N-[4-(1-naphthylamino)-4-oxobutanoyl]-β-alanine | 1252687-39-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-[4-(1-naphthylamino)-4-oxobutanoyl]-β-alanine
• 英文别名: N-[4-(1-naphthylamino)-4-oxobutanoyl]-beta-alanine；3-[[4-(naphthalen-1-ylamino)-4-oxobutanoyl]amino]propanoic acid
• CAS: 1252687-39-0
• 化学式: C₁₇H₁₈N₂O₄
• 分子量: 314.341
• InChiKey: BVJHOQFIAAZHBQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  95.5
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4-(naphthalene-1-ylamino)-4-oxo-butanoic acid 在 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 23.0h， 生成 N-[4-(1-naphthylamino)-4-oxobutanoyl]-β-alanine
  参考文献：
  名称：

  具有抗淀粉样变性活性的新型萘衍生物可作为阿尔茨海默氏病的潜在治疗剂

  摘要：

  β-淀粉样肽的聚集与阿尔茨海默氏病（AD）患者的神经退行性疾病有关。因此，抑制β-淀粉样肽的低聚和原纤维化被认为是AD的合理治疗方法。在此，提出了新的萘衍生物的合成及其作为抗β淀粉样生成剂的评价。分子动力学模拟预测了化合物，Aβ1-42肽和原纤维之间热力学稳定的复合物的形成。在人小胶质细胞中，这些化合物抑制Aβ1-42肽的聚集。铅化合物8在小鼠脑离体测定中显示出对淀粉样斑块的高亲和力，并具有足够的log Poct / PBS值。化合物8还改善了3xTg-AD雌性小鼠大脑的认知功能并降低了海马β-淀粉样蛋白负担。总之，我们的结果表明8可能是AD的新型治疗剂。

  DOI：

  10.1016/j.bmc.2020.115700

文献信息

• Method for Obtaining Novel Derivatives of Naphthalene for the In Vivo Diagnosis of Alzheimer's Disease
  申请人：Carrazana Marquiza Sablón

  公开号：US20120321560A1

  公开（公告）日：2012-12-20

  This invention relates to a chemistry branch, particularly to the field of compounds' organic synthesis that belongs to the aromatic bicyclic or naphthalene category, used in the detection of amyloid sheets. These new naphthalene derivatives have a general formula: Wherein R represents mutually independent groups. In I: R 1 :-alkylenyl-C(O)NH-alkylenyl-R 3 , -alkylenyl-C(O)O—R 4 , R 3 :—COOH, —OH, —SH, —NH 2 , -alkyl-NH-alkyl-N-dithiocarbamate alkaline earth metal salts, R 4 : H, succinimidyl group, R 2 : —H,-alkyl. In II: R 1 : -alkyl, -alkylenyl-halide-alkylenyl-hydroxyl-alkylenyl-O-aryl, —O-alkylsulfonate alkylenyl, R 2 : -halide-alkylenyl-O-aryl, -alkylenyl-O-alkylsulfonate, -alkylenyl-halide-, —CH(O), —HC═C(CN) 2 , —HC═CHNO 2 , -alkylenyl-NH 2 , -alkylenyl-NH-alkyl, -alkylenyl-alkyl-N-dithiocarbamate alkaline salts. The terms “alkyl” and “alkylenyl” refer to linear or branched aliphatic chains, preferably from 1 to 4 carbon atoms and the term halide to fluorine, bromine or iodine. These compounds are neutral, lipophilic and have low molecular weight and therefore they cross the blood brain barrier and attach to the amyloid sheets. The present invention provides procedures for obtaining naphthalene derivatives with good yields, which can be practical, economical and adapted to a larger-scale manufacturing. We are unaware whether the compounds presented in this invention have been previously reported.

