WO2015161747A1 - 神经保护剂及其适应症 - Google Patents

神经保护剂及其适应症 Download PDF

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WO2015161747A1
WO2015161747A1 PCT/CN2015/076528 CN2015076528W WO2015161747A1 WO 2015161747 A1 WO2015161747 A1 WO 2015161747A1 CN 2015076528 W CN2015076528 W CN 2015076528W WO 2015161747 A1 WO2015161747 A1 WO 2015161747A1
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high altitude
hypoxia
triol
androst
altitude
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PCT/CN2015/076528
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English (en)
French (fr)
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银巍
陈婕思
颜光美
陆秉正
朱文博
胡海燕
邱鹏新
黄奕俊
张静夏
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广州市赛普特医药科技有限公司
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Priority to US15/306,437 priority Critical patent/US10357500B2/en
Priority to SG11201608829SA priority patent/SG11201608829SA/en
Priority to EP15783742.8A priority patent/EP3135288B1/en
Priority to ES15783742T priority patent/ES2711842T3/es
Priority to RS20190348A priority patent/RS58476B1/sr
Priority to DK15783742.8T priority patent/DK3135288T3/en
Priority to AU2015251359A priority patent/AU2015251359B2/en
Application filed by 广州市赛普特医药科技有限公司 filed Critical 广州市赛普特医药科技有限公司
Priority to RU2016141462A priority patent/RU2672264C2/ru
Priority to KR1020167032304A priority patent/KR101873791B1/ko
Priority to SI201530624T priority patent/SI3135288T1/sl
Priority to PL15783742T priority patent/PL3135288T3/pl
Priority to CA2946647A priority patent/CA2946647C/en
Priority to JP2016563798A priority patent/JP6277289B2/ja
Priority to LTEP15783742.8T priority patent/LT3135288T/lt
Publication of WO2015161747A1 publication Critical patent/WO2015161747A1/zh
Priority to IL248424A priority patent/IL248424B/en
Priority to CY20191100322T priority patent/CY1121566T1/el
Priority to US16/363,007 priority patent/US10835539B2/en
Priority to HRP20190806TT priority patent/HRP20190806T1/hr

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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to novel pharmaceutical uses of the compounds 5 ⁇ -androst-3 ⁇ , 5,6 ⁇ -triol and analogues thereof.
  • hypobaric hypoxia occurs mainly in the special environment of the plateau, also known as high altitude hypoxia.
  • HASH Acute Hypobaric Hypoxia
  • AMS Acute mountain sickness
  • HACE high altitude cerebral edema
  • HAPE high-altitude pulmonary edema
  • the former representative drugs are carbonic anhydrase inhibitors such as acetazolamide, the latter representing drugs such as glucocorticoids and some Antioxidant (Wright A, Brearey S, Imray C. High hopes at high altitudes: pharmacotherapy for acute mountain sickness and high-altitude cerebral and pulmonary oedema. Expert Opin Pharmacother 2008Jan; 9(1): 119-27), but none The drug belongs to a neuroprotective agent.
  • 5 ⁇ -androst-3 ⁇ ,5,6 ⁇ -triol is a newly discovered neuroprotective agent (Zhongshan University (Yan Guangmei; Hu Haiyan; Leng Tiandong; Sang Hanfei; Zhang Jingxia; Qiu Pengxin; Zhou Shujia; Chen Yusi; You Xiuhua), 5 ⁇ -
  • the application of androstenane-3 ⁇ ,5,6 ⁇ -triol in the preparation of neuroprotective drugs Chinese invention patent number: ZL 2010 1 0224173.3
  • the structural formula is:
  • An object of the present invention is to provide a 3 ⁇ , 5 ⁇ , 6 ⁇ -trihydroxy steroid compound of the following formula A or a pharmaceutically acceptable salt thereof for use in the preparation of a pharmaceutical composition for treating or preventing high altitude hypoxia caused by high altitude hypoxia Provide a new drug for the prevention and treatment of high altitude disease:
  • R1 is H or a linear or branched alkyl or terminal alkenyl group having 1 to 5 carbon atoms.
  • R1 is H
  • the compound is 5 ⁇ -androst-3 ⁇ ,5,6 ⁇ -triol (also referred to as "YC-6" in the specification and the drawings).
  • the high altitude disease is an acute high altitude disease caused by high altitude hypobaric hypoxia.
  • the high altitude disease is high altitude cerebral edema, in particular angioedema.
  • the high altitude disease is a neuronal injury, specifically a degenerative injury of a neuron, including neuronal damage caused by high altitude hypobaric hypoxia and caused by high altitude hypobaric hypoxia. Neuronal damage.
  • the pharmaceutical composition comprises an additional active ingredient for treating or preventing high altitude hypoxia caused by high altitude hypoxia, such as carbonic anhydrase inhibitors (such as acetazolamide), glucocorticoids. And antioxidants.
