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(8)E-4-[1-((3-氯-2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(9)E-4-[1-((3,5-二氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(10)E-4-[1-((2-氟-6-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(11)E-4-[1-((2,3-二氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(12)E-4-[1-((2,4,6-三氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(13)E-4-[1-((2-氟-N,6-二甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(14)E-4-[1-((2,4-二氯-5-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(15)E-4-[1-((4-氯-2-氟-5-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(16)E-4-[1-((4,5-二氯-2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(17)E-4-[1-((呋喃-2-磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(18)E-4-[1-(3,5-二氯-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(19)E-4-[1-((噻吩-2-磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(20)E-4-[1-((2-(三氟甲基)-4-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(21)E-4-[1-((3,4-二氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(22)E-4-[1-((2-氟-N-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(23)E-4-[1-((4-三氟甲氧基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(24)E-4-[1-((2,3-二氟-苯氨基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(25)E-4-[1-((3,4-二氟-苯氨基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(26)E-4-[1-((1-甲基-1H-吲哚-5-磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(27)E-4-[1-((1-甲基-1H-吡唑-5-磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(28)E-4-[1-((苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(29)E-4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酸;
(30)N-(双环[2.2.1]庚烷-2-基)-1-((2-氟-N-甲基苯磺酰胺基)甲基)环丙基甲酰胺;
(31)N-(金刚烷-1-基)-1-((2-氟-N-甲基苯磺酰胺基)甲基)环丙基甲酰胺;
(32)E-4-[1-((N-乙基-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(33)E-3-(4-(1((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基)金刚烷-1-基)丙酸;
(34)E-N-(5-(3-氨基-3-氧代丙基)金刚烷-2-基)-1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺;
(35)E-N-(5-氨基金刚烷-2-基)-1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺盐酸盐;
(36)E-4-[1-((2,4,5-三氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(37)E-4-[1-((4-氯-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(38)E-4-[1-(3-氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(39)E-4-[1-(2-氟-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(40)E-4-[1-(2-氟-6-甲基-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(41)E-4-[1-(3-氯-2-甲基-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(42)E-4-[1-(4-氟-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(43)E-4-[1-(2,4-二氯-5-甲基-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(44)E-4-[1-(2,4-二氟氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(45)E-4-[1-(2-氟-4,5-二氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(46)E-4-[1-(2-氟-4-氯-5-甲基-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(47)E-4-[1-(2,3,4-三氟-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(48)E-4-[1-(噻吩-2-磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(49)E-4-[3-(6-三氟甲基-吡啶-2-磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(50)E-4-[1-(1-甲基-1H-吲哚-7-磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(51)1-(3-氯-苯磺酰胺基)-N-(4-氟-2-(三氟甲基)苯基)环丙基甲酰胺;
(52)E-4-[1-(3-氯-苯磺酰胺基)环丙基甲酰胺基]-N-羟基金刚烷-1-甲酰胺;
(53)1-(3-氯-苯磺酰胺基)-N-[4-(1,1,1-三氟-2-羟丙-2-基)苯基]环丙基甲酰胺;
(54)E-4-[1-(3-氯-苯氨基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(55)N-(双环[2.2.1]庚烷-2-基)-1-(3-氯-苯磺酰胺基)环丙基甲酰胺;
(56)E-4-[1-(1,1-二氧苯并[d]异噻唑-2(3H)-基)环丙基甲酰胺基]金刚烷-1-甲酰胺;
(57)E-4-[1-(3,4-二氟-苯氨基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(58)E-4-[1-(1-甲基-1H-吡唑-5-磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(59)E-4-[1-(2,3-二氟-苯氨基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(60)E-4-[1-(苯磺酰胺基)环丙基甲酰胺基]-N-羟基金刚烷-1-甲酰胺;
(61)E-4-[1-(2-氟-N-甲基苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(62)E-4-[1-(3-氯-N-甲基苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(63)E-4-[1-(2-氟苯甲酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(64)E-N-[1-(5-氨基甲酰基金刚烷-2-基)氨基甲酰基)环丙基)-5-(三氟甲基)吡咯啉酰胺;
(65)E-4-(1-(苯并[d][1,3]二氧杂环戊烯-5-磺酰胺基)环丙甲酰胺基)金刚烷-1-甲酰胺;
(66)1-(3-氯-苯磺酰胺基)-N-环庚基-N-丙基环丙基甲酰胺;
(67)E-4-(3-(3-氯-苯磺酰胺基)-2,2-二甲基丙酰胺基)金刚烷-1-甲酰胺;
(68)E-4-[3-(2-氟-苯磺酰胺基)-2,2-二甲基丙酰胺基]金刚烷-1-甲酰胺;
(69)E-4-[3-(苯磺酰胺基)-2,2-二甲基丙酰胺基]金刚烷-1-甲酰胺;
(70)E-4-[3-(3-氯-2-甲基-苯磺酰胺基)-2,2-二甲基丙酰胺基]金刚烷-1-甲酰胺;
(71)E-4-[2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺基]-金刚烷-1-甲酰胺;
(72)E-4-[2-(2-氟-N-甲基-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(73)E-4-[2-(3-氯-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(74)E-N-(5-氰基金刚烷-2-基)-2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺;
(75)E-2-(2-氟-苯磺酰胺基)-N-[5-(N'-甲脒基)金刚烷-2-基]-2-甲基丙酰胺;
(76)E-2-(2-氟-苯磺酰胺基)-N-[5-(羟甲基)金刚烷-2-基]-2-甲基丙酰胺;
(77)E-2-(2-氟-苯磺酰胺基)-N-(5-甲酰金刚烷-2-基)-2-甲基丙酰胺;
(78)E-[4-(2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺基)金刚烷-1-基]甲基-4-甲苯磺酸酯;
(79)E-2-[4-(2-(2-氟苯磺酰胺基)-2-甲基丙酰胺基)金刚烷-1-基]乙酸;
(80)E-N-[5-(2-氨基-2-氧代乙基)金刚烷-2-基]-2-(2-氟苯磺酰胺基)-2-甲基丙酰胺;
(81)E-4-[2-甲基-2-(苯磺酰胺基)丙酰胺基]金刚烷-1-甲酰胺;
(82)E-4-[2-(2-氟-3-氯-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(83)E-4-[2-(3,5-二氟-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(84)E-4-[2-(2,6-二氟-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(85)E-2-(2-氟-苯磺酰胺基)-N-(5-(肼基羰基)金刚烷-2-基)-2-甲基丙酰胺;
(86)E-N-(5-(3-氨基-3-氧代丙基)金刚烷-2-基)-2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺;
(87)E-2-(2-氟-苯磺酰胺基)-N-(5-(肼基羰基)金刚烷-2-基)-2-甲基丙酰胺;
(88)E-4-[2-(4-氯-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(89)E-4-[2-(2,5-二氯-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(90)2-(3-氯-苯磺酰胺基)-N-环庚基-2-甲基-N-丙基丙酰胺;
(91)E-4-[3-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(92)E-4-[2-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(93)E-4-[4-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(94)E-4-[3-(4-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(95)E-4-[3-(3-氯-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(96)E-4-[3-(3-氯-2-甲基-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(97)E-4-{3-[(3-氯-苯磺酰基)-甲胺基]-苯甲酰胺基}-金刚烷-1-甲酰胺;
(98)E-4-[3-N-(2-羟乙基)-2-(三氟甲基-苯磺酰胺基)苯甲酰胺基]-金刚烷-1-甲酰胺;
(99)E-4-{3-[(2-三氟甲基-苯磺酰基)-甲胺基]-苯甲酰胺基}-金刚烷-1-甲酰胺;
(100)E-[3-((5-氨基甲酰基金刚烷-2-基)氨基甲酰基)苯基](2-(三氟甲基)苯磺酰钠;
(101)E-N-(5-氨基甲酰基金刚烷-2-基)-5-[(N-甲基-2-(三氟甲基)苯磺酰胺基]烟酰胺;
(102)E-4-[3-(噻吩-2-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(103)E-4-[3-(呋喃-2-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(104)E-4-[3-(吡啶-3-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(105)E-4-(3-(苯磺酰胺基-苯甲酰胺基)-金刚烷-1-甲酰胺;
(106)E-4-[3-[(2-氯-苯磺酰胺基]苯甲酰胺基]-金刚烷-1-甲酰胺;
(107)E-4-[3-[(2,4-二甲基-噻唑-5-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(108)E-4-[3-(3,5-二甲基-1H-吡唑-4-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(109)E-N-(5-羟基-金刚烷-2-基)-3-苯磺酰胺基-苯甲酰胺;
(110)E-N-环庚基-3-苯氨基磺酰基-苯甲酰胺;
(111)E-N-(5-羟基金刚烷-2-基)-3-(2-(三氟甲基)苯磺酰胺基)苯甲酰胺;
(112)E-4-(3-(N-苯氨基磺酰基苯甲酰胺基)-金刚烷-1-甲酰胺;
(113)E-[3-((5-氨基甲酰基金刚烷-2-基)氨基甲酰基)苯基]-2-氟-3-氯-苯磺酰钠;
(114)E-4-[3-(3-氯-4-(三氟甲基)苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(115)E-4-[3-[(2-(三氟甲基)苯磺酰胺基]-苯甲酰胺基]-金刚烷-1-甲酰胺;
(116)E-4-[3-(2-氯-4-溴-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(117)E-4-[3-(2,4,6-三氯-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(118)E-4-[3-(3-氯-5-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(119)E-4-[3-(3,5-二氯-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(120)E-4-[3-(3-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(121)E-4-[3-(2,4-二氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(122)E-4-[3-(2,5-二氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(123)E-4-[3-(2,6-二氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(124)E-N-环庚基-N-丙基-3-(2-(三氟甲基)苯磺酰胺基)苯甲酰胺;
(125)E-4-[2-氟-3-(2-(三氟甲基)苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(126)E-4-[2-氯-5-(3-氯-苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(127)E-4-[3-(3-氯苯磺酰胺基)-4-氟苯甲酰胺基]金刚烷-1-甲酰胺;
(128)E-4-[4-氯-3-(3,5-二氯苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(129)E-4-[2-氯-5-(3,5-二氯苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(130)E-4-[3-(3,5-二氯苯磺酰胺基)-4-氟苯甲酰胺基]金刚烷-1-甲酰胺;
(131)E-4-[5-(3,5-二氯苯磺酰胺基)-2-氟苯甲酰胺基]金刚烷-1-甲酰胺;
(132)E-4-[2-氟-3-(3-氯-苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(133)E-4-[2-氯-5-(3-氯-4-甲氧基苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(134)E-4-[4-氯-3-(3-氯-4-甲氧基苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(135)E-4-[5-(3-氯-4-甲氧基苯磺酰胺基)-2-氟苯甲酰胺基]金刚烷-1-甲酰胺;
