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5-beta-sapogenin and pseudosapogenin derivatives and their use in the treatment of dementia

A technology of aglycone and derivatives, applied in the field of sapogenin derivatives and in the treatment of cognitive impairment and similar symptoms, can solve the problems of lack of synaptic transmission, defective basic key, not provided, etc.

Inactive Publication Date: 2008-12-24
PHYTOPHARM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantages in the above three traditional methods of treating AD / SDAT are: Ach precursor supplementation, stimulant replacement and inhibition of acetylcholinesterase
However, this disclosure is of uncertain value because it is well recognized that there is no infectious factor for a very large number of symptoms characterized by a lack of synaptic transmission, so the fundamental key to the so-called invention is flawed
In addition, they do not provide any data that would enable those skilled in the art to select a preferred compound from the large number of compounds they claim

Method used

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  • 5-beta-sapogenin and pseudosapogenin derivatives and their use in the treatment of dementia
  • 5-beta-sapogenin and pseudosapogenin derivatives and their use in the treatment of dementia
  • 5-beta-sapogenin and pseudosapogenin derivatives and their use in the treatment of dementia

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0152] In CHO cell lines expressing recombinant human muscarinic receptors in vitro, the number of muscarinic receptors tended to decrease over time. Muscarinic receptor density was increased after 72 hours of incubation with saponin derivatives (1-10 μm) according to the invention.

[0153] method:

[0154] Effect of saponin derivatives of the present invention on muscarinic receptor density in CHO cells expressing recombinant human muscarinic receptors.

[0155] Chinese hamster ovary (CHO) cells expressing high levels of receptor (-2.2 pmole receptor / mg protein) were cultured in flasks (150 ml) for 24 hours before starting the experiment. Vehicle (DMSO) and saponin derivatives (1 and 10 [mu]M) were added to the medium for 48 hours. The culture medium was removed, the cells were scraped and resuspended in Hanks solution, centrifuged, and passed through with [ 3 [H]-QNB were incubated for 30 minutes, after which the level of m receptor was determined by liquid scintillation...

Embodiment 2

[0159]

[0160] 3-O-2Oxycarbonyl-5β, 20α, 22α, 25R-spirostan-3β-ol

[0161] Ethyl chloroformate (1.40g, 12.9mmol) was added dropwise to a solution of smilagenin (2.08g, 5.0mmol) in anhydrous dichloromethane (15ml) and anhydrous pyridine (1.02g, 12.9mmol). in the stirred solution. The mixture was stirred at room temperature for 18 hours, then partitioned between water (30 mL) and dichloromethane. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were washed with water, then dried over magnesium sulfate (anhydrous). The solvent was evaporated in vacuo to give an oil which crystallized rapidly (2.1 g). This material was chromatographed on silica gel (about 70 g), eluting with ethyl acetate-hexane (1:9), and recrystallized from methanol to give 3-O-2oxycarbonyl-5β, 20α, 22α, 25R-spiro White crystals of stan-3β-ol (1.08 g).

[0162] mp 154-156°C; m / z 488 (M + for C 30 h 48 o 5 ); 1 H nmr (270MHz, CDCl 3 )δ0.76 (3H, s, 18-CH 3...

Embodiment 3

[0164] Epismilagen succinate

[0165]

[0166] A solution of epismilagenin (200 mg, 0.48 mmol) and succinic anhydride (60 mg, 0.59 mmol) in anhydrous pyridine was stirred overnight at room temperature under nitrogen. Another portion of succinic anhydride (120 mg, 1.18 mmol) was added and the reaction mixture was stirred for an additional 24 hours. After adding another portion of succinic anhydride (120 mg, 1.18 mmol), the reaction mixture was heated at 50° C. for a further 24 hours with stirring. After the reaction was cooled, water (10 mL) was added. The aqueous solution was extracted with ether (4 x 20 mL). The combined organic extracts were washed with water (3 x 20 mL). Dry (anhydrous magnesium sulfate), filter. The solvent was evaporated in vacuo to give an orange oil (1.8 g), which was chromatographed on silica gel using ethyl acetate / petroleum ether (1:4) as eluent. Recrystallization from acetone gave white crystals of epismilagenyl succinate (87 mg).

[0167] ...

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PUM

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Abstract

The present invention relates to the use of sapogenin derivatives in the treatment of cognitive dysfunction and similar conditions. Treatment methods and pharmaceutical compositions are also contemplated.

Description

technical field [0001] 本发明涉及皂草苷配基衍生物及其在治疗认知障碍和类似症状中的用途,并涉及用于这种治疗的组合物。本发明还涉及一些症状的治疗,这些症状的特征在于膜结合受体的数量和功能缺陷。在下面,将主要参考早老性痴呆(AD)和早老性痴呆型的老年性痴呆(SDAT)的治疗来描述本发明,其中显示了许多受体类型的缺陷。然而,应该明白本发明总的涉及归因于固有病理症状和 / 或暴露于有害条件下的症状的治疗,其中所述症状的特征在于膜结合受体的数量和功能的缺陷或神经元之间接点处,或在神经元和效应细胞的接点处的传递缺陷。 Background technique [0002] 上面提到的病症类型包括帕金森氏病、路易斯体痴呆、体位性低血压、孤独症、慢性疲劳综合症、重症肌无力、肌无力综合症、与Gulf War综合症相关的疾病和问题,暴露于有机磷化合物的职业病和与老化有关的问题。 [0003] 早老性痴呆(AD)和早老性痴呆型的老年性痴呆(SDAT)是严重的并日益引起全社会关注的问题,这是由于平均寿命的增加和对偶发疾病的控制,使人口统计分布日益向老龄人群扩展的缘故。所以迫切需要能够治疗和帮助AD / SDAT的处理的药物。 [0004] 年龄相关的记忆损伤(AAMI)是那些抱怨记忆力退化的精神和体力正常的老年病人的特征。这是一个很难定义的综合症,但能够有效治疗AD / SDAT的药物在这些人群中还是很有价值的。 [0005] 用传统和常规的医学研究的方法和规则对AD / SDAT进行了研究。在常规医学中,有几种方法来治疗AD / SDAT。众所周知,促进大脑皮质中的记忆的生物化学方法是由胆碱能介导的(至少部分是如此)。本领域普通技术人员熟知“胆碱能介导的”机制可直接归因于乙酰胆碱作用于受体,这是直接效应。另外,通过调节突触前神经末稍释放乙酰胆碱或抑制破坏乙酰胆碱的酶可产生临床有用的效果。这些调节因子可通过其递质不是胆碱能的神经元来发挥作用。这被称为间接效应。在治疗中的几种尝试将注意力集中在诸如5-羟色胺这些其它递质的作用上,5-羟色胺是大脑的其它区域,如中脑核中的递质。然而,由于来自这些区域的纤维被向前投射到其初级递质是乙酰胆碱的大脑皮质,所以注意力已经集中到寻求一些适当的治疗药物来处理这些递质的方面。 [0006] 用于AD / SDAT治疗...

Claims

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Application Information

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IPC IPC(8): C07J71/00A61K31/58A61P25/28A61P25/14A61P25/16A61P9/02A61P21/04A61P43/00
CPCC07J71/00C07J71/0005A61P21/04A61P25/00A61P25/14A61P25/16A61P25/28A61P43/00A61P9/02
Inventor P·巴勒克拉夫J·汉森P·冈宁D·里斯夏宗勤胡雅儿
Owner PHYTOPHARM LTD
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