  • 5 ⁇ -androst-3 ⁇ ,5,6 ⁇ -triol significantly blocked the increase of brain water content caused by hypobaric hypoxia. Electron microscopic morphology and pathological analysis of HE staining showed that 5 ⁇ -androst-3 ⁇ ,5, 6 ⁇ -triol can reduce cerebral vasogenic edema caused by hypobaric hypoxia and neuronal vacuolar degeneration damage, thereby preventing or treating high altitude disease.
  • R1 is -CH (CH 3) (CH 2 ) 3 CH (CH 3) 2, i.e. the compound is a cholestane--3 ⁇ , 5 ⁇ , 6 ⁇ --triol (Compound I).
  • Compound I also has neuroprotective effects (Zhongshan University, the application of cholestane-3 ⁇ , 5 ⁇ , 6 ⁇ -triol in the preparation of neuroprotective drugs, Chinese invention patent No. ZL 200810198703.4).
  • this compound can also effectively reduce angioedema caused by hypobaric hypoxia and neuronal degeneration damage, and thus be used for the prevention or treatment of high altitude disease.
  • the structural formula of Compound I is:
  • R1 is -CHCH 2 CH 3 , -CH(CH 3 ) 2 or -CH(CH 2 ) 3 CH 3 , ie, the compound is 17-propylene-androst-3 ⁇ , respectively. 5 ⁇ ,6 ⁇ -triol (compound II), 17-isopropyl-androst-3 ⁇ , 5 ⁇ , 6 ⁇ -triol (compound III), 17-butyl-androst-3 ⁇ , 5 ⁇ , 6 ⁇ -triol ( Compound IV).
  • Another aspect of the invention provides a method of treating or preventing a high altitude hypoxia-induced high altitude disease comprising administering to a subject in need thereof an effective amount of a 3 ⁇ , 5 ⁇ , 6 ⁇ -trihydroxysteroid compound of formula A or a pharmaceutical thereof Acceptable salt,
  • R1 is H or a linear or branched alkyl or terminal alkenyl group having 1 to 5 carbon atoms.
  • R1 is H, ie the compound is 5 ⁇ -androst-3 ⁇ ,5,6 ⁇ -triol.
  • R1 is -CH (CH 3) (CH 2 ) 3 CH (CH 3) 2, i.e. the compound is a cholestane--3 ⁇ , 5 ⁇ , 6 ⁇ --triol (Compound I).
  • R1 is -CHCH 2 CH 3 , -CH(CH 3 ) 2 or -CH(CH 2 ) 3 CH 3 , ie, the compound is 17-propylene-androst-3 ⁇ , 5 ⁇ , respectively , 6 ⁇ -triol (compound II), 17-isopropyl-androst-3 ⁇ , 5 ⁇ , 6 ⁇ -triol (compound III), 17-butyl-androst-3 ⁇ , 5 ⁇ , 6 ⁇ -triol (compound) IV).
  • the high altitude disease is selected from the group consisting of acute high altitude disease, high altitude cerebral edema, neuronal damage caused by acute hypobaric hypoxia, or neuronal damage caused by chronic hypobaric hypoxia.
  • the subject is a mammal, such as a human.
  • 5 ⁇ -androst-3 ⁇ , 5,6 ⁇ -triol and the like are structurally characterized by 3 ⁇ , 5 ⁇ , 6 ⁇ -trihydroxysteroids, which are functionally characterized by neuroprotective effects.
  • the present inventors have found that the above 5 ⁇ -androst-3 ⁇ ,5,6 ⁇ -triol analog can also effectively prevent or treat high altitude hypoxia-induced altitude sickness.
  • Figure 1 5 ⁇ -androst-3 ⁇ ,5,6 ⁇ -triol significantly improved neurological impairment in acute hypobaric hypoxic cynomolgus monkeys. *: 5 ⁇ -androst-3 ⁇ ,5,6 ⁇ -triol treated group compared with the solvent control group, P ⁇ 0.05.
  • Figure 2 5 ⁇ -androst-3 ⁇ ,5,6 ⁇ -triol attenuates angioedema in the cortical tissue of acute hypobaric hypoxic cynomolgus monkeys (TEM, 3900 ⁇ ).
  • Con plain control group
  • H/R+V solvent control group
  • H/R+YC-6 5 ⁇ -androst-3 ⁇ , 5,6 ⁇ -triol treatment group.
  • the thick arrows indicate capillaries in the frontal cortex tissue of the brain, and the thin arrows indicate the perivascular VRS.
  • Figure 3 5 ⁇ -androst-3 ⁇ ,5,6 ⁇ -triol attenuates degenerative damage in hypoxic-anoxia cynomolgus monkey cortical neurons (HE staining, 400 ⁇ ).