(136)E-4-(3-(4-氯-苯磺酰胺基-苯甲酰胺基)-金刚烷-1-甲酰胺;
(137)E-4-(3-(4-氯-苯磺酰胺基-苯甲酰胺基)-金刚烷-1-甲酰胺;
(138)E-4-(3-(环丙基磺酰胺基)苯甲酰胺基)金刚烷-1-甲酰胺;
(139)E-4-(3-(1-甲基乙基磺酰胺基)苯甲酰胺基)金刚烷-1-甲酰胺;
(140)E-[3,4-二氢-1H-异喹啉-2-甲酸-1-[(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)环丙基甲基]-酰胺;
(141)E-3,4-二氢-2H-喹啉-1-甲酸[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-酰胺;
(142)E-哌啶-1-甲酸[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-酰胺;
(143)E-4-{[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-氨基甲酰基}-3,4-二氢-2H-喹啉-1-甲酸-丁酯;
(144)E-4-嘧啶-2-基-哌嗪-1-甲酸[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-酰胺;
(145)E-4-({1[(3-苯基-脲基)甲基]-环丙基羰基}氨基)-金刚烷-1-甲酰胺;
(146)E-3,4-二氢-2H-喹喔啉-1-甲酸[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-酰胺;
(147)E-3,4-二氢-1H-异喹啉-2-甲酸[4-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-噻唑-2-基]-酰胺;
(148)E-3,4-二氢-2H-喹啉-1-甲酸[4-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-噻唑-2-基]-酰胺;和
(149)E-2-(2-氟-苯甲酰胺基)-噻唑-4-甲酸(5-氨基甲酰基-金刚烷-2-基)酰胺。
本发明式1所示化合物的优选实例如下所示:
(1)N-(金刚烷-2-基)-1-[(3-氯-2-甲基苯磺酰胺基)甲基]环丙基甲酰胺;
(2)(1-[(2-氟-苯磺酰胺基)甲基]-N-(5-羟基金刚烷-2-基)环丙基甲酰胺;
(3)E-4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(4)Z-4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(5)E-4-[1-((3-氯-2-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(6)Z-4-[1-((3-氯-2-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(7)E-4-[1-((3-氯-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(8)E-4-[1-((3-氯-2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(9)E-4-[1-((3,5-二氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(10)E-4-[1-((2-氟-6-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(11)E-4-[1-((2,3-二氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(12)E-4-[1-((2,4,6-三氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(13)E-4-[1-((2-氟-N,6-二甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(14)E-4-[1-((2,4-二氯-5-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(15)E-4-[1-((4-氯-2-氟-5-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(16)E-4-[1-((4,5-二氯-2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(17)E-4-[1-((呋喃-2-磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(18)E-4-[1-(3,5-二氯-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(19)E-4-[1-((噻吩-2-磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(20)E-4-[1-((2-(三氟甲基)-4-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(21)E-4-[1-((3,4-二氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(22)E-4-[1-((2-氟-N-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(23)E-4-[1-((4-三氟甲氧基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(24)E-4-[1-((2,3-二氟-苯氨基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(25)E-4-[1-((3,4-二氟-苯氨基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(26)E-4-[1-((1-甲基-1H-吲哚-5-磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(27)E-4-[1-((1-甲基-1H-吡唑-5-磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(28)E-4-[1-((苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(29)E-4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酸;
(30)N-(双环[2.2.1]庚烷-2-基)-1-((2-氟-N-甲基苯磺酰胺基)甲基)环丙基甲酰胺;
(31)N-(金刚烷-1-基)-1-((2-氟-N-甲基苯磺酰胺基)甲基)环丙基甲酰胺;
(32)E-4-[1-((N-乙基-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(33)E-3-(4-(1((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基)金刚烷-1-基)丙酸;
(34)E-N-(5-(3-氨基-3-氧代丙基)金刚烷-2-基)-1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺;
(35)E-N-(5-氨基金刚烷-2-基)-1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺盐酸盐;和
(36)E-4-[1-((2,4,5-三氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺。
本发明式1所示化合物的其它优选实例如下所示:
(37)E-4-[1-((4-氯-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(38)E-4-[1-(3-氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(39)E-4-[1-(2-氟-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(40)E-4-[1-(2-氟-6-甲基-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(41)E-4-[1-(3-氯-2-甲基-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(42)E-4-[1-(4-氟-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(43)E-4-[1-(2,4-二氯-5-甲基-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(44)E-4-[1-(2,4-二氟氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(45)E-4-[1-(2-氟-4,5-二氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(46)E-4-[1-(2-氟-4-氯-5-甲基-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(47)E-4-[1-(2,3,4-三氟-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(48)E-4-[1-(噻吩-2-磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(49)E-4-[3-(6-三氟甲基-吡啶-2-磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(50)E-4-[1-(1-甲基-1H-吲哚-7-磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(51)1-(3-氯-苯磺酰胺基)-N-(4-氟-2-(三氟甲基)苯基)环丙基甲酰胺;
(52)E-4-[1-(3-氯-苯磺酰胺基)环丙基甲酰胺基]-N-羟基金刚烷-1-甲酰胺;
(53)1-(3-氯-苯磺酰胺基)-N-[4-(1,1,1-三氟-2-羟丙-2-基)苯基]环丙基甲酰胺;
(54)E-4-[1-(3-氯-苯氨基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(55)N-(双环[2.2.1]庚烷-2-基)-1-(3-氯-苯磺酰胺基)环丙基甲酰胺;
(56)E-4-[1-(1,1-二氧苯并[d]异噻唑-2(3H)-基)环丙基甲酰胺基]金刚烷-1-甲酰胺;
(57)E-4-[1-(3,4-二氟-苯氨基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(58)E-4-[1-(1-甲基-1H-吡唑-5-磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(59)E-4-[1-(2,3-二氟-苯氨基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(60)E-4-[1-(苯磺酰胺基)环丙基甲酰胺基]-N-羟基金刚烷-1-甲酰胺;
(61)E-4-[1-(2-氟-N-甲基苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(62)E-4-[1-(3-氯-N-甲基苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(63)E-4-[1-(2-氟苯甲酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(64)E-N-[1-(5-氨基甲酰基金刚烷-2-yl)氨基甲酰基)环丙基)-5-(三氟甲基)吡咯啉酰胺;
(65)E-4-(1-(苯并[d][1,3]二氧杂环戊烯-5-磺酰胺基)环丙甲酰胺基)金刚烷-1-甲酰胺;和
(66)1-(3-氯-苯磺酰胺基)-N-环庚基-N-丙基环丙基甲酰胺。
本发明式1所示化合物的优选实例如下所示:
(67)E-4-(3-(3-氯-苯磺酰胺基)-2,2-二甲基丙酰胺基)金刚烷-1-甲酰胺;
(68)E-4-[3-(2-氟-苯磺酰胺基)-2,2-二甲基丙酰胺基]金刚烷-1-甲酰胺;
(69)E-4-[3-(苯磺酰胺基)-2,2-二甲基丙酰胺基]金刚烷-1-甲酰胺;和
(70)E-4-[3-(3-氯-2-甲基-苯磺酰胺基)-2,2-二甲基丙酰胺基]金刚烷-1-甲酰胺。
本发明式1所示化合物的优选实例如下所示:
(71)E-4-[2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺基]-金刚烷-1-甲酰胺;
(72)E-4-[2-(2-氟-N-甲基-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(73)E-4-[2-(3-氯-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(74)E-N-(5-氰基金刚烷-2-基)-2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺;
(75)E-2-(2-氟-苯磺酰胺基)-N-[5-(N'-甲脒基)金刚烷-2-基]-2-甲基丙酰胺;
(76)E-2-(2-氟-苯磺酰胺基)-N-[5-(羟甲基)金刚烷-2-基]-2-甲基丙酰胺;
(77)E-2-(2-氟-苯磺酰胺基)-N-(5-甲酰金刚烷-2-基)-2-甲基丙酰胺;
(78)E-[4-(2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺基)金刚烷-1-基]甲基-4-甲苯磺酸酯;
(79)E-2-[4-(2-(2-氟苯磺酰胺基)-2-甲基丙酰胺基)金刚烷-1-基]乙酸;
(80)E-N-[5-(2-氨基-2-氧代乙基)金刚烷-2-基]-2-(2-氟苯磺酰胺基)-2-甲基丙酰胺;
(81)E-4-[2-甲基-2-(苯磺酰胺基)丙酰胺基]金刚烷-1-甲酰胺;
(82)E-4-[2-(2-氟-3-氯-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(83)E-4-[2-(3,5-二氟-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(84)E-4-[2-(2,6-二氟-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(85)E-2-(2-氟-苯磺酰胺基)-N-(5-(肼基羰基)金刚烷-2-基)-2-甲基丙酰胺;
(86)E-N-(5-(3-氨基-3-氧代丙基)金刚烷-2-基)-2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺;
(87)E-2-(2-氟-苯磺酰胺基)-N-(5-(肼基羰基)金刚烷-2-基)-2-甲基丙酰胺;
(88)E-4-[2-(4-氯-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(89)E-4-[2-(2,5-二氯-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;和
(90)2-(3-氯-苯磺酰胺基)-N-环庚基-2-甲基-N-丙基丙酰胺。
本发明式1所示化合物的优选实例如下所示:
(91)E-4-[3-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(92)E-4-[2-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(93)E-4-[4-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(94)E-4-[3-(4-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(95)E-4-[3-(3-氯-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(96)E-4-[3-(3-氯-2-甲基-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(97)E-4-{3-[(3-氯-苯磺酰基)-甲胺基]-苯甲酰胺基}-金刚烷-1-甲酰胺;
(98)E-4-[3-N-(2-羟乙基)-2-(三氟甲基-苯磺酰胺基)苯甲酰胺基]-金刚烷-1-甲酰胺;
(99)E-4-{3-[(2-三氟甲基-苯磺酰基)-甲胺基]-苯甲酰胺基}-金刚烷-1-甲酰胺;
(100)E-[3-((5-氨基甲酰基金刚烷-2-基)氨基甲酰基)苯基](2-(三氟甲基)苯磺酰钠;
(101)E-N-(5-氨基甲酰基金刚烷-2-基)-5-[(N-甲基-2-(三氟甲基)苯磺酰胺基]烟酰胺;
(102)E-4-[3-(噻吩-2-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(103)E-4-[3-(呋喃-2-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(104)E-4-[3-(吡啶-3-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(105)E-4-(3-(苯磺酰胺基-苯甲酰胺基)-金刚烷-1-甲酰胺;
(106)E-4-[3-[(2-氯-苯磺酰胺基]苯甲酰胺基]-金刚烷-1-甲酰胺;
(107)E-4-[3-[(2,4-二甲基-噻唑-5-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(108)E-4-[3-(3,5-二甲基-1H-吡唑-4-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(109)E-N-(5-羟基-金刚烷-2-基)-3-苯磺酰胺基-苯甲酰胺;
(110)E-N-环庚基-3-苯氨基磺酰基-苯甲酰胺;
(111)E-N-(5-羟基金刚烷-2-基)-3-(2-(三氟甲基)苯磺酰胺基)苯甲酰胺;
