CN112341356B - (2s,3r)-3-氨基-2-羟基-4-苯丁酰氨衍生物、其制备方法及用途 - Google Patents
(2s,3r)-3-氨基-2-羟基-4-苯丁酰氨衍生物、其制备方法及用途 Download PDFInfo
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- CN112341356B CN112341356B CN202010786112.XA CN202010786112A CN112341356B CN 112341356 B CN112341356 B CN 112341356B CN 202010786112 A CN202010786112 A CN 202010786112A CN 112341356 B CN112341356 B CN 112341356B
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 23
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Classifications
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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
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
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- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明公开了一种式(I)所示的(2S,3R)‑3‑氨基‑2‑羟基‑4‑苯丁酰氨衍生物或其光学异构体、非对映异构体、消旋体混合物,以及药学上可接受的盐,及其制备方法和用途,本发明通过与阳性对照组及模型组对比的抗淋巴水肿试验显示,本发明的化合物显示出明显的抗水肿活性。
Description
技术领域
本发明涉及药物化学领域,具体涉及一类(2S,3R)-3-氨基-2-羟基-4-苯丁酰氨衍生物、其制备方法及用途。
背景技术
乌苯美司(Ubenimex),其药物名称为Bestatin;别名:由必尼美;商品名:百士欣;化学名:N-[(2S,3R)-3-氨基-2-羟基-4-苯丁酰]-L-亮氨酸。乌苯美司是1976年由日本学者梅泽滨夫从橄榄网状链霉菌的培养液中分离得到的小分子二肽化合物,可抑制多种氨肽酶活性。此外,乌苯美司还能增强宿主免疫功能,抑制肿瘤组织血管生成,从而抑制肿瘤的侵袭和转移。1987年,乌苯美司作为抗癌药物在日本正式上市,国内市场,乌苯美司作为抗癌化疗、放疗的辅助用药,特别用于延长成人非急性淋巴细胞白血病治疗后的生存期和维持缓解。
淋巴水肿是指机体某些部位淋巴液回流受阻,引起的软组织液在体表反复感染后,皮下纤维结缔组织增生,脂肪硬化。常表现为肢体增粗,皮肤增厚、粗糙,后期可能坚韧如大象皮肤,亦称“象皮肿”。淋巴水肿可以分为原发性(遗传性)、继发性(后天获得)两种。前者由于出生时淋巴管缺失或者异常造成,后者通常由于感染、恶性肿瘤、手术、瘢痕组织形成、创伤、放疗或者其他癌症治疗引起,致使淋巴管阻塞或中断,造成淋巴水肿。
白三烯B4(Leukotriene B4,LTB4)是一种细胞白三烯类介质,由白细胞产生,使白细胞活化并依附在内皮上,允许其穿过组织。在中性粒细胞中,LTB4也是一种强效化学诱导物,诱导形成活性氧类和溶酶体中酶的释放。它通过白三烯A4(LTA4)在酶的作用下水解生成。该介质在淋巴水肿患者体内出现高表达。并且,LTB4的功能是双面的,低浓度LTB4可以促进人体淋巴内皮细胞生长,高浓度LTB4会抑制淋巴管生成,诱导淋巴细胞凋亡。
有研究显示,乌苯美司不仅可用于肿瘤辅助治疗,同时也是水解酶(LTA4H)抑制剂,通过阻断LTA4水解,减少LTB4生成,使其维持低浓度状态,从而诱导淋巴内皮细胞生成,恢复淋巴管结构及代偿功能,减少淋巴液回流,最终逆转淋巴水肿。该研究最新进展已进入临床二期,虽然最近因为有效性原因停止,但是大量的临床前研究为我们指明了方向,同时安全性得到再次验证(Tian wen etc.,Sci.Transl.Med.2013August 28;5(200):200ra117.;Tian wen etc.,Sci.Transl.Med.2017May 10;9(389);Mitch Leslie,Replumbing the lymphatic systems,Science,2018,Oct 12;362(6411):140-141;NCT02700529)。目前,原发性、继发性淋巴水肿都没有可治疗药物,甚至没有缓解症状的药物,所以,寻找一种安全有效的抗淋巴水肿药物具有重要意义。
