WO2023236485A1 - 一种青蒿素的衍生物及其制备方法与应用 - Google Patents
一种青蒿素的衍生物及其制备方法与应用 Download PDFInfo
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- WO2023236485A1 WO2023236485A1 PCT/CN2022/138838 CN2022138838W WO2023236485A1 WO 2023236485 A1 WO2023236485 A1 WO 2023236485A1 CN 2022138838 W CN2022138838 W CN 2022138838W WO 2023236485 A1 WO2023236485 A1 WO 2023236485A1
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- WIPO (PCT)
- Prior art keywords
- eye tissue
- pharmaceutically acceptable
- formula
- acceptable salt
- artemisinin
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical class C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 title abstract description 22
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/20—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the invention belongs to the field of medicine, and specifically relates to a derivative of artemisinin and its preparation method and application.
- Malaria is an insect-borne infectious disease. It is an infectious disease caused by the bite of an insect infected by Plasmodium. After repeated attacks over a long period of time, hepatosplenomegaly can occur, accompanied by symptoms such as anemia. Malaria can be treated to a certain extent, and artemisinin plays an important role.
- the peroxy bond in the artemisinin structure is oxidizing and is an essential group for antimalarial treatment.
- the mechanism of action is that the free radicals generated by artemisinin in the body bind to malaria proteins and change the cell membrane structure of the malaria parasite. After the free radicals bind to the malaria protein, the double-layer membrane of the mitochondria will swell and eventually fall off, causing damage to the cell structure and function of the malaria parasite.
- artemisinin has certain effects on the treatment of macular degeneration and fundus diseases.
- the physical and chemical properties of artemisinin are unstable, easily oxidized, and difficult to dissolve in water, so it is difficult to apply it to liquid preparations, especially drops.
- both artemisinin and artesunate are difficult to dissolve in water and are not highly absorbed by eye tissue. Therefore, it is very necessary to find an artemisinin derivative that has moderate solubility and can be absorbed into eye tissue. .
- the object of the present invention is to provide a compound represented by formula I or a pharmaceutically acceptable salt thereof, which is an excellent artemisinin derivative.
- n can be an integer from 1 to 15, such as 2, 3, and 4.
- the compound represented by formula I may be a compound represented by formula II:
- n can be an integer from 1 to 15, such as 2, 3, 4;
- X - represents an anion.
- the pharmaceutically acceptable salts of the compounds represented by Formula I in the present invention refer to those that are suitable for contact with tissues of humans and lower animals without causing excessive toxicity, irritation, allergic reactions, etc., within the scope of reliable medical judgment. , and salt commensurate with a reasonable effect/risk ratio.
- the pharmaceutically acceptable salts of the compound represented by formula I are citrate, fumarate, salicylate, L-tartrate, fumarate, hydrochloride, and acetic acid. Salt, nitrate, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, acetate, oxalate, lactate, lysine or aspartate.
- the present invention also provides a method for preparing the compound represented by the above formula I.
- the preparation method of the compound represented by Formula I provided by the invention includes the following steps:
- the alkyl group in the 3-dimethylamino-1-alkyl alcohol can be propyl, butyl, etc.
- the mass usage ratio of dimethylamino-alkyl alcohol and methyl iodide is 1:3-5; the mass usage ratio of dihydroartemisinin and quaternary ammonium salt intermediate is 1:1-2.
- the reaction temperature of the reaction is 20-45°C, and the reaction time of the reaction is 2-6 h.
- the present invention also provides the use of the above-described compound represented by Formula I or a pharmaceutically acceptable salt thereof in the preparation of medicaments for preventing and/or treating ocular tissue diseases.
- the present invention also provides the use of the above-mentioned compound represented by Formula I or a pharmaceutically acceptable salt thereof in the preparation of inhibitors for preventing and/or treating corneal neovascularization.
- the present invention provides a drug or pharmaceutical composition for preventing and/or treating eye tissue diseases, including the compound represented by formula I as described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt. carrier.
- the medicine can be introduced into the body through injection, spraying, nasal drip, eye drop, penetration, absorption, physical or chemical mediated methods, such as muscle, intradermal, subcutaneous, vein, mucosal tissue; or after being mixed or wrapped with other substances Import into the body.