(112)E-4-(3-(N-苯氨基磺酰基苯甲酰胺基)-金刚烷-1-甲酰胺;
(113)E-[3-((5-氨基甲酰基金刚烷-2-基)氨基甲酰基)苯基]-2-氟-3-氯-苯磺酰钠;
(114)E-4-[3-(3-氯-4-(三氟甲基)苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(115)E-4-[3-[(2-(三氟甲基)苯磺酰胺基]-苯甲酰胺基]-金刚烷-1-甲酰胺;
(116)E-4-[3-(2-氯-4-溴-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(117)E-4-[3-(2,4,6-三氯-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(118)E-4-[3-(3-氯-5-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(119)E-4-[3-(3,5-二氯-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(120)E-4-[3-(3-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(121)E-4-[3-(2,4-二氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(122)E-4-[3-(2,5-二氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(123)E-4-[3-(2,6-二氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(124)E-N-环庚基-N-丙基-3-(2-(三氟甲基)苯磺酰胺基)苯甲酰胺;
(125)E-4-[2-氟-3-(2-(三氟甲基)苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(126)E-4-[2-氯-5-(3-氯-苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(127)E-4-[3-(3-氯苯磺酰胺基)-4-氟苯甲酰胺基]金刚烷-1-甲酰胺;
(128)E-4-[4-氯-3-(3,5-二氯苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(129)E-4-[2-氯-5-(3,5-二氯苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(130)E-4-[3-(3,5-二氯苯磺酰胺基)-4-氟苯甲酰胺基]金刚烷-1-甲酰胺;
(131)E-4-[5-(3,5-二氯苯磺酰胺基)-2-氟苯甲酰胺基]金刚烷-1-甲酰胺;
(132)E-4-[2-氟-3-(3-氯-苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(133)E-4-[2-氯-5-(3-氯-4-甲氧基苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(134)E-4-[4-氯-3-(3-氯-4-甲氧基苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(135)E-4-[5-(3-氯-4-甲氧基苯磺酰胺基)-2-氟苯甲酰胺基]金刚烷-1-甲酰胺;
(136)E-4-(3-(4-氯-苯磺酰胺基-苯甲酰胺基)-金刚烷-1-甲酰胺;
(137)E-4-(3-(4-氯-苯磺酰胺基-苯甲酰胺基)-金刚烷-1-甲酰胺;
(138)E-4-(3-(环丙基磺酰胺基)苯甲酰胺基)金刚烷-1-甲酰胺;和
(139)E-4-(3-(1-甲基乙基磺酰胺基)苯甲酰胺基)金刚烷-1-甲酰胺。
本发明式1所示化合物的优选实例如下所示:
(140)E-[3,4-二氢-1H-异喹啉-2-甲酸-1-[(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)环丙基甲基]-酰胺;
(141)E-3,4-二氢-2H-喹啉-1-甲酸[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-酰胺;
(142)E-哌啶-1-甲酸[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-酰胺;
(143)E-4-{[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-氨基甲酰基}-3,4-二氢-2H-喹啉-1-甲酸-丁酯;
(144)E-4-嘧啶-2-基-哌嗪-1-甲酸[1-(5-氨基甲酰基-金刚烷-2-基氨基甲酰基)-环丙基甲基]-酰胺;
(145)E-4-({1[(3-苯基-脲基)甲基]-环丙基羰基}氨基)-金刚烷-1-甲酰胺;
(146)E-3,4-二氢-2H-喹喔啉-1-甲酸[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-酰胺;
(147)E-3,4-二氢-1H-异喹啉-2-甲酸[4-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-噻唑-2-基]-酰胺;
(148)E-3,4-二氢-2H-喹啉-1-甲酸[4-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-噻唑-2-基]-酰胺;和
(149)E-2-(2-氟-苯甲酰胺基)-噻唑-4-甲酸(5-氨基甲酰基-金刚烷-2-基)酰胺。
本发明式1所示化合物可以以一种药学上可接受的盐的形式使用,其中所述盐优选由药学上可接受的游离酸形成的酸加成盐。此处,所述 药学上可接受的盐表示任何如式1所示的基础化合物的有机或无机加成盐,其对患者相对无毒,并且具无害活性,其副作用不会降低所述式1所示基础化合物的有益效果。此处所述的酸加成盐能够从以下项中获得:无机酸如盐酸、溴酸、硝酸、硫酸、高氯酸以及磷酸;或者有机酸例如柠檬酸、乙酸、乳酸、马来酸、富马酸、葡糖酸(gluconic acid)、甲磺酸、乙醇酸(glyconic acid)、琥珀酸、酒石酸、半乳糖醛酸、帕莫酸、谷氨酸、天冬氨酸、草酸、(D)或(L)苹果酸、甲磺酸、乙磺酸、4-甲苯磺酸、水杨酸、柠檬酸、苯甲酸以及丙二酸。本文所述的盐包括碱金属盐(钠盐、钾盐等)和碱土金属盐(钙盐、镁盐等)。例如,酸加成盐的示例为:醋酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、camcilate、柠檬酸盐、乙二磺酸盐、乙醇盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡萄糖醛酸酯、六氟磷酸盐、海苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘化物/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲醇盐、硫酸二甲酯、萘二甲酸盐(naphthalate)、2-萘酸盐(2-naphthylate)、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、糖酸盐、硬脂酸盐、琥珀酸盐、酒石酸盐、甲苯磺酸盐、三氟醋酸盐、铝、精氨酸、苄星(benzathine)、钙、胆碱、二乙胺、二乙醇胺、甘氨酸、赖氨酸、镁、葡甲胺、乙醇胺、钾、钠、氨丁三醇以及锌盐。其中,优选盐酸盐或三氟醋酸盐。
本发明式1所示化合物不仅包含药学上可接受的盐,还包含通过常规方法从该化合物中构建的任何可能的盐、同分异构体、水合物和溶剂化物。
本发明所述酸加成盐可以通过本领域公知的常规方法制备。例如,本发明式1化合物被溶解于水溶性有机溶剂如丙酮、甲醇、乙醇或乙腈中,向其中加入过量的有机酸或无机酸的酸性水溶液以诱发沉淀或结晶。然后,将溶剂或过量的酸从混合物中蒸发除去,接着通过干燥混合物或抽滤沉淀析出的盐以获得加成盐。
式1所示的一些化合物含有手性中心或几何异构体中心(E和Z同分异构体)。应当理解,本发明包含所有具有抑制11β-HSD1活性的光学异构体、非对映体和几何异构体。
本发明还涉及具有抑制11β-HSD1活性的式1化合物的每一种随机的/可能的有利的或非有利的变化。特别应当理解的,式1化合物可以是溶剂化物或非溶剂化物的形式,例如,水合物的形式。因此,本发明包括所有这些化合物的每一种溶剂化物,只要它们显示出11β-HSD1抑制活性。
本发明还提供了一种式1所示化合物的制备方法,所述制备方法包含将式2所示化合物与式3所示化合物发生反应以制备式1所示化合物的步骤,如下述反应式1所示。
[反应式1]
在反应式1中,,
R1-R4、X和A如式1中所定义。
在本发明的制备方法中,式2所示化合物可以是磺酰卤化物的衍生物或乙酰卤化物的衍生物。考虑到此处的取代基,式2和式3化合物可以是市场上的商业化合物,或可由本领域技术人员合成。
特别是,本发明的式1化合物可以容易地通过使式3所示的胺类衍生化合物与式2所示的磺酰卤化物衍生物或乙酰卤化物衍生物,在普通有机溶剂如二氯甲烷存在、并加入适量的二异丙基乙胺的情况下发生反应。此时,反应温度和反应时间随着式2所示的磺酰卤化物衍生物或乙酰卤化物衍生物的化学反应性而变化,优选在室温下反应1-24小时,但并不限于此。
通过上述方法制备式1化合物后,化合物的分子结构通过红外光谱法(IR)、核磁共振谱(NMR)、质谱(Mass)、液相色谱法、X射线结晶法、旋光法,并比较代表性化合物的估算数据与分析数据而进行确认。
此外,本发明提供了一种药物组合物,用于预防或治疗由11β-HSD1酶过度活化引发的疾病,所述药物组合物包含式1所示是化合物或其药学上可接受的盐作为活性成分。
式1所示化合物被证实具有优异的11β-HSD1抑制活性。确切地,所述化合物的IC50,即抑制11β-HSD1活性50%的化合物浓度为0.02-672nM。
因此,由于本发明式1所示化合物具有优异的抑制11β-HSD1的活性,该化合物能够有效地用于预防或治疗由异常活化的11β-HSD1所介导的疾病,诸如非胰岛素依赖型Ⅱ型糖尿病、胰岛素耐受、肥胖、血脂异常、代谢综合征,以及其它由糖皮质激素过度活跃介导的疾病。
含有式1所示化合物或其药学上可接受的盐作为活性成分的本发明的药物组合物,可以通过口服给药或肠道外给药,并且以药物制剂的一般形式使用,但不不限于此。
用于口服给药的制剂的示例为片剂、丸剂、硬/软胶囊剂、溶液剂、混悬剂、乳剂、糖浆剂、颗粒剂等。这些制剂除活性成分以外可以包含稀释剂(例如,乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素和/或甘氨酸)和润滑剂(例如,二氧化硅、滑石、硬脂酸盐及其镁盐或钙盐,和/或聚乙二醇)。片剂可以包含粘结剂比如硅酸镁铝、淀粉糊、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮,如有必要,还可包含崩解剂诸如淀粉、琼脂糖、海藻酸或其钠盐或共沸混合物,和/或吸附剂、着色剂、调味剂和甜味剂也可被包含在其中。
本发明化合物的有效剂量可以根据年龄、体重、性别、给药方法、健康状况和病症严重程度来确定。例如,一个体重70kg的成年人的剂量为0.1-1,000mg/天,优选1-500mg/天。这样的给药可以一天一次至多次,根据医生或者药剂师的决定执行。
本发明实用的且目前优选的实施方式如以下方实施例说明。
然而,应当理解,本领域技术人员考虑本公开后可在本发明的精神和范围内做出修饰和改进。
制备实施例1:1-(氨甲基)-环丙乙酸盐酸盐的制备
将200mg(1.75mmol)的1-氰基-1-环丙乙酸溶解于10ml的甲醇中,并向其中加入40mg(20wt%)氧化铂。将0.3ml的浓盐酸溶液加入其中,并将混合物于氢气流中室温搅拌4小时。反应结束时,过滤混合液去除氧化铂。减压蒸发溶剂,得到256mg的1-(氨甲基)-环丙乙酸盐酸盐(产率为97%)。
1H NMR(400MHz,MeOD)δ3.13(s,2H),1.36-1.38(m,2H),1.16-1.18(m,2H)
制备实施例2:1-(氨甲基)-环丙甲酸甲酯盐酸盐的制备
将273mg(1.8mmol)制备实施例1中制备的1-(氨甲基)-环丙乙酸盐酸盐溶解于6ml的甲醇,并向其中加入0.26ml(3.6mmol)的亚硫酰氯,随后在室温下搅拌3小时。反应结束时,减压蒸发溶剂,得到291mg的1-(氨甲基)-环丙甲酸甲酯盐酸盐(产率为98%)。
1H NMR(400MHz,D2O)δ3.60(s,3H),3.06(s,2H),1.28-1.31(m,2H),0.97-0.99(m,2H)
制备实施例3:1-[(2-氟-苯磺酰胺基)甲基]-环丙甲酸甲酯的制备
将150mg(0.91mmol)制备实施例2中制备的1-(氨甲基)-环丙甲酸甲酯盐酸盐溶解于3ml的二氯甲烷中,并向其中加入0.25ml的TEA,随后在室温下搅拌5分钟。向反应物中加入194mg(1.0mmol)的2-氟磺酰氯,随后在室温下搅拌3小时,然后减压蒸发去除反应溶剂。将残留物溶解于5ml的水中,随后用310ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,并进行减压蒸发,随后通过柱色谱法获得215mg的1-[(2-氟-苯磺酰胺基)甲基]-环丙甲酸甲酯(产率为83%)。
1H NMR(400MHz,CDCl3)δ7.86-7.92(m,1H),7.56-7.60(m,1H),7.20-7.32(m,2H),5.67(d,J=5.2Hz,1H),3.64-3.72(m,3H),3.14-3.21(m,2H),1.17-1.21(m,2H),0.84-0.91(m,2H)
制备实施例4:1-[(2-氟-苯磺酰胺基)甲基]-环丙甲酸的制备
将215mg(0.75mmol)制备实施例3中制备的1-[(2-氟-苯磺酰胺基)甲基]-环丙甲酸甲酯溶解于7.5ml的蒸馏水和THF(1:2)的混合溶剂中,并向其加入94mg(2.25mmol)的一水合氢氧化锂,随后在室温下搅拌16小时。反应结束时,减压蒸发去除反应溶剂,残留物用1N HCl酸化至pH为3,随后用320ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,随后减压蒸发,得到200mg的1-[(2-氟-苯磺酰胺基)甲基]-环丙甲酸(产率为98%)。
1H NMR(400MHz,CDCl3)δ7.85-7.90(m,1H),7.56-7.61(m,1H),6.98-7.31(m,2H),5.90(t,J=6.2Hz,1H),3.15-3.17(m,2H),1.29-1.32(m,2H),0.93-0.97(m,2H)
制备实施例5:1-[(叔丁氧羰基氨基)甲基]环丙乙酸的制备
将256mg(1.69mmol)制备实施例1中制备的1-(氨甲基)-环丙乙酸盐酸盐溶解于3ml的二氯甲烷中,向其中加入0.26ml(1.86mmol)的TEA,随后搅拌10分钟。减压蒸发去除二氯甲烷。将反应物溶解于2ml的1.0N NaOH和6ml的1,4-二噁烷中,然后加入443mg(2.0mmol)的Boc2O。将反应混合液在室温下搅拌16小时后,减压蒸发去除1,4-二噁烷。残留物用1N HCl酸化至pH为3,随后用320ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,随后减压蒸发,得到345mg的1-[(叔丁氧羰基氨基)甲基]环丙乙酸(产率为95%)。
1H NMR(400MHz,MeOD)δ1.51(s,2H),1.43(s,9H),1.13-1.16(m,2H),0.89-0.91(m,2H)
制备实施例6:4-氧代-金刚烷-1-甲酸甲酯的制备
将30%发烟硫酸溶液加热到60℃,在1小时之内缓慢加入1g(6.02mmol)的、溶解于6ml 99%甲酸中的5-羟基-2-金刚烷酮。在1小时之内缓慢加入6ml的99%甲酸后,将混合液在60℃下搅拌1小时。将反应溶液缓慢加入到50ml已冷却至0℃的甲醇中,随后在室温下搅拌2小时。然后,减压蒸发反应溶液。加入15g的冰和50ml的二氯甲 烷,随后用二氯甲烷萃取两次。用盐水洗涤后,萃取液用无水硫酸镁干燥,减压蒸发得到1.09g的4-氧代-金刚烷-1-甲酸甲酯(产率为87%)。
1H NMR(400MHz,CDCl3)δ3.69(s,3H),2.19(m,2H),1.98-2.24(m,11H)
制备实施例7:4-氨基-金刚烷-1-甲酸甲酯的制备
将1.09g(5.234mmol)制备实施例6中制备的4-氧代-金刚烷-1-甲酸甲酯和0.5g的分子筛溶解于9.3ml的甲醇铵(7N)中。混合液在室温下搅拌过夜,然后冷却至0℃。缓慢加入NaBH4,随后在室温下搅拌2小时。过滤去除产生的悬浮物。减压蒸发除去溶剂。将残留物溶解于100ml的二氯甲烷中,随后用10%的柠檬酸酸化。然后,反应物用NaHCO3溶液中和,并用盐水冲洗。反应物用二氯甲烷萃取两次。萃取液用无水硫酸镁干燥,随后减压蒸发,得到800mg的4-氨基-金刚烷-1-甲酸甲酯(产率为73%)。
1H NMR(400MHz,CDCl3)δ3.67(s,3H),3.03(m,1H),1.48-2.02(m,13H)
制备实施例8:叔丁基[(1-(金刚烷-2-基-氨基甲酰基)环丙基)甲基]氨基甲酸酯的制备
将33mg(0.15mmol)制备实施例5中制备的1-[(叔丁氧羰基氨基)甲基]环丙基乙酸和32mg(0.17mmol)的2-金刚烷胺盐酸盐溶解于1.5ml二氯甲烷中,加入44mg(0.17mmol)的BOP-Cl。还加入了0.04ml(0.31mmol)的TEA。将反应混合液在室 温下搅拌16小时,然后减压蒸发去除二氯甲烷。将残留物溶于5ml的水中,用310ml的二氯甲烷萃取。萃取液用无水硫酸镁干燥,并进行减压蒸发,随后通过柱层析法获得34mg的叔丁基[(1-(金刚烷-2-基-氨基甲酰基)环丙基)甲基]氨基甲酸酯(产率为64%)。
1H NMR(400MHz,CDCl3)δ7.02(brs,1H),4.89(s,1H),4.03(d,J=7.2Hz,1H),3.37(d,J=6.8Hz,2H),1.49-2.05(m,14H),1.44(s,9H),1.23-1.26(m,2H).0.60-0.66(m,2H)
制备实施例9:4-[1-(叔丁氧羰基氨基)甲基-环丙基甲酰胺基]-金刚烷-1-甲酸甲酯的制备
将391mg(1.82mmol)制备实施例5中制备的1-[(叔丁氧羰基氨基)甲基]环丙乙酸和492mg(2.00mmol)制备实施例7中制备的4-氨基-金刚烷-1-甲酸甲酯溶解于6.0ml的二氯甲烷中,加入525mg(2.00mmol)的BOP-Cl。还加入了0.5ml(3.64mmol)的TEA。将反应混合液在室温下搅拌16小时,随后减压蒸发去除二氯甲烷。将残留物溶解于10ml的水中,随后用320ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,并进行减压蒸发,随后通过柱层析法得到400mg的4-[1-(叔丁氧羰基氨基)甲基-环丙基甲酰胺基]-金刚烷-1-甲酸甲酯(产率为54%)。