  • Con plain control group
  • H/R+V solvent control group
  • H/R+YC-6 5 ⁇ -androst-3 ⁇ , 5,6 ⁇ -triol treatment group. Arrows indicate degeneration of damaged neurons.
  • Animals 17 healthy male cynomolgus monkeys (Macaca fascicularis), 6 to 6.5 years old, weighing 6.8-7.5 Kg.
  • the use of laboratory animals was approved by the Laboratory Animal Management and Use Committee and the Experimental Animal Ethics Committee, which was in accordance with animal protection, animal welfare, and ethical principles and regulations.
  • the plateau environment simulation low-pressure tank group is a simulated low-temperature and low-pressure experimental platform system for the plateau environment, which can automatically control the low temperature and low pressure environment at any altitude below 10,000 meters and any temperature above -30 °C.
  • the ascending speed is 3 m/s (0 to 6000 m); when descending, it is 2 m/s (6000 to 7500 m), the cabin temperature is constant at 22 ° C, and the average air flow rate is 150 m 3 /h.
  • the animal stayed at a altitude of 7,500 meters in the low-pressure chamber for 24 hours, and then dropped to a simulated altitude of 6,000 meters at a speed of 3 meters per second, according to the literature (Zhu Hua, Lu Shan, Feng Ming, Li Qin, etc.)
  • An improved method for evaluating non-human primate neurological deficits Chinese Journal of Comparative Medicine, 2011, 21(9): 58-62), evaluates and records neurological scores of cynomolgus monkeys. Neurological function scores were assessed and recorded by two trained observers who did not understand the grouping and did not participate in the dosing, and were scored on an average scale.
  • the left hemisphere was placed in a 60 ° C dry box, and the brain weight was weighed every day until the brain weight value no longer changed, and the brain weight was recorded at the end point.
  • Percentage of water content (left hemi-wet weight - left hemi-brain dry weight) / left hemi-brain wet weight ⁇ 100%.
  • a 1 mm 3 brain block was excised and fixed in a 2.5% glutaraldehyde electron microscope fixative to prepare ultrathin sections.
  • the following items were observed by transmission electron microscopy: the morphology of the neurons and the structure of the blood vessels.
  • the experimental monkey brain frontal cortex tissue was removed and cut into 1 cm 3 squares and fixed in 4% paraformaldehyde. Then, according to the conventional HE staining step, paraffin embedding, sectioning, and hematoxylin and eosin staining were observed under a microscope.
  • 5 ⁇ -androst-3 ⁇ ,5,6 ⁇ -triol significantly reduced the water content of cynomolgus monkey brain under hypobaric hypoxia.
  • Calculating and analyzing the percentage of brain water content showed that the brain water content of the cynomolgus monkeys in the plain control group was 76.155%, compared with the low pressure compartment.
  • the brain water content of the cynomolgus monkeys in the solvent control group increased to 76.714% (P ⁇ 0.05).
  • 5 ⁇ -androst-3 ⁇ ,5,6 ⁇ -triol reduces angioedema caused by hypobaric hypoxia.
  • the vesicular cavity of the cynomolgus monkey in the solvent control group showed a significantly widened perivascular space (Virchow Robin Space, VRS), indicating severe angioedema exudation.
  • the perivascular space of the brain tissue of cynomolgus monkeys treated with 5 ⁇ -androst-3 ⁇ ,5,6 ⁇ -triol tends to be normal, indicating no significant angioedema (Fig. 2).
  • 5 ⁇ -androst-3 ⁇ ,5,6 ⁇ -triol attenuates neuronal degeneration damage caused by hypobaric hypoxia treatment.
  • the structure of the frontal cortex of the solvent control group was loose, the edema fluid appeared around the blood vessels, and the lumen was compressed. Some neurons were degenerated, the cell body shrunk, the nucleus was condensed, and the cells showed vacuolar degeneration.
  • the angioedema of the 5 ⁇ -androst-3 ⁇ ,5,6 ⁇ -triol treatment group was not obvious, and the vacuolar degeneration of the neurons in the plain control group was reduced, indicating that 5 ⁇ -androst-3 ⁇ ,5, 6 ⁇ -triol has a protective effect on neurons in hypobaric hypoxia (Figure 3).
  • the 5 ⁇ -androst-3 ⁇ ,5,6 ⁇ -triol injection and the sustained release suspension are used in the present embodiment, and the pharmaceutical dosage forms for preparing or preventing low altitude hypoxia-induced high altitude disease include, but are not limited to, injections, Sustained-release suspension, oral capsules (pellets), suppositories, subcutaneous implants and external plaster preparations.
  • Preparation of 20% HP- ⁇ -CD solution 20.0 g of HP- ⁇ -CD was weighed out, 80 mL of physiological saline was added, and the mixture was stirred to dissolve. Add physiological saline to 100 ml, finely filter through a 0.22 ⁇ m microporous membrane, dispense into a 15 mL centrifuge tube, and seal at 4 ° C for storage.