  这项发明涉及化学领域，特别是属于芳香双环或萘类别的化合物有机合成领域，用于检测淀粉样蛋白片。这些新的萘衍生物具有一般公式：其中R代表相互独立的基团。在I中：R1：-烷基-C（O）NH-烷基-R3，-烷基-C（O）O—R4，R3：—COOH，—OH，—SH，—NH2，-烷基-NH-烷基-N-二硫代氨基甲酸盐，R4：H，琥珀酰亚胺基团，R2：—H，-烷基。在II中：R1：-烷基，-烷基卤代-烷基羟基-烷基-O-芳基，—O-烷基磺酸酯烷基，R2：-卤代-烷基-O-芳基，-烷基-O-烷基磺酸酯，-烷基卤代-，—CH（O），—HC═C（CN）2，—HC═CHNO2，-烷基-NH2，-烷基-NH-烷基，-烷基-烷基-N-二硫代氨基盐。术语“烷基”和“烷基烯基”指直链或支链脂肪链，最好是1到4个碳原子，卤代指氟、溴或碘。这些化合物是中性的、亲脂性的，具有低分子量，因此它们可以穿过血脑屏障并附着在淀粉样蛋白片上。本发明提供了获得萘衍生物的程序，其产率高，可以实用、经济，并适用于大规模生产。我们不知道本发明中提出的化合物是否已经被先前报道。
• METHOD FOR OBTAINING NOVEL DERIVATIVES OF NAPHTHALENE FOR THE IN VIVO DIAGNOSIS OF ALZHEIMER'S DISEASE
  申请人：Sablon Carrazana Marquiza

  公开号：US20150217005A1

  公开（公告）日：2015-08-06

  This invention relates to a chemistry branch, particularly to the field of compounds' organic synthesis that belong to the aromatic bicyclic or naphthalene category, used in the detection of amyloid sheets. These new naphthalene derivatives have a general formula: Wherein R represents mutually independent groups. In I: R 1 : -alkylenyl-C(O)NH-alkylenyl-R 3 , -alkylenyl-C(O)O—R 4 , R 3 : —COOH, —OH, —SH, —NH 2 , -alkyl-NH-alkyl-N-dithiocarbamate alkaline earth metal salts, R 4 : H, succinimidyl group, R 2 : —H, -alkyl. In II: R 1 : -alkyl, -alkylenyl-halide-alkylenyl-hydroxyl-alkylenyl-O-aryl, —O-alkylsulfonate alkylenyl, R 2 : -halide-alkylenyl-O-aryl, -alkylenyl-O-alkylsulfonate, -alkylenyl-halide-, —CH(O), —HC═C(CN) 2 , —HC═CHNO 2 , -alkylenyl-NH 2 , -alkylenyl-NH-alkyl, -alkylenyl-alkyl-N-dithiocarbamate alkaline salts. The terms “alkyl” and “alkylenyl” refer to linear or branched aliphatic chains, preferably from 1 to 4 carbon atoms and the term halide to fluorine, bromine or iodine. These compounds are neutral, lipophilic and have low molecular weight and therefore they cross the blood brain barrier and attach to the amyloid sheets. The present invention provides procedures for obtaining naphthalene derivatives with good yields, which can be practical, economical and adapted to a larger-scale manufacturing.

  本发明涉及化学分支，特别是属于芳香族双环或萘类化合物有机合成领域，用于淀粉样板的检测。这些新的萘衍生物具有下列一般式：其中R代表相互独立的基团。在I中：R1：-烷基-C（O）NH-烷基-R3，-烷基-C（O）O—R4，R3：-COOH，-OH，-SH，-NH2，-烷基-NH-烷基-N-二硫代氨基酸盐，R4：H，琥珀酰亚胺基团，R2：-H，-烷基。在II中：R1：-烷基，-烷基卤代-烷基羟基-烷基-O-芳基，-O-烷基磺酸酯烷基，R2：-卤代-烷基-O-芳基，-烷基-O-烷基磺酸酯，-烷基卤代-，-CH（O），-HC═C（CN）2，-HC═CHNO2，-烷基-NH2，-烷基-NH-烷基，-烷基-烷基-N-二硫代氨基酸盐。术语“烷基”和“烷基烷基”指线性或支链脂肪链，最好是1到4个碳原子，卤素一词指氟、溴或碘。这些化合物是中性、亲脂性和分子量低，因此它们可以穿过血脑屏障并附着在淀粉样板上。本发明提供了获得萘衍生物的程序，其收率良好，可以实用、经济并适用于更大规模的制造。
• METAL OXIDES NANOPARTICLES CONJUGATED WITH NAPHTHALENE DERIVATIVES AS CONTRAST AGENTS FOR THE DETECTION OF BETA AMYLOID PLAQUES BY MAGNETIC RESONANCE IMAGES
  申请人：Centro De Neurociencias De Cuba