1H NMR(400MHz,CDCl3)δ7.16(brs,1H),4.87(t,J=5.8Hz,1H),4.01(d,J=6.8Hz,1H),3.65(s,3H),3.37(d,J=6.4Hz,2H),1.94-2.05(m,9H),1.89(s,2H),1.54(s,J=12.4Hz,2H),1.42(s,9H),1.25-1.28(m,2H).0.63-0.65(m,2H)
制备实施例10:4-[1-(氨甲基)环丙基羰基氨基]-金刚烷-1-甲酸甲酯盐酸盐的制备
将4.0g(9.8mmol)制备实施例9中制备的4-[1-(叔丁氧羰基氨基)甲基-环丙基甲酰胺基]-金刚烷-1-甲酸甲酯溶解于33ml的乙酸乙酯中,加入25ml的4M 1,4-二噁烷的HCl溶液。将反应混合液在室温下搅拌6小时。反应结束时,低压蒸发去除反应溶剂。将残留物溶解于50ml的醋酸乙烯(ethylene acetate)中,并过滤沉淀析出的固体化合物。由此获得3.2g的4-[1-(氨甲基)环丙基羰基氨基]-金刚烷-1-甲酸甲酯盐酸盐(产率为92%)。
1H NMR(400MHz,MeOD)δ3.90(s,1H),3.64(s,3H),3.08(s,2H),1.90-2.05(m,11H),1.55(s,J=12.4Hz,2H),1.35-1.38(s,2H),1.05-1.11(m,2H)
制备实施例11:4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酸甲酯的制备
将1.0g(3.2mmol)制备实施例10中制备的4-[1-(氨甲基)环丙基羰基氨基]-金刚烷-1-甲酸甲酯盐酸盐溶解于10ml的二氯甲烷中,加入0.8ml的TEA,随后在室温下搅拌5分钟。并在反应混合液中加入624mg(3.2mmol)的2-氟磺酰氯,随后在室温下搅拌6小时。低压蒸发去除反应溶剂。将残留物溶解于20ml的水中,随后用350ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,减压蒸发,随后通过柱层析法得到1.5g的4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酸甲酯(产率为99%)。
1H NMR(400MHz,CDCl3)δ7.90(dt,J=7.6,1.7Hz,1H),7.59-7.64(m,1H),7.32(dt,J=7.6,1.0Hz,1H),7.21-7.24(m,1H),6.53(d,J=7.6Hz,1H),5.28(t,J=6.6Hz,1H),4.05(d,J=7.2Hz,1H),3.66(s,3H),3.12(d,J=6.4Hz,2H),1.91-2.05(m,11H),1.47(d,J=12.0Hz,2H),1.21-1.23(m,2H),0.67-0.70(m,2H)
制备实施例12:4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酸的制备
将1.5g(3.23mmol)制备实施例11中制备的4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酸甲酯溶解于20ml的THF/乙醇混合溶液(1:1)中,向其中加入8.0ml的2N NaOH溶液,随后在室温下搅拌过夜。残留物用1N HCl酸化,随后用乙酸乙酯萃取。萃取液用无水硫酸镁干燥,随后减压蒸发,得到1.44g的4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酸(产率为99%)。
1H NMR(400MHz,MeOD)δ7.89(dt,J=7.4,1.6Hz,1H),7.65-7.70(m,1H),7.46(d,J=7.2Hz,1H),7.31-7.39(m,2H),4.00(d,J=7.6Hz,1H),3.15(s,2H),2.16(d,J=13.2Hz,2H),1.98-2.03(m,7H),1.94(s,2H),1.60(d,J=13.2Hz,2H),1.13-1.16(m,2H),0.69-0.72(m,2H)
实施例1:N-(金刚烷-2-基)-1-[(3-氯-2-甲基苯磺酰胺基)甲基]环丙基甲酰胺的制备
将34mg(0.09mmol)制备实施例8中制备的叔丁基[(1-(金刚烷-2-基-氨基甲酰基)环丙基)甲基]氨基甲酸酯溶解于1.0ml的乙酸乙酯中,向其中加入0.12ml的4M 1,4-二噁烷的HCl溶液,随后在室温下搅拌3小时。反应结束时,减压蒸发去除反应溶剂。将残留物溶解于10ml的醋酸乙烯(ethylene acetate)中,并过滤并干燥沉淀析出的固体化合物。将该固体化合物溶解于2ml的二氯甲烷中,加入0.03ml的TEA,随后在室温下搅拌5分钟。在反应物中加入24mg(0.10mmol)的3-氯-2-甲基苯磺酰氯,然后在室温下搅拌4小时。减压蒸发去除反应溶剂。将残留物溶解于10ml的水中,随后用320ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,并进行减压蒸发,通过柱层析法获得16mg的N-(金刚烷-2-基)-1-[(3-氯-2-甲基苯磺酰胺基)甲基]环丙基甲酰胺(产率为39%)。
1H NMR(400MHz,CDCl3)δ7.90(dd,J=8.0,1.2Hz,1H),7.58(dd,J=8.0,0.8Hz,1H),7.26(t,J=8.0Hz,1H),5.96(d,J=7.6Hz,1H),5.62(t,J=6.2Hz,1H),4.01(d,J=7.6Hz,1H),3.04(d,J=6.0Hz,2H),2.72(s,3H),1.66-1.89(m,14H),1.07-1.09(m,2H),0.86-0.88(m,2H)
实施例2:1-[(2-氟-苯磺酰胺基)甲基]-N-(5-羟基金刚烷-2-基)环丙基甲酰胺的制备
将43mg(0.16mmol)制备实施例4中制备的1-[(2-氟-苯磺酰胺基)甲基]-环丙基甲酸溶解于1.6ml的二氯甲烷中,加入44mg(0.32mmol)的BOP-Cl、29mg(0.17mmol)的4-氨基-金刚烷-1-醇和0.04ml(0.32mmol)的TEA。反应混合物在室温下搅拌4小时,随后通过减压蒸发去除二氯甲烷。将残留物溶解于5ml的水中,随后用310ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,并进行减压蒸发,随后通 过柱层析法获得9mg的1-[(2-氟-苯磺酰胺基)甲基]-N-(5-羟基金刚烷-2-基)环丙基甲酰胺(产率为14%)。
1H NMR(400MHz,CDCl3)δ7.88-7.92(m,1H),7.59-7.64(m,1H),7.21-7.33(m,2H),6.48(d,J=6.8Hz,1H),5.29(t,J=6.4Hz,1H),4.04(t,J=4.0Hz,1H),3.12(s,J=6.4Hz,2H),2.12-2.19(m,3H),1.71-1.89(m,9H),1.53(d,J=12.8Hz,2H),1.21-1.23(m,2H),0.67-0.69(m,2H)
实施例3:E-4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺的制备
将1.44g(3.20mmol)制备实施例12中制备的4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酸溶解于107ml的二氯甲烷中,向其中加入533mg(3.84mmol)的HOBt和736mg(3.84mmol)的EDCI。混合物在室温下搅拌10分钟,然后加入107ml 35%的氨水。混合液在室温下搅拌20小时。反应结束时,用二氯甲烷进行萃取。用盐水洗涤后,将萃取液用无水硫酸镁干燥,随后通过柱层析法得到1.09g的E-4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺(产率为76%)。
1H NMR(400MHz,CDCl3)δ7.88-7.92(m,1H),7.59-7.64(m,1H),7.31-7.33(m,1H),7.24(t,J=8.8Hz,1H),6.61(d,J=7.2Hz,1H),5.61(brs,1H),5.45(t,J=6.6Hz,1H),5.33(brs,1H),4.06(t,J=3.8Hz,1H),3.13(d,J=6.4Hz,2H),1.91-2.09(m,11H),1.63(d,J=12.0Hz,2H),1.22-1.24(m,2H),0.67-0.69(m,2H)
实施例4-实施例37的化合物通过实施例3所述的制备方法制备。
【表1】
制备实施例13:1-氨基环丙乙酸盐酸盐的制备
在降低反应釜中的压力后,用氮气充满反应釜,并装入6.8ml 7N NH3的MeOH溶液。将1.0g((6.30mmol)的1,1-环丙烷二甲酸二甲酯溶解于63ml的MeOH中,也加入到反应釜中。如果起始物质仍有剩余,那么可提供NH3气冒泡15分钟。反应结束时,减压蒸发去除反应溶剂,过滤出沉淀析出的固体化合物,用0℃的甲醇洗涤,随后真空干燥。将获得的反应产物溶解于5ml的7.4%NaOH/H2O中,在40℃下搅拌20分钟。然后,将温度降至室温(反应物A)。将7ml的12.3%NaOCl和2ml的30%NaOH/H2O在室温下一同搅拌1小时(反应物B)。将此反应物A和反应物B混合并在80℃下搅拌4分钟。使其温度降低之后,将4ml的盐酸缓慢加入其中,并注意温度升高不要超过60℃。减压蒸发去除溶剂,并将反应物溶解于乙醇中。过滤出沉淀析出的固体化合物。减压蒸发剩余溶液,然后将其溶解于热丙酮。过滤并干燥生成的固体化合物,得到0.5g的1-氨基环丙乙酸盐酸盐(产率为58%)。
1H NMR(400MHz,D2O)δ1.40-1.43(m,2H),1.22-1.25(m,2H)
制备实施例14:1-(叔丁氧羰基氨基)环丙乙酸的制备
将4.18g(30.37mmol)制备实施例13中制备的1-氨基环丙乙酸盐酸盐溶解于61ml的二氯甲烷中,加入4.7ml(33.40mmol)的TEA。将混合液搅拌10分钟后,减压蒸发去除二氯甲烷。将反应物溶解于36.5ml的1N NaOH溶液和101ml的1,4-二噁烷中,加入8.4ml(36.44mmol)的Boc2O。将反应混合液在室温下搅拌16小时,然后减压蒸发去除1,4-二噁烷。残留物用1N HCl酸化至pH为3,然后用3100ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,随后减压蒸发,得到3.59g的1-(叔丁氧羰基氨基)环丙乙酸(产率为59%)。
1H NMR(400MHz,MeOD)δ1.51(s,2H),1.51(s,9H),1.44(s,4H)
制备实施例15:4-[1-(叔丁氧羰基氨基)-环丙基甲酰胺基]-金刚烷-1-甲酸甲酯的制备
将3.59g(17.85mmol)制备实施例14中制备的1-(叔丁氧羰基氨基)环丙乙酸和4.83g(19.64mmol)制备实施例7中制备的4-氨基-金刚烷-1-甲酸甲酯溶解于60ml的二氯甲烷中,加入5.15g(19.64mmol)的BOP-Cl。4.98ml(35.70mmol)的TEA也加入其中。混合液在室温下搅拌16小时,减压蒸发去除二氯甲烷。将残留物溶解于50ml的水中,随后用3100ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,并进行减压蒸发,随后通过柱层析法获得4.95g的4-[1-(叔丁氧羰基氨基)-环丙基甲酰胺基]-金刚烷-1-甲酸甲酯(产率为71%)。
1H NMR(400MHz,CDCl3)δ7.27(brs,1H),5.10(brs,1H),4.00(d,J=6.8Hz,1H),3.66(s,3H),1.90-2.05(m,9H),1.80(d,J=12.8Hz,2H),1.60(d,J=13.6Hz,2H),1.53-1.56(m,2H),1.47(s,9H).0.98-1.01(m,2H)
制备实施例16:4-(1-氨基环丙基甲酰胺基)-金刚烷-1-甲酸甲酯盐酸盐的制备
将4.95g(14.42mmol)制备实施例15中制备的4-[1-(叔丁氧羰基氨基)-环丙基甲酰胺基]-金刚烷-1-甲酸甲酯溶解于48ml的乙酸乙酯中,加入36ml 4M 1,4-二噁烷的HCl溶液,随后在室温下搅拌6小时。反应结束时,减压蒸发去除反应溶剂。将残留物溶解于50ml的醋酸乙烯,过滤出沉淀析出的固体化合物。由此获得4.1g的4-(1-氨基环丙基甲酰胺基)-金刚烷-1-甲酸甲酯盐酸盐(产率为86%)。
1H NMR(400MHz,D2O)δ3.79(s,1H),3.56(s,3H),3.08(s,2H),1.86-1.95(m,7H),1.71(d,J=13.6Hz,2H),1.40-1.46(m,4H),1.30-1.33(m,2H)
制备实施例17:4-[1-(3-氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酸甲酯的制备
将200mg(0.61mmol)制备实施例16中制备的4-(1-氨基环丙甲酰胺基)-金刚烷-1-甲酸甲酯盐酸盐溶解于2ml的二氯甲烷中,加入0.17ml的TEA,在室温下搅拌5分钟。将142mg(0.67mmol)的2-氯磺酰氯加入反应物中,然后在室温下搅拌6小时。减压蒸发去除反应溶剂。将残留物溶解于10ml的水中,随后用330ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,并进行减压蒸发,随后通过柱层析法得到108g的4-[1-(3-氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酸甲酯(产率为38%)。
1H NMR(400MHz,CDCl3)δ7.85(t,J=1.8Hz,1H),7.75(d,J=7.8Hz,1H),7.60(d,J=8.0Hz,1H),7.49(t,J=8.0Hz,1H),7.18(d,J=7.6Hz,1H),5.44(d,J=10.4Hz,1H),3.98(d,J=7.6Hz,1H),3.66 (s,3H),1.89-2.05(m,10H),1.64(s,1H),1.59(d,J=10.4Hz,2H),1.44-1.48(m,2H),0.82-0.85(m,2H)
制备实施例18:4-[1-(3-氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酸的制备
将100mg(0.21mmol)制备实施例17中制备的4-[1-(3-氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酸甲酯溶解于1.5ml的THF/乙醇混合溶液中,加入1.5ml的2N NaOH溶液,随后在室温下搅拌过夜。残留物用1N HCl酸化,随后用乙酸乙酯萃取。萃取液用无水硫酸镁干燥,随后减压蒸发后,得到96mg的4-[1-(3-氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酸(产率为98%)。
1H NMR(400MHz,MeOD)δ8.98(s,1H),7.72-7.78(m,3H),7.62-7.66(m,1H),7.14(d,J=7.6Hz,1H),3.61(d,J=6.8Hz,1H),1.75-2.01(m,11H),1.47(d,J=12.8Hz,2H),1.16-1.19(m,2H),0.88-0.91(m,11H)
实施例38:E-4-[1-(3-氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺的制备
将96mg(0.21mmol)制备实施例18中制备的4-[1-(3-氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酸溶解于1ml的乙腈,加入34mg (0.25mmol)的HOBt、48mg(0.25mmol)的EDCI和60ml(0.42mmol)的TEA。混合液在室温下搅拌10分钟,加入13mg(0.25mmol)的氯化铵,随后在室温下搅拌20小时。反应结束时,减压蒸发去除反应溶剂,并将反应物溶解于60ml的二氯甲烷中。有机层用1N HCl(2×2ml)洗涤后用盐水再次洗涤。反应产物用无水硫酸镁干燥,随后通过柱层析法获得41mg的E-4-[1-(3-氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺(产率为43%)。
1H NMR(400MHz,CDCl3)δ7.84(t,J=2.0Hz,1H),7.75(dt,J=7.2,1.2Hz,1H),7.59(m,1H),7.49(t,J=8.0Hz,1H),7.22(d,J=8.0Hz,1H),5.75(s,1H),5.62(brs,1H),5.35(brs,1H),3.99(t,J=7.6Hz,1H),2.08(s,3H),1.92-1.99(m,8H),1.63(d,J=12.8Hz,2H),1.45-1.48(m,2H),0.82-0.85(m,2H)
实施例39-实施例66的化合物通过实施例38所述的制备方法制备。
【表2】
制备实施例19:3-叠氮基-2,2-二甲基丙酸的制备
将1g(7.32mmol)的3-氯-2,2-二甲基丙酸溶解于15.0ml的水中,加入4.8g(73.22mmol)的NaN3,随后高温回流搅拌18小时。反应混合液用浓HCl酸化至pH为3,随后用320ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,随后减压蒸发,得到1g的3-叠氮基-2,2-二甲基丙酸(产率为95%)。
1H NMR(400MHz,CDCl3)δ3.48(s,2H),1.31(s,6H)
制备实施例20:3-氨基-2,2-二甲基丙酸的制备
将1g(6.99mmol)制备实施例19中制备的3-叠氮基-2,2-二甲基丙酸溶解于100ml的MeOH中,加入695mg的10%Pd/C,在氢气存在下搅拌3小时。向反应混合液中加入100ml的水,搅拌30分钟。混合液过硅藻土过滤,所得的溶液进行减压蒸发,得到753mg的3-氨基-2,2-二甲基丙酸(产率为92%)。
1H NMR(400MHz,DMSO)δ2.65(s,2H),1.30(s,2H),1.01(s,6H)
制备实施例21:3-(叔丁氧羰基氨基)-2,2-二甲基丙酸的制备
将256mg(2.22mmol)制备实施例20中制备的3-氨基-2,2-二甲基丙酸溶解于2.0ml的水和3.0ml的t-BuOH中,加入4.0ml的1.0N NaOH溶液和725mg(3.32mmol)的Boc2O。混合液在室温下搅拌16小时,随后减压蒸发去除溶剂。残留物用1N HCl酸化至pH为3,随后用320ml的乙酸乙酯萃取。萃取物用无水硫酸镁干燥,随后减压蒸发,得到305mg的3-(叔丁氧羰基氨基)-2,2-二甲基丙酸(产率为63%)。