- the ocular tissue disease is ocular tissue inflammation or ocular tissue macular degeneration.
- the pharmaceutically acceptable carrier includes at least one of diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption accelerators, surfactants, adsorption carriers and lubricants. kind.
- the dosage form of the drug or pharmaceutical composition is a liquid preparation; preferably, the liquid preparation is eye drops or injection.
- the pH value of the eye drops is 5.5-6.5.
- the compound represented by Formula I of the present invention has suitable solubility, is relatively stable under storage conditions, and is an excellent artemisinin prodrug.
- the compound of Formula I of the present invention has significant absorption advantages and can be prepared into a liquid preparation. Such as eye drops, injections, etc., used to treat eye tissue diseases.
- Figure 1 is an example of fluorescein staining for each treatment group in Example 6;
- Figure 2 is an illustration of neovascularization in each treatment in Example 6.
- pH value SZY1905-P30(mg/ml) SZY1905-P31(mg/ml) purified water >10 >10 5.0 >1 >1 6.0 >1 >1 7.0 >1 >1 8.0 >1 >1
- artemisinin quaternary ammonium butyl ether iodate (SZY1905-P30) was replaced by artemisinin quaternary ammonium butyl ether iodate (SZY1905-P31), and the sulfate compound of SZY1905-P31 was obtained according to the above method.
- tetracaine hydrochloride (Sun Yat-sen University Eye Hospital; 20220113); tobramycin dexamethasone sodium phosphate eye drops (Sun Yat-sen University Eye Hospital; 20211217); chloral hydrate solution (Sun Yat-sen University Eye Hospital; 20220224 ); 1.0mol/L NaOH solution; filter paper; stopwatch; fluorescein sodium eye drops (Sun Yat-sen University Eye Hospital); 0.9% sodium chloride injection (Guangdong Yixiang Pharmaceutical Co., Ltd., 210926202); 50ml syringe; 1ml syringe .
- Healthy New Zealand rabbits were purchased from Huadong Xinhua Experimental Animal Breeding Farm, Huadu District, Guangzhou City; slit lamp examination was performed to exclude presegmental eye lesions. Age 2.0-2.5 months; weight 2.2kg-2.9kg.
- modeling 24 animals were divided into 4 groups, namely modeling group; SZY1905-P30 eye drops group; SZY1905-P31 eye drops group; 1% SZY1905-P32 eye drops group. Administer 3 times a day, 2 drops each time. Among them, the modeling group was not given drugs.
- the fissures were digitally modeled. Take pictures with a lamp, stain the cornea with sodium fluorescein, observe and take pictures under a slit lamp microscope.
- New Zealand rabbit No. 157 died unexpectedly due to shortness of breath on the 5th day after modeling.
- a total of 5 animals (101, 108, 109, 156, 161) remained in the 1% SZY1905-P32 eye drop group, and 10 eyes were used for subsequent experiments. .
- corneal epithelial staining point is larger than half of the corneal area, or there is a large area of flaky staining
- the fluorescein staining diagram of each treatment group in Example 6 is shown in Figure 1; the neovascularization diagram of each treatment in Example 6 is shown in Figure 2. It can be seen from the figure that some New Zealand rabbits after alkali burn began to generate a small amount of new blood vessels on the seventh day after modeling. Comparing the New Zealand rabbits with new blood vessels in the four groups, we can preliminarily conclude that the SZY1905-P30 administration group and the SZY1905- The P31 group can delay the rapid formation of new blood vessels and is significantly better than the SZY1905-P32 eye drops group. The new blood vessels of New Zealand rabbits in the SZY1905-P32 eye drops group have spread to the entire cornea.