  • YC-6 solution Preparation of 2 mg/ml YC-6 solution: Weigh 6.0 g of HP- ⁇ -CD, add 24 mL of deionized water, and stir to dissolve. YC-60.060 g was weighed, added to the above HP- ⁇ -CD solution, and stirred to dissolve. Weigh 0.270g of sodium chloride, add Into it, stir to dissolve, add deionized water to 30 mL. After fine filtration through a 0.22 ⁇ m microporous membrane, the mixture was dispensed into a 1.5 mL Eppendorf tube, sealed and stored at 4 ° C until use. When it was used, it was administered in a volume of 10 ml/kg, and was converted into a dose of 20 mg/kg.
  • the formulation of the sustained-release suspension was: YC-612.5 g, glycerin 30 mL, HP- ⁇ -CD 50 g, CMC-Na 0.48 g, and water for injection was added to 250 mL.
  • Preparation method 0.8% CMC-Na solution was prepared, and CMC-Na was weighed to 0.8 g of CMC-Na, and added to 90 mL of 90-degree water several times, and stirred while being added until all were added and dissolved. After room temperature, add water to 100 mL and mix well. Centrifuge at 3000r/min for 15min, take the supernatant and set aside.
  • HP- ⁇ -CD solution Preparation of 40% HP- ⁇ -CD solution: Weigh 80 g of HP- ⁇ -CD, add to about 100 mL of water, stir to dissolve, add water to 200 mL, and set aside.
  • YC-6 YC-6 was weighed, placed in a mortar, and the particles were ground and ground. Add 30mL of glycerin, continue to grind it, and make a creamy white lubricating liquid into a fine paste. 125 mL of 40% HP- ⁇ -CD aqueous solution was taken and ground while being added. 0.8% CMC-Na, add 60 mL while adding to the side to avoid excessive bubbles. Transfer to the quantitative tube, make up the water for injection to 250mL, shake to make it even.
  • YC-6 was replaced with the above compounds I, II, III, and IV, and the above experiment of the acute hypotensive hypoxia model of cynomolgus monkey was repeated under the same conditions.
  • the results showed that, similarly, the neurological function of cynomolgus monkeys treated with compounds II, III and IV was effectively protected, the increase in brain water content was inhibited, no significant angioedema occurred, and angioedema was not obvious. It can be seen that 5 ⁇ -androst-3 ⁇ ,5,6 ⁇ -triol analogs, especially compound I and compounds of formula A (especially compounds II, III, IV) are also effective in preventing or treating low altitude hypoxia-induced altitude sickness. .