1H NMR(400MHz,CDCl3)δ3.25(s,2H),1.44(s,9H),1.18(s,6H)
制备实施例22:4-(3-(叔丁氧羰基)氨基)-2,2-二甲基丙酰胺基)金刚烷-1-甲酸甲酯的制备
将305mg(1.40mmol)制备实施例21中制备的3-(叔丁氧羰基氨基)-2,2-二甲基丙酸和379mg(1.54mmol)制备实施例7中制备的4-氨基-金刚烷-1-甲酸甲酯溶解于5.0ml的二氯甲烷中,加入323mg(1.38mmol)的EDCI和227mg(1.68mmol)的HOBt。还加入0.6ml(4.21mmol)的TEA。反应混合液在室温下搅拌16小时,随后减压蒸发去除二氯甲烷。将残留物溶解于10ml的水中,随后用320ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,并进行减压蒸发,随后通过柱层析法获得466mg的4-(3-(叔丁氧羰基)氨基)-2,2-二甲基丙酰胺基)金刚烷-1-甲酸甲酯(产率为95%)。
1H NMR(400MHz,CDCl3)δ6.11(brs,1H),5.12(brs,1H),3.98(m,1H),3.67(s,3H),3.24(d,J=6.4Hz,1H),2.05-1.74(m,10H),1.63(s,3H),1.43(s,9H),1.21(s,6H)
制备实施例23:4-(3-氨基-2,2-二甲基丙酰胺基)金刚烷-1-甲酸甲酯盐酸盐的制备
将466mg(1.33mmol)制备实施例22中制备的4-(3-(叔丁氧羰基)氨基)-2,2-二甲基丙酰胺基)金刚烷-1-甲酸甲酯溶解于6ml的乙酸乙酯中,加入3.32ml 4M 1,4-二噁烷的HCl溶液,随后在室温下搅拌16小 时。反应结束时,减压蒸发去除反应溶剂,得到422mg的4-(3-氨基-2,2-二甲基丙酰胺基)金刚烷-1-甲酸甲酯盐酸盐(产率为92%)。
1H NMR(400MHz,CDCl3)δ8.73(brs,2H),5.98(m,1H),3.96(m,1H),3.72(s,2H),3.66(s,3H),2.04-1.91(m,9H),1.66(s,4H),1.39(s,6H)
制备实施例24:4-(3-(3-氯-苯磺酰胺基)-2,2-二甲基丙酰胺基)金刚烷-1-甲酸甲酯的制备
将80mg(0.23mmol)制备实施例23中制备的4-(3-氨基-2,2-二甲基丙酰胺基)金刚烷-1-甲酸甲酯盐酸盐溶解于1ml的二氯甲烷中,加入0.1ml的TEA,随后在室温下搅拌5分钟。将59mg(0.28mmol)的3-氯磺酰氯加入反应物中,随后在室温下搅拌16小时。减压蒸发去除反应溶剂。残留物溶解于20ml的水中,随后用350ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,并进行减压蒸发,随后通过柱层析法获得101g的4-(3-(3-氯-苯磺酰胺基)-2,2-二甲基丙酰胺基)金刚烷-1-甲酸甲酯(产率为91%)。
1H NMR(400MHz,CDCl3)δ7.83(s,1H),7.72(d,J=7.6Hz,1H),7.53(d,J=8.4Hz,1H),7.45(t,J=8.0Hz,1H),5.88(m,1H),5.57(t,J=6.4Hz,1H),3.92(m,1H),3.66(s,3H),2.95(d,J=6.4Hz,2H),1.99(s,8H),1.85(s,2H),1.65(m,3H),1.26(s,6H)
制备实施例25:4-(3-(3-氯-苯磺酰胺基)-2,2-二甲基丙酰胺基)金刚烷-1-甲酸的制备
将100mg(0.21mmol)制备实施例24中制备的4-(3-(3-氯-苯磺酰胺基)-2,2-二甲基丙酰胺基)金刚烷-1-甲酸甲酯溶解于1.0ml的THF/乙醇混合液(1∶1)中,加入1.0ml的2N NaOH溶液,随后在室温下搅拌过夜。反应物用1N HCl酸化,随后用乙酸乙酯萃取。萃取液用无水硫酸镁干燥,随后减压蒸发,得到98mg的4-(3-(3-氯-苯磺酰胺基)-2,2-二甲基丙酰胺基)金刚烷-1-甲酸(产率为99%)。
1H NMR(400MHz,CDCl3)δ7.85(t,J=1.6Hz,1H),7.73(m,1H),7.54(m,1H),7.43(m,1H),6.00(m,2H),3.92(d,J=6.8Hz,1H),2.95(d,J=6.0Hz,1H),2.00(s,7H),1.93(s,2H),1.66(m,4H),1.26(s,6H)
实施例67:E-4-(3-(3-氯-苯磺酰胺基)-2,2-二甲基丙酰胺基)金刚烷-1-甲酰胺的制备
将98mg(0.21mmol)制备实施例25中制备的4-(3-(3-氯-苯磺酰胺基)-2,2-二甲基丙酰胺基)金刚烷-1-甲酸溶解于1.0ml的二氯甲烷中,加入44mg(0.23mmol)的HOBt和31mg(0.23mmol)的EDCI。混合液在室温下搅拌10分钟,然后向其中加入1.0ml 35%的氨水。混合液在室温下搅拌20小时。反应结束时,用二氯甲烷进行萃取。萃取液用盐水洗涤后过无水硫酸镁干燥,随后通过柱层析法获得20.7mg的4-(3-(3-氯-苯磺酰胺基)-2,2-二甲基丙酰胺基)金刚烷-1-甲酰胺(产率为21%)。
1H NMR(400MHz,CDCl3)δ7.84(s,1H),7.73(d,J=7.6Hz,1H),7.55(d,J=9.2Hz,1H),7.45(m,1H),5.96(d,J=7.2Hz,1H),5.80(m,1H),5.68(s,1H),3.95(s,1H),2.95(d,J=6.4Hz,1H),1.62-2.04(m,11H),1.26(s,6H)
实施例68-实施例70的化合物通过实施例67所述的制备方法制备。
【表3】
制备实施例26:2-(叔丁氧羰基氨基)-2-甲基丙酸的制备
将200mg(1.94mmol)的2-氨基-2-甲基丙酸溶解于8.0ml的1.0N NaOH溶液和8.0ml的1,4-二噁烷溶液中,加入846mg(3.88 mmol)的Boc2O。混合液在室温下搅拌16小时,然后减压蒸发去除1,4-二噁烷。残留物用1N HCl酸化至pH为3,随后用320ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,随后减压蒸发,得到315mg的2-(叔丁氧羰基氨基)-2-甲基丙酸(产率为80%)。
1H NMR(400MHz,CDCl3)δ5.07(brs,1H),1.54(s,6H),1.45(s,9H)
制备实施例27:4-(2-((叔丁氧羰基)氨基)-2-甲基丙酰胺基)金刚烷-1-甲酸甲酯的制备
将380mg(1.87mmol)制备实施例26中制备的2-(叔丁氧羰基氨基)-2-甲基丙酸和505mg(2.06mmol)制备实施例7中制备的4-氨基-金刚烷-1-甲酸甲酯溶解于10.0ml的二氯甲烷中,加入430mg(2.24mmol)的EDCI和303mg(2.24mmol)的HOBt。此外,还加入了0.8ml(5.61mmol)的TEA。反应混合液在室温下搅拌16小时,减压蒸发去除二氯甲烷。将残留物溶解于10ml的水,用320ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,并进行减压蒸发,通过柱层析法获得580mg的4-(2-((叔丁氧羰基)氨基)-2-甲基丙酰胺基)金刚烷-1-甲酸甲酯(产率为92%)。
1H NMR(400MHz,CDCl3)δ5.30(s,1H),4.84(brs,1H),3.98(brs,1H),3.66(s,3H),2.02-1.44(m,28H)
制备实施例28:4-(2-氨基-2-甲基丙酰胺基)金刚烷-1-甲酸甲酯盐酸盐的制备
将580mg(1.72mmol)制备实施例27中制备的4-(2-((叔丁氧羰基)氨基)-2-甲基丙酰胺基)金刚烷-1-甲酸甲酯溶解于6ml的乙酸乙酯中,加入4.31ml的4M 1,4-二噁烷盐酸溶液。混合液在室温下搅拌16小时。反应结束时,减压蒸发去除反应溶剂后得到495mg的4-(2-氨基-2-甲基丙酰胺基)金刚烷-1-甲酸甲酯盐酸盐(产率为87%)。
1H NMR(400MHz,CDCl3)δ8.80(brs,2H),6.48(brs,1H),4.01(brs,1H),3.66(s,3H),2.09-1.60(m,19H)
制备实施例29:4-[2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺基]-金刚烷-1-甲酸甲酯的制备
将100mg(0.3mmol)制备实施例28中制备的4-(2-氨基-2-甲基丙酰胺基)金刚烷-1-甲酸甲酯盐酸盐溶解于1ml的二氯甲烷中,加入0.13ml的TEA,随后在室温下搅拌5分钟。将70mg(0.36mmol)的3-氯磺酰氯加入反应物中,随后在室温下搅拌16小时。减压蒸发去除反应溶剂。将残留物溶解于20ml的水中,用350ml的乙酸乙酯萃取。萃取液用无水硫酸镁过滤,并进行减压蒸发,随后通过柱层析法获得107g的4-[2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺基]-金刚烷-1-甲酸甲酯(产率为78%)。
1H NMR(400MHz,CDCl3)δ7.89(td,J1=1.6Hz,J2=6.0Hz,1H),7.60(m,1H),7.28(m,2H),7.00(d,J=9.2Hz,1H),3.97(m,1H), 3.66(s,3H),2.03(m,7H),1.88(m,4H),1.62(d,J=13.2Hz,2H),1.39(s,6H)
制备实施例30:4-[2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺基]-金刚烷-1-甲酸的制备
将105mg(0.23mmol)制备实施例29中制备的4-[2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺基]-金刚烷-1-甲酸甲酯溶解于1.0ml的THF/乙醇混合溶液(1:1)中,加入1.0ml的2N NaOH溶液,随后在室温下搅拌过夜。反应物用1N HCl酸化,随后用乙酸乙酯萃取。萃取液用无水硫酸镁干燥,随后减压蒸发,得到100mg的4-[2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺基]-金刚烷-1-甲酸(产率为99%)。
1H NMR(400MHz,CDCl3)δ7.89(td,J1=2.0Hz,J2=6.0Hz,1H),7.60(m,1H),7.28(m,2H),7.03(d,J=8.0Hz,1H),3.98(d,J=8.0Hz,1H),2.05(m,7H),1.95(s,2H),1.88(d,J=12.8Hz,2H),1.45(d,J=12.0Hz,2H),1.39(s,6H)
实施例71:E-4-[2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺基]-金刚烷-1-甲酰胺的制备
将100mg(0.23mmol)制备实施例30中制备的4-[2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺基]-金刚烷-1-甲酸溶解于7.0ml的二氯甲烷中,加入34mg(0.25mmol)的HOBt和48mg(0.25mmol)的EDCI。 混合液在室温下搅拌10分钟,然后向其中加入7.0ml 35%的氨水。混合液在室温下搅拌20小时。反应结束时,用二氯甲烷进行萃取。萃取液用盐水洗涤后过无水硫酸镁干燥,随后通过柱层析法获得15mg的4-[2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺基]-金刚烷-1-甲酰胺(产率为15%)。
1H NMR(400MHz,CDCl3)δ7.89(td,J1=1.6Hz,J2=6.0Hz,1H),7.61(m,1H),7.36(d,J=4.8Hz,1H),7.30(m,1H),7.24(m,1H),7.03(d,J=7.6Hz,1H),5.57(brs,1H),3.97(d,J=7.6Hz,1H),2.09(s,3H),2.00(m,4H),1.89(m,4H),1.63(d,J=12.4Hz,2H),1.39(s,6H)
实施例72-实施例90的化合物通过实施例71所述的制备方法制备。
【表4】
制备实施例31:4-(3-硝基-苯甲酰胺基)-金刚烷-1-甲酸甲酯的制备
将33mg(0.2mmol)的3-硝基苯甲酸和50mg(0.2mmol)的4-氨基-金刚烷-1-甲酸甲酯溶解于5.0ml的二氯甲烷中,加入60mg(0.3mmol)的EDC和140mg(0.3mmol)的HOBt。还加入了0.3ml的TEA。反应混合液在室温下搅拌12小时,随后减压蒸发去除二氯甲烷。将残留物溶解于10ml的水中,用320ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,并进行减压蒸发,随后通过柱层析法获得70mg的4-(3-硝基-苯甲酰胺基)-金刚烷-1-甲酸甲酯(产率为97%)。
1H NMR(400MHz,CDCl3)δ8.56(s,1H),8.37-8.35(m,1H),8.16-8.14(m,1H)7.66(t,J=8.0Hz,1H),6.46(d,J=4.0Hz,1H),4.27-4.26(m,1H),3.96(s,3H),2.21(s,2H),2.12-2.03(m,5H),1.96(s,2H),1.89-1.85(m,2H),1.68-1.66(m,2H)。
制备实施例32:4-(3-氨基-苯甲酰胺基)-金刚烷-1-甲酸甲酯的制备
将30mg(0.08mmol)制备实施例31中制备的4-(3-硝基-苯甲酰胺基)-金刚烷-1-甲酸甲酯溶解于10ml的甲醇中,加入3mg的Pd/C。混合液在氢气存在下于室温下搅拌12小时,然后过滤。减压蒸发去除甲醇。所得的化合物不进行纯化就继续下一个反应。
1H NMR(400MHz,CDCl3)δ7.40(t,J=4.0Hz,1H),7.15(s,1H),7.09-7.07(m,2H),6.84-6.81(m,1H),6.36-6.35(m,1H),4.24(s,1H),3.70(s,1H),2.18-1.85(m,9H),1.88-1.85(m,2H)1.69-1.61(m,2H)。
制备实施例33:4-[3-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酸甲酯的制备
将30mg(0.09mmol)制备实施例32中制备的4-(3-氨基-苯甲酰胺基)-金刚烷-1-甲酸甲酯溶解于5.0ml的二氯甲烷中,加入14mg(0.18mmol)的吡啶。还加入20mg(0.11mmol)的2-氟-苯磺酰氯。混合液在室温下搅拌12小时,随后减压蒸发去除二氯甲烷。将残留物溶解于10ml的水,随后用320ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,并进行减压蒸发,随后通过柱层析法获得30mg的4-[3-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酸甲酯(产率为70%)。
1H NMR(400MHz,CDCl3)δ7.85(s,1H),7.60-7.46(m,3H),7.22-7.09(m,2H)7.01(s,1H),6.33-6.28(m,2H),4.19(s,1H),3.68(s,3H),2.14-1.93(m 9H),1.78-1.65(m,4H)。
制备实施例34:4-[3-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酸的制备
将30mg(0.06mmol)制备实施例33中制备的4-[3-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酸甲酯溶解于1.0ml的甲醇和1.0ml的水中,加入24mg(0.6mmol)的氢氧化钠。混合液在室温下搅拌12小时,随后减压蒸发除去甲醇。残留物用1N HCl酸化,随后用320ml的氯仿萃取。萃取液用无水硫酸镁干燥,随后减压蒸发。所得的化合物不进行纯化继续下一个反应。
1H NMR(400MHz,CDCl3)δ7.85-7.80(m,1H),7.60(s,1H),7.50-7.45(m,1H)7.35-7.21(m,4H),7.11(s,1H),6.30(d,J=4.0Hz,1H),4.20(s,1H),2.20-2.00(m 9H),1.89-1.82(m,2H),1.72-1.69(m,2H)。
实施例91:E-4-[3-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺的制备
将15mg(0.03mmol)制备实施例34中制备的4-[3-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酸溶解于5.0ml的二氯甲烷中,加入9mg(0.045mmol)的EDC和6mg(0.045mmol)的HOBt。然后,还加入氨水。混合液在室温下搅拌12小时,随后减压蒸发去除二氯甲烷。将残留物溶解于10ml的水中,随后用320ml的二氯甲烷萃取。萃取液用无水硫酸镁干燥,并进行减压蒸发,随后通过柱层析法获得6mg的4-[3-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺(产率为43%)。
1H NMR(400MHz,CDCl3)δ8.53(s,1H),7.89-7.80(m,2H),7.50(s,1H)7.46-7.32(m,2H),7.28-7.12(m,3H),6.42(s,1H),5.75(s,1H),5.30(s,1H),4.12(s,1H),2.17-1.94(m,9H),1.84-1.81(m,2H),1.69-1.66(m,2H).
实施例92-实施例139的化合物通过实施例91所述的制备方法制备。
【表5】
制备实施例35:4-[(1-[3,4-二氢-1H-异喹啉-2-羰基)-氨基]-甲基-环丙基羰基)-氨基]-金刚烷-1-甲酸甲酯的制备
将30mg(0.1mmol)4-[(1-氨甲基-环丙基羰基-氨基]-金刚烷-1-甲酸甲酯溶解于1.0ml的氯仿中,加入16mg(0.1mmol)的碳化二亚胺和TEA。然后,也加入14mg(0.1mmol)的1,2,3,4-四氢异喹啉。混合液回流搅拌12小时,随后减压蒸发去除氯仿。将残留物溶解于10ml 的水,随后用320ml的乙酸乙酯萃取。萃取液用无水硫酸镁干燥,并进行减压蒸发,随后通过柱层析法获得30mg的4-[(1-[3,4二氢-1H-异喹啉-2-羰基)-氨基]-甲基-环丙基羰基)-氨基]-金刚烷-1-甲酸甲酯(产率为65%)。
1H NMR(400MHz,CDCl3)δ7.63(d,J=7.2Hz,1H),7.29-7.10(m,4H),4.94-4.91(m,1H),4.55(s,2H),4.00-3.82(m,1H),3.65(s,3H),3.62-3.53(m,4H),2.87(t,J=6.4Hz,2H),2.19-1.74(m,11H),1.48-1.42(m,2H),0.90-0.87(m,2H),0.71-0.68(m,2H).