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Abstract
公开了一种青蒿素衍生物及其制备方法与应用。所述青蒿素衍生物的结构式如式I所示。该化合物具有适宜的溶解度,储存条件下相对稳定,经过药代实验表明在眼组织中能够检测到青蒿素,并且角膜、结膜、房水中均有分布,达到较高的药物浓度,为优良的青蒿素前体药物,式I化合物具有显著的可吸收性,在眼组织中的药物浓度显示吸收良好,在烧伤模型的新生血管抑制作用显著优于青蒿素,能够制备成液体制剂,如滴眼液和注射液等,用于治疗眼组织疾病。
Description
本发明属于医药领域,具体涉及一种青蒿素的衍生物及其制备方法与应用。
治疗疟疾耐药性效果最好的药物,以青蒿素类药物为主的联合疗法,也是当下治疗疟疾的最有效最重要手段。但是近年来随着研究的深入,青蒿素其它作用也越来越多被发现和应用研究,如抗肿瘤、治疗肺动脉高压、抗糖尿病、胚胎毒性、抗真菌、免疫调节等。
疟疾属于虫媒传染病,是受疟原虫感染的按虫叮咬人体后而引起的一种传染病,长时间多次发作后出现可肝脾肿大,且伴随贫血等症状。疟疾能够得到一定程度的治疗,青蒿素功不可没。青蒿素结构中过氧键具有氧化性,是抗疟的必需基团。作用机理是青蒿素在体内产生的自由基团与虐原蛋白结合,改变疟原虫的细胞膜结构。自由基团与疟原蛋白结合之后会使线粒体的双层膜胀裂,最终脱落,导致疟原虫的细胞结构和功能受到破坏,同时细胞核内的染色质也会受到一定的影响。另一方面,氨基酸是构成蛋白质的基本物质,青蒿素作用后。疟原虫对异亮氨酸的吸收减少,导致虫体蛋白的合成受阻。黄花蒿不仅可以杀灭病原虫,还具有抗血吸虫作用、治疗弓形虫感染作用、抗卡氏肺孢子虫作用、抗球虫作用等。经临床试验证明,青蒿素及其衍生物在治疗疟疾的过程中,并未发现特别明显的副作用。
近年来发现青蒿素对于治疗视网膜黄斑变性及眼底疾病具有一定效果,然而青蒿素的理化性质具有不稳定、易氧化、难溶于水等特点,因此较难应用于液体制剂,尤其是滴眼液制剂形式,青蒿素及青蒿琥酯均难溶于水,并且眼组织吸收不高,因此寻找一个能够具备适中的溶解度,能够吸收进入眼组织的青蒿素衍生物是非常必要的。
发明内容
本发明的目的是提供一种式I所示的化合物或其药学上可接受的盐,该化合物为优良的青蒿素衍生物。
为实现上述目的,所采取以下技术方案:
式I所示的化合物或其药学上可接受的盐:
式I中,n可为1-15的整数,如2、3、4。
进一步的,式I所示的化合物可为式II所示化合物:
式II中,n可为1-15的整数,如2、3、4;X
-代表阴离子。
进一步的,所述X
-选自下述酸电离时产生的酸根阴离子:盐酸、硫酸、磷酸、HBr、HI、柠檬酸、富马酸、琥珀酸、醋酸、硝酸、硫酸氢、乳酸、甲磺酸、苯甲磺酸。
本发明中所述式I所示化合物药学上可接受的盐是指在可靠的医学判断范围内,适合用于与人类和低等动物的组织接触而不出现过度的毒性、刺激、过敏反应等,且与合理的效果/风险比相称的盐。
优选地,所述式I所示的化合物药学上可接受的盐为柠檬酸盐、反丁烯二酸盐、水杨酸盐、L-酒石酸盐、富马酸盐、盐酸盐、醋酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、乙酸盐、草酸盐、乳酸盐、赖氨酸盐或天冬氨酸盐。
本发明还提供了上述式I所示的化合物的制备方法。
本发明所提供的式I所示的化合物的制备方法,包括以下步骤:
1)将3-二甲氨基-1-烷基醇溶于乙腈,滴加碘甲烷搅拌反应,得到季铵盐中间体;
2)将双氢青蒿素分散于二氯甲烷中,依次加入季铵盐中间体、催化量三氟化硼乙醚后反应,得到所述式(I)所示的化合物。
其中,所述3-二甲氨基-1-烷基醇中的烷基可为丙基、丁基等。
所述二甲氨基-烷基醇和碘甲烷的质量用量比为1:3-5;双氢青蒿素与季铵盐中间体的质量用量比为1:1-2。
优选地,所述反应的反应温度为20-45℃,所述反应的反应时间为2-6h。