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Abstract

5α-雄甾-3β，5，6β-三醇及其类似物在制备治疗或预防低压缺氧造成的高原病的药物中的应用。

Description

神经保护剂及其适应症
相关申请的交叉引用
本申请要求2014年4月25日提交中国发明专利申请201410170263.7号的优先权，通过引用将其所有内容合并至本文中。
技术领域
本发明涉及化合物5α-雄甾-3β,5,6β-三醇及其类似物的新的药物用途。
背景技术
随着海拔上升，大气压降低且氧分压降低，吸入气氧分压过低导致动脉血氧分压降低，氧含量减少，组织供氧不足。这种低压缺氧(hypobaric hypoxia,HH)主要发生在高原这一特殊环境，也被称作高原低氧(high altitude hypoxia)。
当个体近期到达超过海拔2500米以上地区，在急性低压缺氧(Acute Hypobaric Hypoxia)发生时，如果个体适应不了这种环境变化，会相继发生高原性头痛(High-altitude headache，HAH)、急性高原病(Acute mountain sickness，AMS)，并且AMS可进一步发展为高原脑水肿(High altitude cerebral edema，HACE)和高原肺水肿(High-altitude pulmonary edema,HAPE)。已有大量报道，高原病根据程度不同主要表现出头痛、多言、失眠、步态不稳、受损伤的心智能力、嗜睡、神情恍惚麻木以及共济失调等神经功能上的症状。
目前，针对高原病药物的研发思路主要是靶向提高携氧能力和细胞因子、炎症反应，前者的代表性药物为碳酸酐酶抑制剂如乙酰唑胺，后者代表药物如糖皮质激素和一些抗氧化剂(Wright A,Brearey S,Imray C.High hopes at high altitudes:pharmacotherapy for acute mountain sickness and high-altitude cerebral and pulmonary oedema.Expert Opin Pharmacother 2008Jan；9(1):119-27)，但没有一种药物属于神经保护剂。
5α-雄甾-3β,5,6β-三醇是新发现的神经保护剂(中山大学(颜光美；胡海燕；冷田东；桑韩飞；张静夏；邱鹏新；周树佳；陈婕思；游秀华)，5α-雄甾(烷)-3β,5,6β-三醇在制备神经元保护药物中的应用；中国发明专利号：ZL 2010 1 0224173.3)，其结构式为：
Figure PCTCN2015076528-appb-000001
我们的研究发现，5α-雄甾-3β,5,6β-三醇及其类似物出人意料地可以显著改善低压缺氧处理的神经功能学评分，保护低压缺氧造成的脑部病理损伤，从而有效预防或治疗低压缺氧引起的高原病。
发明内容
本发明的目的在于提供下式A的3β,5α,6β-三羟基甾体化合物或其药学上可接受的盐在制备治疗或预防低压缺氧造成的高原病的药物组合物中的应用，从而为高原病的预防与治疗提供一种新药物：
Figure PCTCN2015076528-appb-000002
其中R1为H或具有1至5个碳原子的直链或支链的烷基或末端烯基。
在一个实施方式中，其中R1为H，即所述化合物为5α-雄甾-3β,5,6β-三醇(在本说明书及说明书附图中也被简称为“YC-6”)。
在本发明的一个实施方式中，所述高原病为由高原性急性低压缺氧引起的急性高原病。
在本发明的另一个实施方式中，所述高原病为高原脑水肿，具体是血管性水肿。
在本发明的另一个实施方式中，所述高原病为神经元损伤，具体是神经元的变性损伤，包括由高原性急性低压缺氧引起的神经元损伤和由高原性慢性低压缺氧引起的神经元损伤。
在本发明的另一个实施方式中，所述药物组合物包含额外的用于治疗或预防低压缺氧造成的高原病的活性成分，例如碳酸酐酶抑制剂(如乙酰唑胺)、糖皮质激素和抗氧化剂。
非人灵长类低压缺氧模型动物模型的研究表明，5α-雄甾-3β,5,6β-三醇处理可以显著 改善低压缺氧环境下的实验动物的神经功能学评分，对低压缺氧导致的神经功能损伤具有显著保护作用,表明5α-雄甾-3β,5,6β-三醇对AMS(High altitude cerebral edema)和HACE(High-altitude pulmonary edema)具有预防和治疗效果。