制备实施例36:4-[(1-[3,4-二氢-1H-异喹啉-2-羰基)-氨基]-甲基-环丙基羰基)-氨基]-金刚烷-1-甲酸的制备
将25mg(0.05mmol)制备实施例35中制备的4-[(1-[3,4二氢-1H-异喹啉-2-羰基)-氨基]-甲基-环丙基羰基)-氨基]-金刚烷-1-甲酸甲酯溶解于1.0ml的甲醇和1.0ml的水中,加入20mg(0.5mmol)的氢氧化钠。混合液在室温下搅拌12小时,随后减压蒸发去除甲醇。残留物用1N HCl酸化,随后用320ml的氯仿萃取。萃取液用无水硫酸镁干燥,随后进行减压蒸发。所得化合物不进行纯化继续下一个反应。
实施例140:E-[3,4二氢-1H-异喹啉-2-甲酸-1-[(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)环丙基甲基]-酰胺的制备
将15mg(0.03mmol)制备实施例36中制备的4-[(1-[3,4二氢-1H-异喹啉-2-羰基)-氨基]-甲基-环丙基羰基)-氨基]-金刚烷-1-甲酸溶解于5.0ml的二氯甲烷中,加入11mg(0.06mmol)的EDC和8mg(0.06mmol)的HOBt,然后加入氨水。混合液在室温下搅拌12小时,随后减压蒸发去除二氯甲烷。将残留物溶解于10ml的水中,随后用320ml的二氯甲烷萃取。萃取液用无水硫酸镁干燥,并进行减压蒸发,随后通过柱层析法获得7mg的[3,4二氢-1H-异喹啉-2-甲酸-1-[(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)环丙基甲基]-酰胺(产率为50%)。
1H NMR(400MHz,CDCl3)δ7.73(d,J=7.2Hz,1H),7.22-7.11(m,4H),5.63(brs,1H),5.41(brs,1H),4.97(t,J=7.2Hz,1H),4.55(s,1H),4.13-4.11(m,1H),3.64(t,J=6.4Hz,1H),3.55(d,J=5.2Hz,2H),2.87(t,J=6.4Hz,1H),2.05-1.86(m,1H),1.48-1.45(m,2H).1.31-1.20(m,2H),0.71-0.68(m,2H).
实施例141-实施例149的化合物通过实施例140所述的制备方法制备。
【表6】
实验实施例1:11β-HSD1抑制效果的检验
为研究本发明实施例中制备的化合物的11β-HSD1抑制活性,进行了以下实验。
采用HTRF试验(62CO2PEB,Cisbio)测量源自微粒体片段的11β-HSD1的抑制活性。将不同浓度的化合物加到96孔板上,随后加入含有200μM NADPH(N1630,Sigma)和160nM皮质酮(C2755,Sigma)的TE缓冲液(20mM Tris缓冲液和5mM EDTA,pH 6.0)。这些反应通过加入人微粒体片段(M0317,Sigma)而起始,并在37℃温育2h。然后将铕(Eu3+)穴状化合物和XL665-共轭皮质醇加到每个孔中,并在室温下再温育2h。使用校正曲线计算皮质醇的浓度。使用GraphPad Prism软件从剂量响应曲线中计算IC50值。从而获得实施例化合物对11β-HSD1的IC50值。结果如表7所示。
【表7】
实施例 | 人IC50(nM) | 实施例 | 人IC50(nM) |
1 | 14.2 | 2 | 26.6 |
3 | 6.2 | 4 | - |
5 | 2.7 | 6 | - |
7 | 2.6 | 8 | 0.3 |
9 | 608.0 | 10 | 2.5 |
11 | 10.4 | 12 | 9.5 |
13 | 2.8 | 14 | 13.3 |
15 | 28.0 | 16 | 5.0 |
17 | 132.0 | 18 | 23.9 |
19 | 17.8 | 20 | 102.0 |
21 | 30.8 | 22 | 0.02 |
23 | - | 24 | 156.0 |
25 | 9.6 | 26 | 1.3 |
27 | - | 28 | 1.3 |
29 | - | 30 | - |
31 | 1.2 | 32 | 1.4 |
33 | 1.5 | 34 | 28.9 |
35 | - | 36 | 73.0 |
37 | 17.1 | - | - |
38 | 6.7 | 39 | 24.7 |
40 | 1.7 | 41 | 10.0 |
42 | 6.4 | 43 | 29.7 |
44 | 79.1 | 45 | 32.5 |
46 | 34.7 | 47 | 495.0 |
48 | 62.8 | 49 | - |
50 | 0.4 | 51 | - |
52 | - | 53 | - |
54 | - | 55 | - |
56 | 8.3 | 57 | 9.3 |
58 | 17.3 | 59 | 11.2 |
60 | 12.6 | 61 | 2.8 |
62 | 0.12 | 63 | 672.0 |
64 | 111.0 | 65 | - |
66 | - | 67 | 7.1 |
68 | 8.9 | 69 | 28.6 |
70 | 6.2 | 71 | 0.6 |
72 | 1.2 | 73 | 0.83 |
74 | 2.6 | 75 | 54.6 |
76 | 2.4 | 77 | - |
78 | - | 79 | - |
80 | 14.8 | 81 | 2.1 |
82 | - | 83 | 9.9 |
84 | 0.36 | 85 | - |
86 | - | 87 | - |
88 | 33.8 | 89 | - |
90 | - | - | - |
91 | - | 92 | 148.0 |
93 | - | 94 | 75.7 |
95 | 13.1 | 96 | 15.4 |
97 | 15.6 | 98 | 58.6 |
99 | 1.9 | 100 | 15.3 |
101 | - | 102 | 1.1 |
103 | 23.8 | 104 | - |
105 | 42.7 | 106 | 4.8 |
107 | 60.3 | 108 | 51.2 |
109 | - | 110 | - |
111 | - | 112 | - |
113 | 2.7 | 114 | 30.7 |
115 | 19.1 | 116 | 14.5 |
117 | 5.0 | 118 | 20.4 |
119 | 0.9 | 120 | 27.2 |
121 | 7.8 | 122 | 15.1 |
123 | 12.8 | 124 | - |
125 | 11.6 | 126 | 67.5 |
127 | 78.3 | 128 | - |
129 | 41.8 | 130 | - |
131 | - | 132 | 148.0 |
133 | 14.8 | 134 | - |
135 | - | 136 | - |
137 | - | 138 | 62.1 |
139 | - | 140 | 97.8 |
141 | 52.5 | 142 | - |
143 | - | 144 | - |
145 | - | 146 | 128.0 |
147 | - | 148 | - |
149 | - | - | - |
如表7所示,实施例化合物对11β-HSD1的IC50值为0.02-672.0nM,这表明化合物具有显著的11β-HSD1抑制活性。特别是,实施例8、22、50、62、71、73、84和119制备的那些化合物的IC50全部小于1.0nM,这表明它们具有优异的11β-HSD1抑制活性。
因此,本发明式1所示化合物可以有效地用于预防和治疗由11β-HSD1异常活化所引起的疾病,诸如非胰岛素依赖型II型糖尿病、胰岛 素耐受、肥胖、血脂异常、代谢综合征,以及其它由糖皮质激素过度活跃所介导的疾病。
实验实施例2:KKAy小鼠模型中对降血糖作用的体内研究
对本发明实施例中制备的、并显现出优异的11β-HSD1活性的化合物的血糖抑制作用进行体内研究。
<2-1>体内研究
将Ay基因引入KK小鼠以诱导严重的肥胖和高血糖。由此制备的雄性KKAy小鼠(9周大,DaehanBioLink,韩国)具有严重的肥胖和高血糖,以50mg/kg和100mg/kg的浓度向其口服施用实施例3、22、71、
84、113和119制备的化合物。空腹4小时之后,测量血糖和胰岛素水平。此检测持续3周。
<2-2>降血糖作用
以100mg/kg的浓度,向KKAy小鼠口服施用实施例3、22、71和113制备的化合物,施用3周。此后,测量空腹后的血糖。结果,在用实施例3化合物治疗的组中,其降血糖作用为约9%。在用实施例22化合物治疗的组中,血糖水平降低了约32%。在用实施例71和113化合物治疗的组中,降血糖作用分别为27%和28%。
在用浓度为50mg/kg的实施例84化合物治疗的组中,降血糖作用为约19%。在用浓度为50mg/kg的实施例119化合物治疗的组中,降血作用为约47%。结果如表8所示。
【表8】
<2-3>降血浆胰岛素作用
以100mg/kg的浓度,向KKAy小鼠口服施用实施例22、71和113制备的化合物,施用3周。此后,测量空腹后血浆胰岛素的水平。结果,在用实施例22化合物治疗的组中,降血浆胰岛素作用为约53%。在用实施例71和113化合物治疗的组中,降血浆胰岛素作用分别为40%和60%。
在用浓度为50mg/kg的实施例84化合物治疗的组中,降血浆胰岛素作用为43%。在用浓度为50mg/kg的实施例119化合物治疗的组中,降血浆胰岛素作用为52%。结果如表9所示。
【表9】
如表8和表9中所示,当以100mg/kg或50mg/kg浓度,用实施例3、22、71、84、113和119制备的化合物治疗KKAy小鼠时,血糖和血浆胰岛素的水平显著降低。这些结果表明这些化合物具有优异的抗糖尿病作用。
因此,本发明式1所示化合物可以有效滴用于预防和治疗由11β-HSD1异常活化引起的疾病,诸如非胰岛素依赖型II型糖尿病、胰岛素耐受、肥胖、血脂异常、代谢综合征,以及其它由糖皮质激素过度活跃所介导的疾病。
本发明式1所示化合物可以根据使用目的制成多种形式。以下是包含本发明式1化合物作为活性成分的制剂的实施例,但这些并不能将本发明限制于此。
制造实施例1:散剂的制备
式1化合物 2g
乳糖 1g
散剂是通过将所有以上成分混合,并根据制备散剂的常规方法将其装入密封袋中而制得。
制造实施例2:片剂的制备
片剂是通过制备片剂的常规方法将所有以上成分混合而制得。
制造实施例3:胶囊剂的制备
胶囊剂是通过将所有以上成分混合,并按照制备胶囊剂的常规方法将其装入明胶胶囊中而制得。
制造实施例4:注射液的制备
注射液是通过制备注射液的常规方法将所有以上成分混合后而制得。
工业应用
由于本发明化合物选择性地抑制11β-HSD1(11β- 羟基类固醇脱氢酶1型)的活性,因此,本发明的化合物可以有效地用作治疗由11β-HSD1的过度活化引起的疾病的一种治疗剂,诸如非胰岛素依赖型II型糖尿病、胰岛素耐受、肥胖、血脂异常、代谢综合征,以及其它由糖皮质激素过度活跃介导的疾病。
Claims (16)
1.一种具有抑制11β-HSD1酶活性的式1所示化合物或其药学上可接受的盐:
[式1]
(在式1中,
X为羰基或磺酰基;
R1为C1-4直链或支链烷基、C3-7环烷基、C5-12芳基、C5-12芳基胺、5-8元单环或8-12元二环杂环烷基、或5-8元单环或8-12元二环杂芳基;
R2和R3独立地为氢、C1-4直链或支链烷基、C5-8环烷基、C5-8二环烷基、C5-8芳基、1-金刚烷基或2-金刚烷基,其中,所述1-金刚烷基或2-金刚烷基是未被取代的或被选自羟基、氨基、醛基、羟基C1-4直链或直链的烷基、羟基羰基、氨基羰基、N-羟氨羰基、腈基、羟基羰基C1-4直链或支链烷基、氨基羰基C1-4直链或支链烷基、 的一个或多个取代基所取代;
R4为氢、C1-4直链或支链烷基、羟基C1-4直链或支链烷基或钠;
A为 其中Y是未被取代的或卤素;
其中,所述R1-R3、芳基是未被取代的或被选自羟基、卤素、氨基、C1-4直链或支链烷基、C1-4直链或支链卤代烷基、C1-4直链或支链卤代烷氧基、C1-4直链或支链烷氧基、-O-Z1-NZ2Z3、-O-NZ2Z3和-Z1-NZ2Z3的一个或多个取代基所取代,其中所述Z1为C1-4直链或支链烷基,并且所述Z2和Z3各自独立地为氢或C1-4直链或支链烷基;
其中,所述R1-R3、杂环烷基或杂芳基是含有一个或多个选自氧、氮和硫的杂原子的单环或二环,其中杂环烷基或杂芳基是未被取代的或被选自三氟C1-4直链或支链烷基、嘧啶基、C1-4直链或支链烷基和C1-4直链或支链烷氧羰基的一个或多个取代基所取代,并且所述杂环烷基也可以是与C5-12芳基或杂芳基稠合成的二环,所述杂环芳基也可以是与C3-7环烷基或杂环烷基稠合成的二环;
其中,R1和R4可与连接在R1和R4上的X和N形成5-8元单环或8-12元二环杂环烷基;
其中,R4可与连接在R4上的N和A形成5-8元单环杂环烷基)。
2.根据权利要求1所述的化合物,
X为羰基或磺酰基;
R1为C1-4直链或支链烷基、C3-7环烷基、C5-6芳基、C5-6芳基胺、5-6元单环或9-10元二环杂环烷基、或5-6元单环的或9-10元二环杂芳基;
R2和R3独立地为氢、甲基、乙基、丙基、C6-7环烷基、C6-8二环烷基、C5-6芳基、1-金刚烷基或2-金刚烷基,其中所述1-金刚烷基或2-金刚烷基是未被取代的或被选自羟基、氨基、醛基、羟甲基、羟乙基、羟基羰基、氨基羰基、N-羟氨羰基、腈基、羟基羰基甲基、羟基羰基乙基、氨基羰基甲基、氨基羰基乙基、中的一个或多个取代基所取代;
R4为氢、甲基、乙基、丙基、羟甲基、羟乙基或钠;
A为 其中Y为Cl或F;
其中所述R1-R3、芳基是未被取代的或被选自卤素、三氟甲基、三氟乙基、三氟甲基氧基、三氟乙氧基、甲氧基、乙氧基、丙氧基、甲基、乙基、1,1,1-三氟-2-醇-异丙基、-O(CH2)nNZ2Z3和-(CH2)nNZ2Z3的一个或多个取代基所取代,n为1或2,Z2和Z3独立地为氢、甲基或乙基;
其中所述R1-R3、杂环基烷基或含有一个或多个选自氧、氮、硫的杂原子的杂芳基,其中杂环烷基或杂芳基是未被取代的或者被选自三氟甲基、三氟乙基、嘧啶基、甲基、乙基和异丁氧羰基的一个或多个取代基所取代,并且杂环烷基也可以是与C5-12芳基或杂芳基稠合成的二环,杂芳基也可以是与C3-7环烷基或杂环烷基稠合成的二环;
其中,R1和R4可与连接在R1和R4上的X和N形成5-6元单环或8-9元二环杂环烷基;
R4可与连接在R4上的N和A形成5-6元单环杂环烷基。
3.根据权利要求1所述的化合物,
X为羰基或磺酰基,
R1为
R2为-H或-(CH2)2CH3,
R3为
R4为-H、-CH3、-CH2CH3、-CH2CH2OH或-Na,
A为
4.根据权利要求1所述的化合物,
X为磺酰基;
R1为苯基,其中苯基是未被取代的或被选自卤素和三氟甲基的一个或多个取代基所取代,并且卤素可以被取代一个或多个;
R2为-H或-CH3;
R3为
R4为-H,
A为
5.根据权利要求1所述的化合物,
X为磺酰基;
R1为苯基,其中苯基是未被取代的或被选自卤素和三氟甲基的一个或多个取代基所取代,并且卤素可以被取代一个或多个;
R2为-H;
R3为
R4为-H或-Na,
A为
6.根据权利要求1所述的化合物,
X为磺酰基;
R1为苯基,其中苯基是未被取代的或被选自卤素和三氟甲基的一个或多个取代基所取代,并且卤素可以被取代一个或多个;
R2为-H;
R3为
R4为-H或-Na,
A为
7.根据权利要求1所述的化合物,其特征在于,式1所示化合物选自以下化合物:
(1)N-(金刚烷-2-基)-1-[(3-氯-2-甲基苯磺酰胺基)甲基]环丙基甲酰胺;
(2)(1-[(2-氟-苯磺酰胺基)甲基]-N-(5-羟基金刚烷-2-基)环丙基甲酰胺;
(3)E-4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(4)Z-4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(5)E-4-[1-((3-氯-2-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(6)Z-4-[1-((3-氯-2-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(7)E-4-[1-((3-氯-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(8)E-4-[1-((3-氯-2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(9)E-4-[1-((3,5-二氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(10)E-4-[1-((2-氟-6-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(11)E-4-[1-((2,3-二氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(12)E-4-[1-((2,4,6-三氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(13)E-4-[1-((2-氟-N,6-二甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(14)E-4-[1-((2,4-二氯-5-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(15)E-4-[1-((4-氯-2-氟-5-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(16)E-4-[1-((4,5-二氯-2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(17)E-4-[1-((呋喃-2-磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(18)E-4-[1-(3,5-二氯-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(19)E-4-[1-((噻吩-2-磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(20)E-4-[1-((2-(三氟甲基)-4-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(21)E-4-[1-((3,4-二氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(22)E-4-[1-((2-氟-N-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(23)E-4-[1-((4-三氟甲氧基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(24)E-4-[1-((2,3-二氟-苯氨基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(25)E-4-[1-((3,4-二氟-苯氨基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(26)E-4-[1-((1-甲基-1H-吲哚-5-磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(27)E-4-[1-((1-甲基-1H-吡唑-5-磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(28)E-4-[1-((苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(29)E-4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酸;
(30)N-(双环[2.2.1]庚烷-2-基)-1-((2-氟-N-甲基苯磺酰胺基)甲基)环丙基甲酰胺;
(31)N-(金刚烷-1-基)-1-((2-氟-N-甲基苯磺酰胺基)甲基)环丙基甲酰胺;
(32)E-4-[1-((N-乙基-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(33)E-3-(4-(1((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基)金刚烷-1-基)丙酸;
(34)E-N-(5-(3-氨基-3-氧代丙基)金刚烷-2-基)-1-((2-氟苯磺酰胺基)甲基)环丙基甲酰胺;
(35)E-N-(5-氨基金刚烷-2-基)-1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺盐酸盐;