本发明还提供了上述所述的式I所示的化合物或其药学上可接受的盐在制备预防 和/或治疗眼组织疾病的药物中的应用。
本发明同时提供了上述所述的式I所示的化合物或其药学上可接受的盐在制备预防和/或治疗角膜新生血管抑制剂中的应用。
本发明提供了一种用于预防和/或治疗眼组织疾病的药物或药物组合物,包括如上述所述的式I所示的化合物或其药学上可接受的盐,以及药学上可接受的载体。
所述药物可通过注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮内、皮下、静脉、粘膜组织;或是被其他物质混合或包裹后导入机体。
优选地,所述眼组织疾病为眼组织炎症或眼组织黄斑变性。
优选地,所述药学上可接受的载体包括稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体和润滑剂中的至少一种。
优选地,所述药物或药物组合物的剂型为液体制剂;优选地,所述液体制剂为滴眼液或注射液。优选地,所述滴眼液的pH值为5.5-6.5。
有益效果:本发明式I所示的化合物,具有适宜的溶解度,储存条件下相对稳定,为优良的青蒿素前体药物,本发明式I化合物具有显著的吸收优势,能够制备成液体制剂,如滴眼液、注射液等,用于治疗眼组织疾病。
图1为实施例6中各处理组荧光素点染图例;
图2为实施例6中各处理新生血管生成图例。
下面结合具体实施例对本发明作进一步阐述,但本发明并不限于以下实施例。所述方法如无特别说明均为常规方法。所述原材料如无特别说明均能从公开商业途径获得。
实施例1:
SZY1905-P30的合成
100ml单口烧瓶中加入3-二甲氨基-1-丙醇5g,加入乙腈100ml搅拌溶解,滴加碘 甲烷20.7g,加毕,室温搅拌2h,TLC监测原料反应完毕。向反应液中滴加100ml甲叔醚,溶液中有白色固体析出,抽滤,得到10.4g的季铵盐中间体Ⅰ。
100ml单口烧瓶中依次加入10g季铵盐中间体Ⅰ、双氢青蒿素8.0g,加入二氯甲烷100ml搅拌分散,滴加催化量的三氟化硼乙醚溶液,加毕,澄清溶液逐渐变为深红色,室温搅拌2h,TLC监测原料反应完毕。反应液依次经饱和氯化铵和饱和氯化钠洗,有机相减压旋干得到SZY1905-P30粗品10.8g;粗品经二氯甲烷:甲醇(1:0-30:1)柱层析纯化,得到1.4g的泡沫状固体SZY1905-P30。
1HNMR CDCl
3δ:5.4(s,1H),5.3(m,1H),5.0(m,1H),4.6-4.4(m,2H),3.7-3.4(m,12H),1.9-1.8(m,3H),1.6-1.3(m,12H),1.1(m,3H),0.8(m,3H)。
LC-MS:m/z=384.3(M+1)。
实施例2:
SZY1905-P31的合成
100ml单口烧瓶中加入3-二甲氨基-1-丁醇1g,加入乙腈20ml搅拌溶解,滴加碘甲烷3.64g,加毕,室温搅拌2h,TLC监测原料反应完毕。向反应液中滴加20ml的甲叔醚,溶液中有白色固体析出,抽滤,得到2.0g的季铵盐中间体Ⅱ。
100ml单口烧瓶中依次加入2.0g季铵盐中间体Ⅱ、双氢青蒿素2.0g,加入二氯甲烷40ml搅拌分散,滴加催化量的三氟化硼乙醚,加毕,澄清溶液逐渐变为深红色,室温搅拌2h,TLC监测原料反应完毕。反应液依次经饱和氯化铵和饱和氯化钠洗,有机相减压旋干得到SZY1905-P31粗品2.5g;粗品经二氯甲烷:甲醇(1:0-30:1)柱层析纯化,得到300mg的泡沫状固体SZY1905-P31。
1HNMR CDCl
3δ:5.4(s,1H),5.0(m,1H),3.8(m,1H),3.6-3.5(m,4H),3.3(m,10H),2.2(m,1H),2.0(m,1H),1.9-1.8(m,4H),1.6-1.3(m,11H),1.1(m,3H),0.8(m,3H)。
LC-MS:m/z=398.1.0(M+1)。
实施例3:马来酸盐化合物的合成