  公开号：EP3878475A1

  公开（公告）日：2021-09-15

  This invention is related to Chemistry and Physics applied to the field of Medicine and refers to the use of compounds with magnetic properties, which belong to the category of metal oxide nanoparticles, coated and conveniently functionalized, which are conjugated with naphthalene compounds related to agglomerates and β-amyloid plaques present in neurodegenerative diseases. These new nanoparticles (NPs) are used for the non-invasive detection of agglomerates and amyloid plaques using the Magnetic Resonance Imaging (MRI) technique. The nanoparticles described here cross the blood-brain barrier (BBB), without the use of any membrane-disrupting agent. Likewise, they bind with high affinity and specificity to the agglomerates and β-amytoid plaques, and are used as contrast agents in MRI for the early detection of Alzheimer's disease (AD). The new nanoparticles, coated, functionalized and conjugated with the naphthalene derivatives, have general Formula I; wherein: R1: is an organic coating to the metal oxide core, of polymeric type, catechol derivatives and trialkoxyalkylaminosilane; R2: -NHCO-alkylenyl-C(O)NH-alkylenyl-R3; R3: -COO-, -CO-, -NH, -O-, -S-, -NH-alkylenyl-NH-, -NR4-CSS-; R4: -H, -CH3, -CH2-CH3, -CH2CH2CH3, and MxOy: iron oxide (Fe3O4/γFe2O3), gadolinium oxide(III), manganese oxide(II) and copper(II) oxide; wherein the conjugated, functionalized and coated magnetic nanoparticle is capable of, when it is administered to a mammal, crossing the blood-brain barrier and specifically binding to the agglomerates and amyloid plaques present in brain tissue; wherein with this nanoparticle bound to the agglomerates and β-amyloid plaques in the brain tissue, hypo- or hyper-intense signals are observed in the region of interest through MRI. The compounds of Formula I are capable of acting as positive (T1) and / or negative (T2) contrast agents for MRI for the early and non-invasive diagnosis of AD, through a hypo- or hyper-intense signal of the β-amytoid agglomerates or Aβ plaques. In the NPs of Formula I, the metallic oxide magnetic core is coated with a functionalized polymeric layer that allows conjugation to naphthalene compounds, the preparation of which has been previously described in CU 2010/0204, EP 2 436 666 A20, P58243ZA00, US 9,764,047, CA 2789869C, PI 2012003534. The covalent and stable bond between the two chemical units form, in the NPs, a carbon chain with a singular structure, which surprisingly facilitates the NPs passage through the BBB, without the use of a disrupting agent, what are not described in the current state-of-the-art. These NPs unexpectedly enhance the affinity and selectivity properties of the naphthalene derivatives towards the Aβ agglomerates and β-plaques, they are stable molecules and do not show toxicity. We are not aware that the compounds presented in this invention have been previously reported.

  本发明与应用于医学领域的化学和物理学有关，是指使用具有磁性的化合物，这些化合物属于金属氧化物纳米粒子的范畴，经过涂层和方便的功能化处理，与神经退行性疾病中存在的团聚体和β-淀粉样蛋白斑块相关的萘化合物共轭。这些新型纳米粒子（NPs）可用于利用磁共振成像（MRI）技术对团块和淀粉样蛋白斑块进行无创检测。这里描述的纳米粒子可穿过血脑屏障（BBB），无需使用任何膜破坏剂。同样，它们还能以高亲和力和特异性与团块和β-类淀粉样蛋白斑块结合，可用作核磁共振成像中的造影剂，用于早期检测阿尔茨海默病（AD）。 新的纳米粒子具有萘衍生物的涂层、功能化和共轭，其通式为 I； 其中 R1：是金属氧化物核心的有机涂层，聚合物类型，邻苯二酚衍生物和三烷氧基烷基氨基硅烷； R2：-NHCO-烯基-C(O)NH-烯基-R3； R3：-COO-、-CO-、-NH、-O-、-S-、-NH-烯基-NH-、-NR4-CSS-； R4：-H、-CH3、-CH2- 、- ，以及 MxOy：氧化铁（Fe3O4/γFe2O3）、氧化钆（III）、氧化锰（II）和氧化铜（II）； 其中，共轭、功能化和涂层的磁性纳米粒子在给哺乳动物用药时，能够穿过血脑屏障，并与脑组织中的团聚体和淀粉样斑块特异性结合； 其中，当该纳米粒子与脑组织中的团聚体和β-淀粉样蛋白斑块结合后，通过核磁共振成像可在相关区域观察到低强或高强信号。 式 I 的化合物能够作为磁共振成像的阳性（T1）和/或阴性（T2）造影剂，通过 β 淀粉样蛋白团块或 Aβ 斑块的低强或高强信号，进行 AD 的早期无创诊断。 在式 I 的 NPs 中，金属氧化物磁芯上涂有一层可与萘化合物共轭的官能化聚合物层，其制备方法已在 CU 2010/0204、EP 2 436 666 A20、P58243ZA00、US 9,764,047、CA 2789869C、PI 2012003534 中进行过描述。 两个化学单元之间的共价稳定键在 NPs 中形成了一个具有奇异结构的碳链，这出乎意料地促进了 NPs 通过 BBB，而无需使用干扰剂，这在目前的先进技术中还没有描述。 这些 NPs 意外地增强了萘衍生物对 Aβ 团聚体和β斑块的亲和性和选择性，它们是稳定的分子，没有毒性。我们不知道本发明中提出的化合物以前是否被报道过。
• Method for obtaining novel derivatives of naphthalene for the in vivo diagnosis of Alzheimer's disease
  申请人：Carrazana Marquiza Sablon