发明内容
本发明涉及一类(2S,3R)-3-氨基-2-羟基-4-苯丁酰氨衍生物及其制备方法和在医药上的应用,特别是涉及如下式(I)所述的(2S,3R)-3-氨基-2-羟基-4-苯丁酰氨衍生物或异构体,在制备淋巴水肿药物中的用途,尤其是在制备适用于肿瘤及外科手术引起的淋巴水肿药物中的用途。
本发明的一个目的在于提供如式(I)所示的化合物或其光学异构体、非对映异构体、消旋体混合物,以及药学上可接受的盐,其中:
R1选自氢,C1-C6烷基,C1-C6烷氧基,卤素,硝基,氰基或氨基;
R2选自:
n为1-5。
在部分实施方案中,本发明所述的化合物或其光学异构体、非对映异构体、消旋体混合物,以及药学上可接受的盐,其中:
R1选自氢,C1-C2烷基,C1-C2烷氧基,氟,氯,溴或硝基;
优选地,R1选自氢,甲基,甲氧基,氟或硝基;
特别优选地,R1为氢。
在部分实施方案中,本发明所述的化合物或其光学异构体、非对映异构体、消旋体混合物,以及药学上可接受的盐,其中:
在部分实施方案中,本发明所述的化合物或其光学异构体、非对映异构体、消旋体混合物,以及药学上可接受的盐,其中:n为1、2、3、4或5;优选地,n为1或3;特别优选地,n为1。
本发明式(I)所述的化合物的优选化合物包括,但不限于:
优选地,本发明式(I)所述的化合物的优选化合物包括,但不限于:
本发明的另一目的在于提供制备上述式(I)化合物的制备方法,所述方法包括以下步骤:
第一步:将化合物(Ia)中的氨基进行保护得到化合物(Ib);
第二步:将化合物(Ib)与(Ie)进行缩合反应得到化合物(Ic);
第三步:将化合物(Ic)脱去保护基团G得到化合物(Id);
第四步:将化合物(Id)脱去保护基团P得到式(I)化合物;
其中,保护基P为氨基保护基,选自-Bn,-Boc,-Cbz,-Fmoc,-Tos,-PMB;优选地,P选自-Bn,-Boc,-Cbz;特别优选地,P为-Boc;
保护基G为羧基保护基,选自C1-C6烷基,苄基;优选地,G选自C1-C4烷基,苄基;特别优选地,G为甲基;
R1,R2和n如上文所定义。
本发明的又一目的在于提供上述式(I)所述化合物或其光学异构体、非对映异构体、消旋体混合物,以及药学上可接受的盐在制备淋巴水肿药物中的用途。
本发明的又一目的在于提供上述式(I)所述化合物或其光学异构体、非对映异构体、消旋体混合物,以及药学上可接受的盐在制备适用于肿瘤或外科手术继发性淋巴水肿药物中的用途。
本发明通过与阳性对照组及模型组对比的抗淋巴水肿试验显示,本发明的化合物显示出明显的抗水肿活性,较现有技术有明显改进,具有显著地进步。
以下对本发明的术语进行解释,对于特定的术语,如果本发明中的含义与本领域技术人员通常理解的含义不一致,以本发明中的含义为准;如果在本发明中没有定义,则其具有本领域技术人员通常理解的含义。除非有相反陈述,本发明中使用的术语具有下述含义:
本发明所用术语“C1-6烷基”是指具有1-6个碳原子的直链或支链烷基,例如C1-4烷基、C1-2烷基、C1烷基、C2烷基、C3烷基、C4烷基、C5烷基或C6烷基,优选为C1-4烷基。具体的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。
本发明中所用术语“C1-6烷氧基”是指具有“C1-6烷基-O-”结构的基团,其中C1-6烷基具有前述相同的含义。例如C1-4烷氧基、C1-2烷氧基、C1烷氧基、C2烷氧基、C3烷氧基、C4烷氧基、C5烷氧基或C6烷氧基,优选为C1-4烷氧基。具体的实例包括但不限于甲氧基、乙氧基、丙氧基、正丁氧基、2-丁氧基、异丙氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基等。
本发明所用术语“药学上可接受的盐”包括与药学上可以接受的无机酸或者有机酸、或者无机碱或有机碱形成的常规盐。合适的酸加成盐的例子包括盐酸、氢溴酸、硫酸、磷酸、硝酸、高氯酸、富马酸、乙酸、丙酸、琥珀酸、羟基乙酸、甲酸、乳酸、马来酸、酒石酸、柠檬酸、扑酸、丙二酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、富马酸、甲苯磺酸、甲磺酸、萘-2-磺酸、苯磺酸、羟基萘甲酸、氢碘酸、苹果酸、鞣酸等形成的盐。合适的碱加成盐的例子包括钠、钾、镁、锂、铝、钙、锌、N,N’-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因等形成的盐。