100ml单口烧瓶中加入1g的SZY1905-P30,加入乙醇20ml搅拌溶解,滴加0.32g马来酸的乙醇溶液3mL,滴毕,冰水浴降温至0℃,逐渐有白色固体析出,0℃搅拌2h,抽滤,得到0.8g的马来酸盐化合物。
1HNMR d6-DMSOδ:6.2(s,2H),5.5(s,1H),5.3(d,1H),3.6-3.5(m,2H),3.3(m,1H),2.9(s,6H)2.2-2.0(m,4H),1.9-1.8(m,5H),1.7-1.3(m,9H),1.2(m,3H),0.9(m,3H)。
LC-MS:m/z=384.3(M+1)。
同理,将马来酸替换为其他有机酸,按照上述方法获得其他有机酸盐。
实施例3:不同pH值下的溶解度试验
首先利用磷酸和NaOH配制pH=5-8的系列溶液,配制方法如表1所示。
表1不同pH值溶液的配制方法
配制方法 | |
纯化水 | 自制 |
pH=5.0 | 磷酸水溶液稀释所得 |
pH=6.0 | 磷酸水溶液稀释所得 |
pH=7.0 | KH 2PO 4与NaOH配置的缓冲溶液 |
pH=8.0 | KH 2PO 4与NaOH配置的缓冲溶液 |
SZY1905-P30和SZY1905-P31的不同pH值下的溶解度如表2所示。
表2 SZY1905-P30和SZY1905-P31在25℃(室温)不同pH值下的溶解度
pH值 | SZY1905-P30(mg/ml) | SZY1905-P31(mg/ml) |
纯化水 | >10 | >10 |
5.0 | >1 | >1 |
6.0 | >1 | >1 |
7.0 | >1 | >1 |
8.0 | >1 | >1 |
实施例4:不同pH值下的稳定性试验
1、SZY1905-P30在不同pH下的稳定性
称取10mg的样品,加入10ml不同pH的水溶液,超声溶解,过滤后HPLC测试,结果如表3所示。
表3 SZY1905-P30在不同pH下的稳定性
0天(%) | 8天(%) | 20天(%) | 30天(%) | |
纯化水 | 97.09 | 96.91 | 97.04 | 97.28 |
pH=5.0 | 97.23 | 96.90 | 97.01 | 97.25 |
pH=6.0 | 97.24 | 96.95 | 96.81 | 97.23 |
pH=7.0 | 97.34 | 97.09 | 96.97 | 97.26 |
pH=8.0 | 97.22 | 97.13 | 96.98 | 97.13 |
2、SZY1905-P31在不同pH下的稳定性
称取10mg的样品,加入10ml不同pH的水溶液,超声溶解,过滤后HPLC测试,结果如表4所示。
表4 SZY1905-P31在不同pH下的稳定性
0天(%) | 8天(%) | 20天(%) | 30天(%) | |
纯化水 | 98.05 | 97.68 | 97.35 | 97.46 |
pH=5.0 | 98.11 | 97.69 | 97.38 | 97.48 |
pH=6.0 | 98.16 | 97.64 | 97.39 | 97.48 |
pH=7.0 | 98.26 | 97.85 | 97.57 | 97.58 |
pH=8.0 | 98.14 | 97.64 | 97.33 | 97.49 |
实施例5:SZY1905-P30硫酸盐化合物的合成
100ml单口烧瓶中加入3.5g的SZY1905-P30,加入乙醇35ml搅拌溶解,冰水浴降温,滴加1.1g的30%氢氧化钠溶液,搅拌10min后滴加3N H
2SO
4乙醇溶液2.8mL,逐渐有白色固体析出,0℃搅拌2h,抽滤,得到1.6g的SZY1905-P30硫酸盐化合物。
1HNMR d6-DMSOδ:5.8(s,1H),5.5(d,1H),3.6-3.4(m,2H),3.3(m,1H),3.0(s,9H),2.6-2.2(m,5H),2.2-1.8(m,4H),1.7-1.4(m,9H),1.2(m,3H),0.9(m,3H)。