进一步的研究表明，5α-雄甾-3β,5,6β-三醇显著阻断低压缺氧导致的脑含水量上升，电镜形态学和HE染色病理分析表明，5α-雄甾-3β,5,6β-三醇可以减少低压缺氧导致的脑血管源性水肿和神经元空泡样变性损伤，从而预防或治疗高原病。
在另外的实施方式中，R1为-CH(CH3)(CH2)3CH(CH3)2，即所述化合物为胆甾烷-3β，5α，6β-三醇(化合物I)。研究表明，化合物I也具有神经保护作用(中山大学，胆甾烷-3β，5α，6β-三醇在制备神经元保护药物中的应用，中国发明专利号ZL 200810198703.4)。相似地，我们发现，该化合物也能够有效减轻低压缺氧引起的血管性水肿及神经元变性损伤，从而用于高原病的预防或治疗。化合物I的结构式为：
Figure PCTCN2015076528-appb-000003
同样类似地，通式A的其他化合物也具有神经保护作用(中山大学，3β,5α,6β-三羟基甾体化合物及其合成方法和应用，中国发明专利号ZL 201110061235.8)。相似地，我们发现，这些化合物也能够有效减轻低压缺氧引起的血管性水肿，降低脑含水量上升，保护低压缺氧引起的神经元变性损伤，从而用于高原病预的防或治疗。
在具体的实施方式中，R1为-CHCH2CH3、-CH(CH3)2或-CH(CH2)3CH3，即所述化合物分别是17-亚丙基-雄甾-3β,5α,6β-三醇(化合物II)、17-异丙基-雄甾-3β,5α,6β-三醇(化合物III)、17-丁基-雄甾-3β,5α,6β-三醇(化合物IV)。
本发明的另一个方面提供一种治疗或预防低压缺氧造成的高原病的方法，包括向有需要的对象施用有效量的式A的3β,5α,6β-三羟基甾体化合物或其药学上可接受的盐，
Figure PCTCN2015076528-appb-000004
其中R1为H或具有1至5个碳原子的直链或支链的烷基或末端烯基。
在一个实施方式中，其中R1为H，即所述化合物为5α-雄甾-3β,5,6β-三醇。在另一个实施方式中，R1为-CH(CH3)(CH2)3CH(CH3)2，即所述化合物为胆甾烷-3β，5α，6β-三醇(化合物I)。在其他实施方式中，R1为-CHCH2CH3、-CH(CH3)2或-CH(CH2)3CH3，即所述化合物分别是17-亚丙基-雄甾-3β,5α,6β-三醇(化合物II)、17-异丙基-雄甾-3β,5α,6β-三醇(化合物III)、17-丁基-雄甾-3β,5α,6β-三醇(化合物IV)。
在本发明的实施方式中，所述高原病选自急性高原病、高原脑水肿、急性低压缺氧引起神经元损伤或慢性低压缺氧引起的神经元损伤。
在本发明的实施方式中，所述对象为哺乳动物，例如人。
5α-雄甾-3β,5,6β-三醇及其类似物在结构上的特征都是3β,5α,6β-三羟基甾体类化合物，功能上的特征在于都具备神经保护作用。本发明发现上述5α-雄甾-3β,5,6β-三醇类似物同样能够有效预防或治疗低压缺氧引起的高原病。
附图说明
图1:5α-雄甾-3β,5,6β-三醇显著改善急性低压缺氧的食蟹猴的神经功能损伤。*：5α-雄甾-3β,5,6β-三醇处理组与溶剂对照组比较，P<0.05。
图2：5α-雄甾-3β,5,6β-三醇减轻急性低压缺氧食蟹猴脑皮层组织的血管性水肿(透射电镜，3900×)。Con：平原对照组；H/R+V：溶剂对照组；H/R+YC-6：5α-雄甾-3β,5,6β-三醇处理组。粗箭头指示大脑额叶皮层组织内的毛细血管，细箭头指示血管周隙VRS。
图3：5α-雄甾-3β,5,6β-三醇减轻低压缺氧食蟹猴脑皮层神经元的变性损伤(HE染色，400×)。Con：平原对照组；H/R+V：溶剂对照组；H/R+YC-6：5α-雄甾-3β,5,6β-三醇处理组。箭头指示变性受损的神经元。
具体实施方式
下面通过具体实施例进一步解释本发明，但是本发明不仅限于实施例中。
5α-雄甾-3β,5,6β-三醇的新用途验证
1.动物：健康雄性食蟹猴(Macaca fascicularis)17只，6至6.5岁，体重6.8-7.5Kg。实验动物的使用经过实验动物管理与使用委员会和实验动物伦理委员会批准，实验方案符合动物保护、动物福利和伦理原则和规定。
17只雄性食蟹猴随机分为3组(表1)
表1.实验动物分组说明
Figure PCTCN2015076528-appb-000005
2.主要仪器与参数：高原环境模拟低压舱群是模拟高原环境低温低压实验平台体系，可以自动化控制模拟1万米以下任意海拔高度、-30℃以上任意温度的低温低压环境。上升速度为3米/秒(0至6000m)；下降时为2米/秒(6000至7500m)，舱内温度恒定于22℃，平均空气流速为150m3/h。
3.食蟹猴急性低压缺氧模型的制作及给药：
(1)采用低压舱控制模拟7500米海拔高度造成食蟹猴急性缺氧。将饲养于动物房的食蟹猴做好标识然后放入低压舱内饲养1天以适应实验环境。实验开始后通过调节低压舱内气压来模拟3000、4500、6000米海拔高度，每个高度停留30分钟后，以及模拟7500米处理24小时后，按设计剂量和方式给药。7500米处理48小时后，以3米/秒速度将模拟海拔下降到6000米，氯胺酮麻醉后放血处死动物，并进行解剖、取材、固定。平原对照组的食蟹猴一直饲养于海拔高度为350米的动物房，直到评价和麻醉处死取材。