具体实施方式
以下结合实施例对本发明作进一步的详细描述,但并非对本发明的限制,凡依照本发明公开内容所作的任何本领域的等同替换,均属于本发明的保护范围。
化合物的结构是通过质谱(MS)或核磁共振(1HNMR)来确定的。
核磁共振(1HNMR)位移(δ)以百万分之一(ppm)的单位给出;核磁共振(1HNMR)的测定是用BrukerAVANCE-400核磁仪,测定溶剂为氘代二甲亚砜(DMSO),内标为四甲基硅烷(TMS),化学位移是以10-6(ppm)作为单位给出。
质谱(MS)的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Therm,型号:FinniganLCQ advantage MAX)进行。
薄层硅胶使用烟台黄海HSGF254或青岛GF254硅胶板。
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
在本发明未给出特殊说明的情况下,本发明反应中提及的溶液是水溶液。
在本发明的术语“室温”是指温度处于10℃-25℃之间。
实施例1:化合物1的制备
中间体1b的制备:
将化合物1a(31g,0.16mol)溶解到310mL四氢呋喃/水(1:1)混合溶剂中,于冰浴下加入三乙胺(32g,0.32mol)、二碳酸二叔丁酯(42g,0.19mol),加毕后于室温下反应。待原料反应完全后,冰水浴下加入水淬灭反应,然后加入稀盐酸调节pH值至酸性,用乙酸乙酯萃取2次,有机相合并后,用水洗涤1次,用无水硫酸钠干燥,抽滤,将滤液浓缩,得到38g中间体1b,收率:81.0%;
ESI-MS:m/z=296(M+H)+。
中间体1d的制备:
将化合物1c(1.2g,10mmol)溶解到10mL甲醇中,于冰浴下加入二氯亚砜(5.95g,50mmol),加毕后于室温下反应。待原料反应完全后,将反应体系浓缩,得到1.7g中间体1d,收率:100%。
中间体1e的制备:
将中间体1b(2.2g,7.46mmol)、中间体1d(1.39g,8.2mmol)溶解到20mL二氯甲烷中,于冰浴下滴加三乙胺(3.03g,30mmol)、1-羟基苯并三唑(1.2g,8.95mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.72g,8.95mmol),加毕后于室温下反应。待原料反应完全后,浓缩除去溶剂,再加入水与乙酸乙酯(20/20ml)溶解,并用稀盐酸调节pH到5~6,乙酸乙酯萃取2次,有机相合并后,用水、饱和食盐水各洗涤1次,无水硫酸钠干燥,浓缩后用柱层析纯化,得到2.4g中间体1e,收率:78.3%;
ESI-MS:m/z=411(M+H)+。
中间体1f的制备
将中间体1e(1.68g,4.1mmol)溶解到10mL四氢呋喃中,于冰浴下滴加氢氧化钠(0.5g,12.3mmol)与10mL水的混合溶液,加毕后于室温下反应。待原料反应完全后,浓缩,再加入水与乙酸乙酯溶解,并用稀盐酸调节pH到5~6,分液后用乙酸乙酯萃取3次,有机相合并,并用水、饱和食盐水各洗涤1次,用无水硫酸钠干燥,抽滤,将滤液浓缩,得到1.37g中间体1f,收率:84.8%;
ESI-MS:m/z=397(M+H)+。
化合物1的制备
将中间体1f(1.12g,2.84mmol)溶解到10mL乙酸乙酯中,于冰浴下滴加4N盐酸乙酸乙酯溶液(7.6mL,30.4mmol),加毕后于室温下反应。待原料反应完全后,浓缩,再加入水溶解,并用稀氢氧化钠调节pH到6~7,体系中会有大量的白色固体析出,并于室温下搅拌反应30min,抽滤,用石油醚洗涤滤饼,将滤饼旋干得到734mg化合物1,收率:87.3%;
ESI-MS:m/z=297(M+H)+;
1H NMR(400MHz,CF3COOD)δ7.39–7.31(m,3H),7.25(d,J=6.4Hz,2H),4.91-4.86(m,1H),4.84–4.80(m,2H),4.22(t,J=6.4Hz,1H),3.33(dd,J=14.4,6.4Hz,1H),3.15(dd,J=14.4,9.2Hz,1H),1.45(d,J=6.4Hz,3H).