LC-MS:m/z=384.3。
同理,将青蒿素季铵基丙醚碘酸盐(SZY1905-P30)替换为青蒿素季铵基丁醚碘酸盐(SZY1905-P31),按照上述方法获得SZY1905-P31的硫酸盐化合物。
同理也可获得SZY1905-P30、SZY1905-P31的其它盐。
对比例1:SZY1905-P32的盐酸盐化合物的合成
100ml单口烧瓶中依次加入3-氨基-1-丙醇3.0g、双氢青蒿素6.0g,加入二氯甲烷40ml搅拌分散,滴加催化量的三氟化硼乙醚,加毕,澄清溶液逐渐变为深红色,室温搅拌2h,TLC监测原料反应完毕。反应液依次经饱和氯化铵和饱和氯化钠洗,有机相减压旋干得到粗品,粗品经二氯甲烷:甲醇(1:0-10:1)柱层析纯化,得到2.3g的泡沫状SZY1905-P32。
100ml单口烧瓶中加入2.3g SZY1905-P32,加入乙醇20ml搅拌溶解,冰水浴降温,滴加3N HCl乙醇溶液2.5mL,滴毕,逐渐有白色固体析出,0℃搅拌2h,抽滤,得到1.8g的SZY1905-P32盐酸盐化合物。
1HNMR d6-DMSOδ:5.4(s,1H),5.0(d,1H),3.9-3.5(m,4H),3.3(m,2H),2.5-2.1(m,5H),1.9-1.8(m,3H),1.6-1.1(m,9H),1.0(m,3H),0.9(m,3H)。
LC-MS:m/z=342.2(M+1)。
实施例6、碱烧伤对新西兰兔角膜新生血管的影响
一、实验目的
观察浓度为1%的SZY1905-P30、1%的SZY1905-P31、1%的SZY1905-P32滴眼液对碱烧伤的新西兰兔角膜新生血管的作用。
二、实验材料、仪器、实验动物
1.实验材料
0.5%盐酸丁卡因(中山大学附属眼科医院;20220113);妥布霉素地塞米松磷酸钠滴眼液(中山大学附属眼科医院;20211217);水合氯醛溶液(中山大学附属眼科医院;20220224);1.0mol/L NaOH溶液;滤纸;秒表;荧光素钠滴眼液(中山大学附属眼科医院);0.9%氯化钠注射液(广东怡翔制药有限公司,210926202);50ml注射器;1ml注射器。
2.实验仪器
数码裂隙灯显微镜BX-900(瑞士;Haag-Streit Gruppe)、电子称。
3. 1%SZY1905-P30(22030201;5.0ml/每支);1%SZY1905-P30(22030202;5.0ml/每支);1%的SZY1905-P32(22031501;5.0ml/每支)
4.实验动物
健康新西兰兔,购于广州市花都区花东信华实验动物养殖场;行裂隙灯检查排除眼节前病变。月龄2.0-2.5个月;体重2.2kg-2.9kg。
三、实验过程
1.实验动物称重:用电子称称量实验动物体重,并记录
编号 | 体重(kg) | 编号 | 体重(kg) |
71 | 2.6 | 117 | 2.6 |
73 | 2.2 | 118 | 2.8 |
86 | 2.4 | 143 | 2.4 |
87 | 2.3 | 145 | 2.9 |
89 | 2.4 | 147 | 2.4 |
93 | 2.4 | 148 | 2.7 |
94 | 2.4 | 151 | 2.8 |
97 | 2.3 | 156 | 2.7 |
101 | 2.2 | 157 | 2.6 |
108 | 2.7 | 161 | 2.8 |
109 | 2.7 | 166 | 2.7 |
110 | 2.3 | 168 | 2.9 |
2.实验动物造模
24只新西兰兔先用水合氯醛溶液静脉注射麻醉,给药剂量约为0.5ml/kg,然后用0.5%的盐酸丁卡因滴眼液滴眼进行眼表面麻醉。然后用1张约直径为8mm大小的滤纸片浸于1mol/L的NaOH溶液中1min达饱和后,置于角膜中央1min,取下滤纸,立即用0.9%氯化钠注射液反复冲洗角膜及结膜囊1min,再给予妥布霉素地塞米松磷酸钠滴眼液滴眼。
3.实验动物给药