(36)E-4-[1-((2,4,5-三氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(37)E-4-[1-((4-氯-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(38)E-4-[1-(3-氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(39)E-4-[1-(2-氟-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(40)E-4-[1-(2-氟-6-甲基-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(41)E-4-[1-(3-氯-2-甲基-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(42)E-4-[1-(4-氟-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(43)E-4-[1-(2,4-二氯-5-甲基-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(44)E-4-[1-(2,4-二氟氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(45)E-4-[1-(2-氟-4,5-二氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(46)E-4-[1-(2-氟-4-氯-5-甲基-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(47)E-4-[1-(2,3,4-三氟-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(48)E-4-[1-(噻吩-2-磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(49)E-4-[3-(6-三氟甲基-吡啶-2-磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(50)E-4-[1-(1-甲基-1H-吲哚-7-磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(51)1-(3-氯-苯磺酰胺基)-N-(4-氟-2-(三氟甲基)苯基)环丙基甲酰胺;
(52)E-4-[1-(3-氯-苯磺酰胺基)环丙基甲酰胺基]-N-羟基金刚烷-1-甲酰胺;
(53)1-(3-氯-苯磺酰胺基)-N-[4-(1,1,1-三氟-2-羟丙-2-基)苯基]环丙基甲酰胺;
(54)E-4-[1-(3-氯-苯氨基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(55)N-(双环[2.2.1]庚烷-2-基)-1-(3-氯-苯磺酰胺基)环丙基甲酰胺;
(56)E-4-[1-(1,1-二氧苯并[d]异噻唑-2(3H)-基)环丙基甲酰胺基]金刚烷-1-甲酰胺;
(57)E-4-[1-(3,4-二氟-苯氨基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(58)E-4-[1-(1-甲基-1H-吡唑-5-磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(59)E-4-[1-(2,3-二氟-苯氨基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(60)E-4-[1-(苯磺酰胺基)环丙基甲酰胺基]-N-羟基金刚烷-1-甲酰胺;
(61)E-4-[1-(2-氟-N-甲基苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(62)E-4-[1-(3-氯-N-甲基苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(63)E-4-[1-(2-氟苯甲酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(64)E-N-[1-(5-氨基甲酰基金刚烷-2-基)氨基甲酰基)环丙基)-5-(三氟甲基)吡咯啉酰胺;
(65)E-4-(1-(苯并[d][1,3]二氧杂环戊烯-5-磺酰胺基)环丙甲酰胺基)金刚烷-1-甲酰胺;
(66)1-(3-氯-苯磺酰胺基)-N-环庚基-N-丙基环丙基甲酰胺;
(67)E-4-(3-(3-氯-苯磺酰胺基)-2,2-二甲基丙酰胺基)金刚烷-1-甲酰胺;
(68)E-4-[3-(2-氟-苯磺酰胺基)-2,2-二甲基丙酰胺基]金刚烷-1-甲酰胺;
(69)E-4-[3-(苯磺酰胺基)-2,2-二甲基丙酰胺基]金刚烷-1-甲酰胺;
(70)E-4-[3-(3-氯-2-甲基-苯磺酰胺基)-2,2-二甲基丙酰胺基]金刚烷-1-甲酰胺;
(71)E-4-[2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺基]-金刚烷-1-甲酰胺;
(72)E-4-[2-(2-氟-N-甲基-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(73)E-4-[2-(3-氯-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(74)E-N-(5-氰基金刚烷-2-基)-2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺;
(75)E-2-(2-氟-苯磺酰胺基)-N-[5-(N'-甲脒基)金刚烷-2-基]-2-甲基丙酰胺;
(76)E-2-(2-氟-苯磺酰胺基)-N-[5-(羟甲基)金刚烷-2-基]-2-甲基丙酰胺;
(77)E-2-(2-氟-苯磺酰胺基)-N-(5-甲酰金刚烷-2-基)-2-甲基丙酰胺;
(78)E-[4-(2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺基)金刚烷-1-基]甲基-4-甲苯磺酸酯;
(79)E-2-[4-(2-(2-氟苯磺酰胺基)-2-甲基丙酰胺基)金刚烷-1-基]乙酸;
(80)E-N-[5-(2-氨基-2-氧代乙基)金刚烷-2-基]-2-(2-氟苯磺酰胺基)-2-甲基丙酰胺;
(81)E-4-[2-甲基-2-(苯磺酰胺基)丙酰胺基]金刚烷-1-甲酰胺;
(82)E-4-[2-(2-氟-3-氯-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(83)E-4-[2-(3,5-二氟-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(84)E-4-[2-(2,6-二氟-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(85)E-2-(2-氟-苯磺酰胺基)-N-(5-(肼基羰基)金刚烷-2-基)-2-甲基丙酰胺;
(86)E-N-(5-(3-氨基-3-氧代丙基)金刚烷-2-基)-2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺;
(87)E-2-(2-氟-苯磺酰胺基)-N-(5-(肼基羰基)金刚烷-2-基)-2-甲基丙酰胺;
(88)E-4-[2-(4-氯-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(89)E-4-[2-(2,5-二氯-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(90)2-(3-氯-苯磺酰胺基)-N-环庚基-2-甲基-N-丙基丙酰胺;
(91)E-4-[3-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(92)E-4-[2-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(93)E-4-[4-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(94)E-4-[3-(4-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(95)E-4-[3-(3-氯-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(96)E-4-[3-(3-氯-2-甲基-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(97)E-4-{3-[(3-氯-苯磺酰基)-甲胺基]-苯甲酰胺基}-金刚烷-1-甲酰胺;
(98)E-4-[3-N-(2-羟乙基)-2-(三氟甲基-苯磺酰胺基)苯甲酰胺基]-金刚烷-1-甲酰胺;
(99)E-4-{3-[(2-三氟甲基-苯磺酰基)-甲胺基]-苯甲酰胺基}-金刚烷-1-甲酰胺;
(100)E-[3-((5-氨基甲酰基金刚烷-2-基)氨基甲酰基)苯基](2-(三氟甲基)苯磺酰钠;
(101)E-N-(5-氨基甲酰基金刚烷-2-基)-5-[(N-甲基-2-(三氟甲基)苯磺酰胺基]烟酰胺;
(102)E-4-[3-(噻吩-2-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(103)E-4-[3-(呋喃-2-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(104)E-4-[3-(吡啶-3-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(105)E-4-(3-(苯磺酰胺基-苯甲酰胺基)-金刚烷-1-甲酰胺;
(106)E-4-[3-[(2-氯-苯磺酰胺基]苯甲酰胺基]-金刚烷-1-甲酰胺;
(107)E-4-[3-[(2,4-二甲基-噻唑-5-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(108)E-4-[3-(3,5-二甲基-1H-吡唑-4-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(109)E-N-(5-羟基-金刚烷-2-基)-3-苯磺酰胺基-苯甲酰胺;
(111)E-N-(5-羟基金刚烷-2-基)-3-(2-(三氟甲基)苯磺酰胺基)苯甲酰胺;
(113)E-[3-((5-氨基甲酰基金刚烷-2-基)氨基甲酰基)苯基]-2-氟-3-氯-苯磺酰钠;
(114)E-4-[3-(3-氯-4-(三氟甲基)苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(115)E-4-[3-[(2-(三氟甲基)苯磺酰胺基]-苯甲酰胺基]-金刚烷-1-甲酰胺;
(116)E-4-[3-(2-氯-4-溴-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(117)E-4-[3-(2,4,6-三氯-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(118)E-4-[3-(3-氯-5-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(119)E-4-[3-(3,5-二氯-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(120)E-4-[3-(3-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(121)E-4-[3-(2,4-二氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(122)E-4-[3-(2,5-二氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(123)E-4-[3-(2,6-二氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(124)E-N-环庚基-N-丙基-3-(2-(三氟甲基)苯磺酰胺基)苯甲酰胺;
(125)E-4-[2-氟-3-(2-(三氟甲基)苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(126)E-4-[2-氯-5-(3-氯-苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(127)E-4-[3-(3-氯苯磺酰胺基)-4-氟苯甲酰胺基]金刚烷-1-甲酰胺;
(128)E-4-[4-氯-3-(3,5-二氯苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(129)E-4-[2-氯-5-(3,5-二氯苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(130)E-4-[3-(3,5-二氯苯磺酰胺基)-4-氟苯甲酰胺基]金刚烷-1-甲酰胺;
(131)E-4-[5-(3,5-二氯苯磺酰胺基)-2-氟苯甲酰胺基]金刚烷-1-甲酰胺;
(132)E-4-[2-氟-3-(3-氯-苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(133)E-4-[2-氯-5-(3-氯-4-甲氧基苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(134)E-4-[4-氯-3-(3-氯-4-甲氧基苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(135)E-4-[5-(3-氯-4-甲氧基苯磺酰胺基)-2-氟苯甲酰胺基]金刚烷-1-甲酰胺;
(136)E-4-(3-(4-氯-苯磺酰胺基-苯甲酰胺基)-金刚烷-1-甲酰胺;
(137)E-4-(3-(4-氯-苯磺酰胺基-苯甲酰胺基)-金刚烷-1-甲酰胺;
(138)E-4-(3-(环丙基磺酰胺基)苯甲酰胺基)金刚烷-1-甲酰胺;
(139)E-4-(3-(1-甲基乙基磺酰胺基)苯甲酰胺基)金刚烷-1-甲酰胺;
(140)E-[3,4-二氢-1H-异喹啉-2-甲酸-1-[(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)环丙基甲基]-酰胺;
(141)E-3,4-二氢-2H-喹啉-1-甲酸[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-酰胺;
(142)E-哌啶-1-甲酸[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-酰胺;
(143)E-4-{[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-氨基甲酰基}-3,4-二氢-2H-喹啉-1-甲酸-丁酯;
(144)E-4-嘧啶-2-基-哌嗪-1-甲酸[1-(5-氨基甲酰基-金刚烷-2-基氨基甲酰基)-环丙基甲基]-酰胺;
(145)E-4-({1[(3-苯基-脲基)甲基]-环丙基羰基}氨基)-金刚烷-1-甲酰胺;
(146)E-3,4-二氢-2H-喹喔啉-1-甲酸[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-酰胺;
(147)E-3,4-二氢-1H-异喹啉-2-甲酸[4-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-噻唑-2-基]-酰胺;
(148)E-3,4-二氢-2H-喹啉-1-甲酸[4-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-噻唑-2-基]-酰胺;和
(149)E-2-(2-氟-苯甲酰胺基)-噻唑-4-甲酸(5-氨基甲酰基-金刚烷-2-基)酰胺。
8.根据权利要求1所述的化合物,其特征在于,所述式1所示化合物选自以下化合物:
(1)N-(金刚烷-2-基)-1-[(3-氯-2-甲基苯磺酰胺基)甲基]环丙基甲酰胺;
(2)(1-[(2-氟-苯磺酰胺基)甲基]-N-(5-羟基金刚烷-2-基)环丙基甲酰胺;
(3)E-4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(4)Z-4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(5)E-4-[1-((3-氯-2-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(6)Z-4-[1-((3-氯-2-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(7)E-4-[1-((3-氯-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(8)E-4-[1-((3-氯-2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(9)E-4-[1-((3,5-二氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(10)E-4-[1-((2-氟-6-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(11)E-4-[1-((2,3-二氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(12)E-4-[1-((2,4,6-三氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(13)E-4-[1-((2-氟-N,6-二甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(14)E-4-[1-((2,4-二氯-5-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(15)E-4-[1-((4-氯-2-氟-5-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(16)E-4-[1-((4,5-二氯-2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(17)E-4-[1-((呋喃-2-磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(18)E-4-[1-(3,5-二氯-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(19)E-4-[1-((噻吩-2-磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(20)E-4-[1-((2-(三氟甲基)-4-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(21)E-4-[1-((3,4-二氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(22)E-4-[1-((2-氟-N-甲基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(23)E-4-[1-((4-三氟甲氧基-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(24)E-4-[1-((2,3-二氟-苯氨基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(25)E-4-[1-((3,4-二氟-苯氨基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(26)E-4-[1-((1-甲基-1H-吲哚-5-磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(27)E-4-[1-((1-甲基-1H-吡唑-5-磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(28)E-4-[1-((苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(29)E-4-[1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酸;
(30)N-(双环[2.2.1]庚烷-2-基)-1-((2-氟-N-甲基苯磺酰胺基)甲基)环丙基甲酰胺;
(31)N-(金刚烷-1-基)-1-((2-氟-N-甲基苯磺酰胺基)甲基)环丙基甲酰胺;