(2)5α-雄甾-3β,5,6β-三醇处理组的动物在未开始模拟升高前、模拟升至3000米停留30分钟后以及模拟升至4500米停留30分钟后，按10mg/kg的剂量分别静脉推注葡萄糖生理盐水稀释的5α-雄甾-3β,5,6β-三醇10mL；溶剂对照组只静脉推注葡萄糖生理盐水10mL。
(3)5α-雄甾-3β,5,6β-三醇处理组的动物在低压舱内模拟高度6000米停留30分钟后，5α-雄甾-3β,5,6β-三醇缓释剂按30mg/kg的剂量分成5点进行骨骼肌肌肉注射；急性高原缺氧模型组只静脉推注葡萄糖生理盐水10mL。
(4)5α-雄甾-3β,5,6β-三醇处理组的动物在低压舱内模拟高度7500米停留24小时后，5α-雄甾-3β,5,6β-三醇注射液按10mg/kg的剂量用葡萄糖生理盐水稀释至10mL，一次性静脉推注，并且5α-雄甾-3β,5,6β-三醇缓释剂按30mg/kg的剂量分成5点进行骨骼肌肌肉注射。急性高原缺氧模型组只静脉推注葡萄糖生理盐水10mL。
4.检测指标
4.1动物神经功能评分
根据本实验的特点，动物在低压舱内模拟海拔7500米停留24小时后，以3米/秒速度下降到模拟海拔6000米，按照文献(朱华,卢珊,冯铭,李秦等，一种改进的非人灵长类神经功能缺损评价方法,中国比较医学杂志,2011,21(9):58-62)的方法评估并记录食蟹猴的神经功能评分。由两位不了解分组情况且未参与给药的经培训的观察者评估并记录神经功能评分，按平均评分计分。
4.2左半球脑含水量测量
根据文献(Patir H,Sarada SK,Singh S,Mathew T,Singh B,Bansal A.Quercetin as a prophylactic measure against high altitude cerebral edema.Free Radic Biol Med 2012Aug 15；53(4):659-68)介绍的方法进行脑含水量测量。低压舱模拟高度7500米停留48小时后以及平原对照组实验猴，由不了解分组情况且未参与给药的实验者麻醉放血处死，迅速取出猴脑，切取左半脑，称取其湿重。然后将左半脑置于60℃干燥箱，每天固定时间称取脑重，直至脑重数值不再变化，记录终点脑重。含水量百分比＝(左半脑湿重－左半脑干重)/左半脑湿重×100％。
4.3大脑额叶皮层组织的透射电镜分析
实验猴大脑额叶皮层组织取出后切出1mm3脑块，固定于2.5％戊二醛电镜固定液后制作超薄切片，用透射电镜观察分析以下项目：神经元的形态和血管的结构等。
4.4大脑额叶皮层组织的HE染色分析
实验猴大脑额叶皮层组织取出后切出1cm3的方块后固定于4％多聚甲醛中。之后按照常规HE染色步骤，进行石蜡包埋，切片，苏木素伊红染色后在显微镜下观察。
4.5统计学处理
实验结果以均数±标准差表示，采用SigmaPlot软件进行统计分析。P<0.05表示差异有统计学意义。
结果表明，5α-雄甾-3β,5,6β-三醇显著保护低压缺氧环境食蟹猴的神经功能。实验猴在低压舱模拟海拔6000米环境下停留30分钟后，行为活动明显减少，对威迫刺激的反应也有所降低。将模拟海拔提高到7500米24小时后，溶剂对照组食蟹猴出现明显的意识抑制，行为活动大为减少，且出现运动、感觉系统的功能障碍，神经功能评分为31.6±4.2；与之相比，5α-雄甾-3β,5,6β-三醇处理组的动物的神经功能评分为20.5±5.7(P<0.01)，显示神经功能得到有效保护(图1)。
5α-雄甾-3β,5,6β-三醇显著减少低压缺氧环境下食蟹猴脑含水量的增加。计算并分析脑含水量百分比后显示，平原对照组食蟹猴的脑含水量为76.155％，与之相比，在低压舱 内模拟海拔7500米处理48小时后，溶剂对照组食蟹猴的脑含水量增加为76.714％(P<0.05)。升至7500米前给予5α-雄甾-3β,5,6β-三醇并在7500米维持24小时后再次给予5α-雄甾-3β,5,6β-三醇，食蟹猴的脑含水量降低至76.283％(P<0.05)，表明给予5α-雄甾-3β,5,6β-三醇可以抑制急性高原缺氧环境下食蟹猴脑含水量的增加(表2)。
表2.5α-雄甾-3β,5,6β-三醇对低压缺氧环境下的食蟹猴脑含水量的影响
Figure PCTCN2015076528-appb-000006
#：与平原对照组比较，P<0.05；*：与溶剂对照组比较，P<0.05。
5α-雄甾-3β,5,6β-三醇减轻低压缺氧引起的血管性水肿。在透射电镜下观察，与平原对照组比较，溶剂对照组食蟹猴大脑额叶皮层毛细血管外出现明显加宽的血管周隙(Virchow Robin Space，VRS)，表明出现严重的血管性水肿渗出；而经5α-雄甾-3β,5,6β-三醇处理的食蟹猴脑组织血管周隙趋于正常，显示并未发生明显的血管性水肿(图2)。
5α-雄甾-3β,5,6β-三醇减轻低压缺氧处理引起的神经元变性损伤。经HE染色后观察，溶剂对照组大脑额叶皮层组织结构明显疏松，血管周围出现水肿液，压迫管腔；部分神经元变性，胞体皱缩、核固缩，细胞出现空泡样变性改变(箭头所示)；5α-雄甾-3β,5,6β-三醇处理组的血管性水肿不明显，与平原对照组近似神经元空泡样变性损伤减轻，表明5α-雄甾-3β,5,6β-三醇对低压缺氧环境下的神经元具有保护作用(图3)。