造模后将24只动物分为4组,分别是造模组;SZY1905-P30滴眼组;SZY1905-P31滴眼组;1%的SZY1905-P32滴眼组。每日给药3次,每次2滴。其中,造模组不给予药物。
组别 | 编号 |
造模组 | 71、73、110、117、118、143 |
SZY1905-P30滴眼组 | 86、89、93、145、148、166 |
SZY1905-P31滴眼组 | 87、94、97、147、151、168 |
SZY1905-P32滴眼组 | 101、108、109、156、157、161 |
4.数码裂隙灯拍照
在造模前、造模后第1天(给药第0天)、造模后第7天(给药第6天)、造模后第14天(给药第13天)用数模裂隙灯拍照,以荧光素钠对角膜进行染色,裂隙灯显微镜下观察并拍照。
四、实验结果
157号新西兰兔于造模后第5天呼吸急促突发意外死亡,1%的SZY1905-P32滴眼 组共剩余5只动物(101、108、109、156、161),10只眼进行后续实验。
(一)眼部炎症情况
造模第1天结膜充血、角膜水肿、新生血管生成以及出现荧光素点染的新西兰兔眼数
造模第7天结膜充血、角膜水肿、新生血管生成以及出现荧光素点染的新西兰兔眼数
造模第14天结膜充血、角膜水肿、新生血管生成以及出现荧光素点染的新西兰兔眼数
(二)荧光素点染评分
评分标准:
0————角膜上皮无染色
1————角膜上皮着色点少于30个
2————角膜上皮着色点少于角膜面积一半
3————角膜上皮着色点大于角膜面积一半,或者出现大面积片状着色
(三)新生血管生成评分
0————角膜无新生血管的生成
1————角膜有少量新生血管生成
2————角膜有大量新生血管生成
3————角膜长满新生血管
实施例6中各处理组荧光素点染图例如图1所示;实施例6中各处理新生血管生成图例如图2所示。由图可知,碱烧伤后部分新西兰兔在造模后第七天开始生成少量 新生血管,比较四个组别中出现新生血管的新西兰兔可以初步得出结论,SZY1905-P30给药组和SZY1905-P31组可以延缓新生血管的快速生成,且显著优于SZY1905-P32滴眼液组,SZY1905-P32滴眼液组的新西兰兔新生血管已经蔓延到整个角膜。
Claims (10)
- 根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于:所述n为3或4。
- 根据权利要求1或2所述的化合物或其药学上可接受的盐,其特征在于:所述式I所示的化合物药学上可接受的盐为柠檬酸盐、反丁烯二酸盐、水杨酸盐、L-酒石酸盐、富马酸盐、钠盐、钾盐、钙盐、盐酸盐、醋酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、乙酸盐、草酸盐、乳酸盐、赖氨酸盐或天冬氨酸盐。
- 权利要求1-3中任一项所述的化合物的制备方法,包括下述步骤:1)将3-二甲氨基-1-烷基醇溶于乙腈,滴加碘甲烷搅拌反应,得到季铵盐中间体;2)将双氢青蒿素分散于二氯甲烷中,依次加入季铵盐中间体、催化量三氟化硼乙醚后反应,得到所述式(I)所示的化合物。
- 权利要求1-3中任一项所述化合物或其药学上可接受的盐在制备预防和/或治疗眼组织疾病的药物中的应用。
- 根据权利要求5所述的应用,其特征在于:所述眼组织疾病为眼组织炎症或眼组织黄斑变性。
- 式I所示的化合物或其药学上可接受的盐在制备预防和/或治疗角膜新生血管抑制剂中的应用。
- 一种用于预防和/或治疗眼组织疾病的药物或药物组合物,包括权利要求1-3中任一项所述化合物或其药学上可接受的盐。
- 根据权利要求8所述的应用,其特征在于:所述眼组织疾病为眼组织炎症或眼组织黄斑变性。
- 一种预防和/或治疗角膜新生血管的抑制剂,其活性成分包括权利要求1-3中任一项所述化合物或其药学上可接受的盐。
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