(32)E-4-[1-((N-乙基-氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(33)E-3-(4-(1((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺基)金刚烷-1-基)丙酸;
(34)E-N-(5-(3-氨基-3-氧代丙基)金刚烷-2-基)-1-((2-氟苯磺酰胺基)甲基)环丙基甲酰胺;
(35)E-N-(5-氨基金刚烷-2-基)-1-((2-氟-苯磺酰胺基)甲基)环丙基甲酰胺盐酸盐;和
(36)E-4-[1-((2,4,5-三氟-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺。
9.根据权利要求1所述的化合物,其特征在于,式1所示化合物选自以下化合物:
(37)E-4-[1-((4-氯-苯磺酰胺基)甲基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(38)E-4-[1-(3-氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(39)E-4-[1-(2-氟-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(40)E-4-[1-(2-氟-6-甲基-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(41)E-4-[1-(3-氯-2-甲基-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(42)E-4-[1-(4-氟-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(43)E-4-[1-(2,4-二氯-5-甲基-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(44)E-4-[1-(2,4-二氟氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(45)E-4-[1-(2-氟-4,5-二氯-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(46)E-4-[1-(2-氟-4-氯-5-甲基-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(47)E-4-[1-(2,3,4-三氟-苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(48)E-4-[1-(噻吩-2-磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(49)E-4-[3-(6-三氟甲基-吡啶-2-磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(50)E-4-[1-(1-甲基-1H-吲哚-7-磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(51)1-(3-氯-苯磺酰胺基)-N-(4-氟-2-(三氟甲基)苯基)环丙基甲酰胺;
(52)E-4-[1-(3-氯-苯磺酰胺基)环丙基甲酰胺基]-N-羟基金刚烷-1-甲酰胺;
(53)1-(3-氯-苯磺酰胺基)-N-[4-(1,1,1-三氟-2-羟丙-2-基)苯基]环丙基甲酰胺;
(54)E-4-[1-(3-氯-苯氨基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(55)N-(双环[2.2.1]庚烷-2-基)-1-(3-氯-苯磺酰胺基)环丙基甲酰胺;
(56)E-4-[1-(1,1-二氧苯并[d]异噻唑-2(3H)-基)环丙基甲酰胺基]金刚烷-1-甲酰胺;
(57)E-4-[1-(3,4-二氟-苯氨基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(58)E-4-[1-(1-甲基-1H-吡唑-5-磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(59)E-4-[1-(2,3-二氟-苯氨基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(60)E-4-[1-(苯磺酰胺基)环丙基甲酰胺基]-N-羟基金刚烷-1-甲酰胺;
(61)E-4-[1-(2-氟-N-甲基苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(62)E-4-[1-(3-氯-N-甲基苯磺酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(63)E-4-[1-(2-氟苯甲酰胺基)环丙基甲酰胺基]-金刚烷-1-甲酰胺;
(64)E-N-[1-(5-氨基甲酰基金刚烷-2-基)氨基甲酰基)环丙基)-5-(三氟甲基)吡咯啉酰胺;
(65)E-4-(1-(苯并[d][1,3]二氧杂环戊烯-5-磺酰胺基)环丙甲酰胺基)金刚烷-1-甲酰胺;和
(66)1-(3-氯-苯磺酰胺基)-N-环庚基-N-丙基环丙基甲酰胺。
10.根据权利要求1所述的化合物,其特征在于,式1所示化合物选自以下化合物:
(67)E-4-(3-(3-氯-苯磺酰胺基)-2,2-二甲基丙酰胺基)金刚烷-1-甲酰胺;
(68)E-4-[3-(2-氟-苯磺酰胺基)-2,2-二甲基丙酰胺基]金刚烷-1-甲酰胺;
(69)E-4-[3-(苯磺酰胺基)-2,2-二甲基丙酰胺基]金刚烷-1-甲酰胺;和
(70)E-4-[3-(3-氯-2-甲基-苯磺酰胺基)-2,2-二甲基丙酰胺基]金刚烷-1-甲酰胺。
11.根据权利要求1所述的化合物,其特征在于,式1所示化合物选自以下化合物:
(71)E-4-[2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺基]-金刚烷-1-甲酰胺;
(72)E-4-[2-(2-氟-N-甲基-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(73)E-4-[2-(3-氯-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(74)E-N-(5-氰基金刚烷-2-基)-2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺;
(75)E-2-(2-氟-苯磺酰胺基)-N-[5-(N'-甲脒基)金刚烷-2-基]-2-甲基丙酰胺;
(76)E-2-(2-氟-苯磺酰胺基)-N-[5-(羟甲基)金刚烷-2-基]-2-甲基丙酰胺;
(77)E-2-(2-氟-苯磺酰胺基)-N-(5-甲酰金刚烷-2-基)-2-甲基丙酰胺;
(78)E-[4-(2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺基)金刚烷-1-基]甲基-4-甲苯磺酸酯;
(79)E-2-[4-(2-(2-氟苯磺酰胺基)-2-甲基丙酰胺基)金刚烷-1-基]乙酸;
(80)E-N-[5-(2-氨基-2-氧代乙基)金刚烷-2-基]-2-(2-氟苯磺酰胺基)-2-甲基丙酰胺;
(81)E-4-[2-甲基-2-(苯磺酰胺基)丙酰胺基]金刚烷-1-甲酰胺;
(82)E-4-[2-(2-氟-3-氯-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(83)E-4-[2-(3,5-二氟-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(84)E-4-[2-(2,6-二氟-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(85)E-2-(2-氟-苯磺酰胺基)-N-(5-(肼基羰基)金刚烷-2-基)-2-甲基丙酰胺;
(86)E-N-(5-(3-氨基-3-氧代丙基)金刚烷-2-基)-2-(2-氟-苯磺酰胺基)-2-甲基丙酰胺;
(87)E-2-(2-氟-苯磺酰胺基)-N-(5-(肼基羰基)金刚烷-2-基)-2-甲基丙酰胺;
(88)E-4-[2-(4-氯-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;
(89)E-4-[2-(2,5-二氯-苯磺酰胺基)-2-甲基丙酰胺基]金刚烷-1-甲酰胺;和
(90)2-(3-氯-苯磺酰胺基)-N-环庚基-2-甲基-N-丙基丙酰胺。
12.根据权利要求1所述的化合物,其特征在于,式1所示化合物选自以下化合物:
(91)E-4-[3-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(92)E-4-[2-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(93)E-4-[4-(2-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(94)E-4-[3-(4-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(95)E-4-[3-(3-氯-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(96)E-4-[3-(3-氯-2-甲基-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(97)E-4-{3-[(3-氯-苯磺酰基)-甲胺基]-苯甲酰胺基}-金刚烷-1-甲酰胺;
(98)E-4-[3-N-(2-羟乙基)-2-(三氟甲基-苯磺酰胺基)苯甲酰胺基]-金刚烷-1-甲酰胺;
(99)E-4-{3-[(2-三氟甲基-苯磺酰基)-甲胺基]-苯甲酰胺基}-金刚烷-1-甲酰胺;
(100)E-[3-((5-氨基甲酰基金刚烷-2-基)氨基甲酰基)苯基](2-(三氟甲基)苯磺酰钠;
(101)E-N-(5-氨基甲酰基金刚烷-2-基)-5-[(N-甲基-2-(三氟甲基)苯磺酰胺基]烟酰胺;
(102)E-4-[3-(噻吩-2-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(103)E-4-[3-(呋喃-2-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(104)E-4-[3-(吡啶-3-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(105)E-4-(3-(苯磺酰胺基-苯甲酰胺基)-金刚烷-1-甲酰胺;
(106)E-4-[3-[(2-氯-苯磺酰胺基]苯甲酰胺基]-金刚烷-1-甲酰胺;
(107)E-4-[3-[(2,4-二甲基-噻唑-5-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(108)E-4-[3-(3,5-二甲基-1H-吡唑-4-磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(109)E-N-(5-羟基-金刚烷-2-基)-3-苯磺酰胺基-苯甲酰胺;
(111)E-N-(5-羟基金刚烷-2-基)-3-(2-(三氟甲基)苯磺酰胺基)苯甲酰胺;
(113)E-[3-((5-氨基甲酰基金刚烷-2-基)氨基甲酰基)苯基]-2-氟-3-氯-苯磺酰钠;
(114)E-4-[3-(3-氯-4-(三氟甲基)苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(115)E-4-[3-[(2-(三氟甲基)苯磺酰胺基]-苯甲酰胺基]-金刚烷-1-甲酰胺;
(116)E-4-[3-(2-氯-4-溴-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(117)E-4-[3-(2,4,6-三氯-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(118)E-4-[3-(3-氯-5-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(119)E-4-[3-(3,5-二氯-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(120)E-4-[3-(3-氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(121)E-4-[3-(2,4-二氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(122)E-4-[3-(2,5-二氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(123)E-4-[3-(2,6-二氟-苯磺酰胺基)-苯甲酰胺基]-金刚烷-1-甲酰胺;
(124)E-N-环庚基-N-丙基-3-(2-(三氟甲基)苯磺酰胺基)苯甲酰胺;
(125)E-4-[2-氟-3-(2-(三氟甲基)苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(126)E-4-[2-氯-5-(3-氯-苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(127)E-4-[3-(3-氯苯磺酰胺基)-4-氟苯甲酰胺基]金刚烷-1-甲酰胺;
(128)E-4-[4-氯-3-(3,5-二氯苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(129)E-4-[2-氯-5-(3,5-二氯苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(130)E-4-[3-(3,5-二氯苯磺酰胺基)-4-氟苯甲酰胺基]金刚烷-1-甲酰胺;
(131)E-4-[5-(3,5-二氯苯磺酰胺基)-2-氟苯甲酰胺基]金刚烷-1-甲酰胺;
(132)E-4-[2-氟-3-(3-氯-苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(133)E-4-[2-氯-5-(3-氯-4-甲氧基苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(134)E-4-[4-氯-3-(3-氯-4-甲氧基苯磺酰胺基)苯甲酰胺基]金刚烷-1-甲酰胺;
(135)E-4-[5-(3-氯-4-甲氧基苯磺酰胺基)-2-氟苯甲酰胺基]金刚烷-1-甲酰胺;
(136)E-4-(3-(4-氯-苯磺酰胺基-苯甲酰胺基)-金刚烷-1-甲酰胺;
(137)E-4-(3-(4-氯-苯磺酰胺基-苯甲酰胺基)-金刚烷-1-甲酰胺;
(138)E-4-(3-(环丙基磺酰胺基)苯甲酰胺基)金刚烷-1-甲酰胺;和
(139)E-4-(3-(1-甲基乙基磺酰胺基)苯甲酰胺基)金刚烷-1-甲酰胺。
13.根据权利要求1所述的化合物,其特征在于,式1所示化合物选自以下化合物:
(140)E-[3,4-二氢-1H-异喹啉-2-甲酸-1-[(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)环丙基甲基]-酰胺;
(141)E-3,4-二氢-2H-喹啉-1-甲酸[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-酰胺;
(142)E-哌啶-1-甲酸[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-酰胺;
(143)E-4-{[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-氨基甲酰基}-3,4-二氢-2H-喹啉-1-甲酸-丁酯;
(144)E-4-嘧啶-2-基-哌嗪-1-甲酸[1-(5-氨基甲酰基-金刚烷-2-基氨基甲酰基)-环丙基甲基]-酰胺;
(145)E-4-({1[(3-苯基-脲基)甲基]-环丙基羰基}氨基)-金刚烷-1-甲酰胺;
(146)E-3,4-二氢-2H-喹喔啉-1-甲酸[1-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-环丙基甲基]-酰胺;
(147)E-3,4-二氢-1H-异喹啉-2-甲酸[4-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-噻唑-2-基]-酰胺;
(148)E-3,4-二氢-2H-喹啉-1-甲酸[4-(5-氨基甲酰基-金刚烷-2-基-氨基甲酰基)-噻唑-2-基]-酰胺;和
(149)E-2-(2-氟-苯甲酰胺基)-噻唑-4-甲酸(5-氨基甲酰基-金刚烷-2-基)酰胺。
14.一种制备权利要求1所述化合物的方法,该制备方法包含式2所示化合物与式3所示化合物在有机溶剂存在下发生反应以制备式1化合物的步骤,如下述反应式1所示:
[反应式1]
(在反应式1中,
R1-R4、X和A如权利要求1中的式1所定义)。
15.一种用于预防或治疗由11β-HSD1酶过度活化引起的疾病的药物组合物,该组合物含有权利要求1所述的化合物或其药学上可接受的盐作为活性成分。
16.根据权利要求15所述的药物组合物,其特征在于,所述由11β-HSD1酶过度活化引起的疾病选自非胰岛素依赖型II型糖尿病、胰岛素耐受、肥胖、血脂异常、代谢综合征,以及其它由糖皮质激素过度活跃介导的疾病。
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CN109438297B (zh) * | 2018-12-03 | 2021-05-14 | 昆明积大制药股份有限公司 | 雄激素受体拮抗剂、其制备方法及其应用 |
CN109593061B (zh) * | 2018-12-03 | 2021-09-14 | 昆明积大制药股份有限公司 | 雄激素受体拮抗剂、其制备方法及其应用 |
CN113527536A (zh) * | 2020-04-21 | 2021-10-22 | 杭州德柯医疗科技有限公司 | 一种含氟多糖高分子化合物及其制备方法 |
CN113527536B (zh) * | 2020-04-21 | 2024-03-22 | 杭州德柯医疗科技有限公司 | 一种含氟多糖高分子化合物及其制备方法 |
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CO7170176A2 (es) | 2015-01-28 |
JP2015525238A (ja) | 2015-09-03 |
EP2865664A1 (en) | 2015-04-29 |
PH12014502802B1 (en) | 2015-02-09 |
MX2014015191A (es) | 2015-04-09 |
AU2013278234A1 (en) | 2015-01-22 |
EP2865664A4 (en) | 2016-05-11 |
PE20150345A1 (es) | 2015-03-10 |
CA2876584C (en) | 2015-11-17 |
KR20130142801A (ko) | 2013-12-30 |
PH12014502802A1 (en) | 2015-02-09 |
US20150210635A1 (en) | 2015-07-30 |
EA201590051A1 (ru) | 2015-05-29 |
JP5775649B2 (ja) | 2015-09-09 |
CA2876584A1 (en) | 2013-12-27 |
EP2865664B1 (en) | 2017-11-01 |
BR112014031649A2 (pt) | 2017-06-27 |
IN2014MN02622A (zh) | 2015-07-10 |
AU2013278234B2 (en) | 2015-05-21 |
BR112014031649A8 (zh) | 2021-03-16 |
US9464044B2 (en) | 2016-10-11 |
HUE035928T2 (en) | 2018-05-28 |
ZA201500362B (en) | 2016-01-27 |
PL2865664T3 (pl) | 2018-03-30 |
ES2652185T3 (es) | 2018-01-31 |
WO2013191396A1 (ko) | 2013-12-27 |
MX336945B (es) | 2016-02-08 |
EA026005B1 (ru) | 2017-02-28 |
CN104903290B (zh) | 2017-04-26 |
CL2014003436A1 (es) | 2015-08-07 |
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