药物组合物
本实施例中使用的是5α-雄甾-3β,5,6β-三醇注射剂与缓释混悬剂，在制备预防或治疗低压缺氧引起的高原病时的药物剂型包括但不限于注射剂、缓释混悬剂、口服胶囊(丸)、栓剂以及皮下埋植剂及外贴膏药型制剂等。
(1)5α-雄甾-3β,5,6β-三醇(YC-6)注射剂的制备
20％HP-β-CD溶液的配制：称取20.0g HP-β-CD，加入80mL生理盐水，搅拌使其溶解。加生理盐水至100ml，经0.22μm微孔滤膜精滤，分装于15mL离心管中，密封于4℃下保存。
2mg/ml YC-6溶液的配制：称取6.0g HP-β-CD，加24mL去离子水，搅拌使其溶解。称取YC-60.060g，加至上述HP-β-CD溶液中，搅拌使其溶解。称取氯化钠0.270g，加 入其中，搅拌使其溶解，加去离子水至30mL。经0.22μm微孔滤膜精滤，分装于1.5mL Eppendorf管中，密封于4℃下保存待用。使用时按10ml/kg液量给药，换算为20mg/kg给药量。
(2)5α-雄甾-3β,5,6β-三醇(YC-6)缓释剂的制备
缓释混悬剂的处方是：YC-612.5g，甘油30mL，HP-β-CD 50g，CMC-Na 0.48g，注射用水加至250mL。
制备方法：0.8％CMC-Na溶液的配制，称取CMC-Na消0.8g CMC-Na，分多次加到90mL的90度的水中，边加边搅，直至全部加入并溶解。放至室温，加水至100mL，搅匀。3000r/min离心15min，取上清液，备用。
40％HP-β-CD溶液的配制：称取HP-β-CD 80g，加到约100mL水中，搅拌溶解，加水至200mL，备用。
称取YC-6约12.5g，置乳钵中，将颗粒研细研匀。加入30mL甘油，继续研匀，使成乳白色润滑液，成细腻糊状。取125mL的40％HP-β-CD水溶液，逐量边加入边研磨。0.8％CMC-Na，取60mL边加入边研匀，避免产生过多的气泡。转移至定量管，补注射用水至250mL，摇晃使均匀。
5α-雄甾-3β,5,6β-三醇类似物的新用途验证
将YC-6替换为上述化合物I、II、III、IV，在相同条件下重复上述食蟹猴急性低压缺氧模型的实验。结果表明，相似地，经过化合物II、III、IV处理的食蟹猴的神经功能得到有效保护，脑含水量的增加被抑制，没有发生明显的血管性水肿，并且血管性水肿不明显。可见5α-雄甾-3β,5,6β-三醇类似物特别是化合物I和具有通式A的化合物(特别是化合物II、III、IV)也能够有效预防或治疗低压缺氧引起的高原病。
以上所述仅为本发明的优选实施方式，并不以此限定本发明的范围。本领域技术人员可以基于本发明的公开内容对其作出修改或修饰，而不超出本发明权利要求界定的范围。

Claims (15)

  1. 下式A的3β,5α,6β-三羟基甾体化合物或其药学上可接受的盐在制备治疗或预防低压缺氧造成的高原病的药物组合物中的应用，
    Figure PCTCN2015076528-appb-100001
    其中R1为H或具有1至5个碳原子的直链或支链的烷基或末端烯基。
  2. 如权利要求1所述的应用，其中R1为H。
  3. 如权利要求1所述的应用，其中R1选自：-CHCH2CH3、-CH(CH3)2、-CH(CH2)3CH3和-CH(CH3)(CH2)3CH(CH3)2。
  4. 根据权利要求1所述的应用，其中所述高原病为急性高原病。
  5. 根据权利要求1所述的应用，其中所述高原病为高原脑水肿。
  6. 根据权利要求1所述的应用，其中所述高原病为神经元损伤。
  7. 根据权利要求6所述的应用，其中所述高原病为由高原性急性低压缺氧引起的神经元损伤。
  8. 根据权利要求6所述的应用，其中所述高原病为由高原性慢性低压缺氧引起的神经元损伤。
  9. 根据权利要求1所述的应用，所述药物组合物包含额外的用于治疗或预防低压缺氧造成的高原病的活性成分。
  10. 一种治疗或预防低压缺氧造成的高原病的方法，包括向有需要的对象施用有效量的式A的3β,5α,6β-三羟基甾体化合物或其药学上可接受的盐，
    Figure PCTCN2015076528-appb-100002
    其中R1为H或具有1至5个碳原子的直链或支链的烷基或末端烯基。
  11. 如权利要求10所述的方法，其中R1为H。
  12. 如权利要求10所述的方法，其中R1选自：-CHCH2CH3、-CH(CH3)2、-CH(CH2)3CH3和-CH(CH3)(CH2)3CH(CH3)2。
  13. 如权利要求10所述的方法，其中所述高原病选自急性高原病、高原脑水肿、急性低压缺氧引起神经元损伤或慢性低压缺氧引起的神经元损伤。
  14. 如权利要求10所述的方法，所述对象为哺乳动物。
  15. 如权利要求14所述的方法，所述哺乳动物是人。
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