  公开号：US10155053B2

  公开（公告）日：2018-12-18

  This invention relates to a chemistry branch, particularly to the field of compounds' organic synthesis that belong to the aromatic bicyclic or naphthalene category, used in the detection of amyloid sheets. These new naphthalene derivatives have a general formula: Wherein R represents mutually independent groups. In I: R1: -alkylenyl-C(O)NH-alkylenyl-R3, -alkylenyl-C(O)O—R4, R3: —COOH, —OH, —SH, —NH2, -alkyl-NH-alkyl-N-dithiocarbamate alkaline earth metal salts, R4: H, succinimidyl group, R2: —H, -alkyl. In II: R1: -alkyl, -alkylenyl-halide-alkylenyl-hydroxyl-alkylenyl-O-aryl, —O-alkylsulfonate alkylenyl, R2: -halide-alkylenyl-O-aryl, -alkylenyl-O-alkylsulfonate, -alkylenyl-halide-, —CH(O), —HC═C(CN)2, —HC═CHNO2, -alkylenyl-NH2, -alkylenyl-NH-alkyl, -alkylenyl-alkyl-N-dithiocarbamate alkaline salts. The terms “alkyl” and “alkylenyl” refer to linear or branched aliphatic chains, preferably from 1 to 4 carbon atoms and the term halide to fluorine, bromine or iodine. These compounds are neutral, lipophilic and have low molecular weight and therefore they cross the blood brain barrier and attach to the amyloid sheets. The present invention provides procedures for obtaining naphthalene derivatives with good yields, which can be practical, economical and adapted to a larger-scale manufacturing.

  本发明涉及化学分支，特别是用于检测淀粉样蛋白片的芳香族双环或萘类化合物的有机合成领域。这些新的萘衍生物具有通式：其中 R 代表相互独立的基团。在 I．R1：-烷烯基-C（O）NH-烷烯基-R3，-烷烯基-C（O）O-R4，R3：-COOH，-OH，-SH，-NH2，-烷基-NH-烷基-N-二硫代氨基甲酸碱土金属盐，R4：H，琥珀酰亚胺基，R2：-H，-烷基。在 II：R1：-烷基，-烷烯基-卤代-烷烯基-羟基-烷烯基-O-芳基，-O-烷基磺酸烷烯基，R2：-CH(O)，-HC═C(CN)2，-HC═CHNO2，-烷基-NH2，-烷基-NH-烷基，-烷基-烷基-N-二硫代氨基甲酸烷基盐。术语 "烷基 "和 "烷烯基 "指直链或支链脂肪族链，最好是 1 至 4 个碳原子，术语卤化物指氟、溴或碘。这些化合物呈中性、亲油且分子量低，因此可以穿过血脑屏障并附着在淀粉样蛋白片上。本发明提供了获得萘衍生物的程序，产量高，实用、经济，可用于大规模生产。
• METHOD FOR OBTAINING NOVEL DERIVATIVES OF NAPHTALENE FOR THE IN VIVO DIAGNOSIS OF ALZHEIMER 'S DISEASE
  申请人：Centro De Neurociencias De Cuba

  公开号：EP2436666B1

  公开（公告）日：2014-04-09