实施例2:化合物2的制备
中间体2b的制备:
将化合物2a(1.2g,10mmol)溶解到10mL甲醇中,于冰浴下加入二氯亚砜(5.95g,50mmol),加毕后于室温下反应。待原料反应完全后,将反应体系浓缩,得到1.7g中间体2b,收率:100%。
中间体2c的制备:
将中间体1b(2.2g,7.46mmol)、中间体2b(1.39g,8.2mmol)溶解到20mL二氯甲烷中,于冰浴下滴加三乙胺(3.03g,30mmol)、1-羟基苯并三唑(1.2g,8.95mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.72g,8.95mmol),加毕后于室温下反应。待原料反应完全后,浓缩,再加入水与乙酸乙酯溶解,并用稀盐酸调节pH到5~6,用乙酸乙酯萃取2次,有机相合并后,水、饱和食盐水洗涤1次,无水硫酸钠干燥,抽滤,将滤液浓缩,使用柱层析纯化,得到2.4g中间体2c,收率:78.3%;
ESI-MS:m/z=411(M+H)+。
中间体2d的制备
将中间体2c(1.68g,4.1mmol)溶解到10mL四氢呋喃中,于冰浴下滴加氢氧化钠(0.5g,12.3mmol)与10mL水的混合溶液,加毕后于室温下反应。待原料反应完全后,浓缩,再加入水与乙酸乙酯溶解,并用稀盐酸调节pH到5~6,乙酸乙酯萃取3次,有机相合并后,水、饱和食盐水洗涤1次,无水硫酸钠干燥,抽滤,将滤液浓缩,得到1.37g中间体2d,收率:84.8%;
ESI-MS:m/z=397(M+H)+。
化合物2的制备
将中间体2d(1.12g,2.84mmol)溶解到10mL乙酸乙酯中,于冰浴下滴加4N盐酸乙酸乙酯溶液(7.6mL,30.4mmol),加毕后于室温下反应。待原料反应完全后,浓缩,再加入水溶解,并用稀氢氧化钠调节pH到6~7,体系中会有大量的白色固体析出,并于室温下搅拌反应30min,抽滤,石油醚洗涤滤饼,将滤饼旋干得到734mg化合物2,收率:87.3%;
ESI-MS:m/z=297(M+H)+;
1H NMR(400MHz,CF3COOD)δ7.39–7.31(m,3H),7.25(d,J=6.4Hz,2H),4.91-4.86(m,1H),4.84–4.80(m,2H),4.22(t,J=6.4Hz,1H),3.33(dd,J=14.4,6.4Hz,1H),3.15(dd,J=14.4,9.2Hz,1H),1.45(d,J=6.4Hz,3H).
实施例3:化合物3的制备
中间体3b的制备:
将化合物3a(1.2g,10mmol)溶解到10mL甲醇中,于冰浴下加入二氯亚砜(5.95g,50mmol),加毕后于室温下反应。待原料反应完全后,将反应体系浓缩,得到1.7g中间体3b,收率:100%。
中间体3c的制备:
将中间体1b(2.2g,7.46mmol)、中间体3b(1.39g,8.2mmol)溶解到20mL二氯甲烷中,于冰浴下滴加三乙胺(3.03g,30mmol)、1-羟基苯并三唑(1.2g,8.95mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.72g,8.95mmol),加毕后于室温下反应。待原料反应完全后,浓缩,再加入水与乙酸乙酯溶解,并用稀盐酸调节pH到5~6,乙酸乙酯萃取2次,有机相合并后,水、饱和食盐水洗涤1次,无水硫酸钠干燥,抽滤,将滤液浓缩,使用柱层析纯化,得到2.4g中间体3c,收率:78.3%;
ESI-MS:m/z=411(M+H)+。
中间体3d的制备:
将中间体3c(1.68g,4.1mmol)溶解到10mL四氢呋喃中,于冰浴下滴加氢氧化钠(0.5g,12.3mmol)与10mL水的混合溶液,加毕后于室温下反应。待原料反应完全后,浓缩,再加入水与乙酸乙酯溶解,并用稀盐酸调节pH到5~6,乙酸乙酯萃取3次,有机相合并后,水、饱和食盐水洗涤1次,无水硫酸钠干燥,抽滤,将滤液浓缩,得到1.37g中间体3d,收率:84.8%;
ESI-MS:m/z=397(M+H)+。
化合物3的制备:
将中间体3d(1.12g,2.84mmol)溶解到10mL乙酸乙酯中,于冰浴下滴加4N盐酸乙酸乙酯溶液(7.6mL,30.4mmol),加毕后于室温下反应。待原料反应完全后,浓缩,再加入水溶解,并用稀氢氧化钠调节pH到6~7,体系中会有大量的白色固体析出,并于室温下搅拌反应30min,抽滤,用石油醚洗涤滤饼,将滤饼旋干得到734mg化合物3,收率:87.3%;
ESI-MS:m/z=297(M+H)+;
1H NMR(400MHz,CF3COOD)δ7.39–7.31(m,3H),7.25(d,J=6.4Hz,2H),4.91-4.86(m,1H),4.84–4.80(m,2H),4.22(t,J=6.4Hz,1H),3.33(dd,J=14.4,6.4Hz,1H),3.15(dd,J=14.4,9.2Hz,1H),1.45(d,J=6.4Hz,3H).
实施例4:化合物4的制备
中间体4b的制备:
将化合物4a(1.81g,10mmol)溶解到10mL甲醇中,于冰浴下加入二氯亚砜(5.95g,50mmol),加毕后于室温下反应。待原料反应完全后,浓缩得到2.32g中间体4b,收率:100%。
中间体4c的制备:
将中间体1b(2.2g,7.46mmol)、中间体4b(1.89g,8.2mmol)溶解到20mL二氯甲烷中,于冰浴下滴加三乙胺(3.03g,30mmol)、1-羟基苯并三唑(1.2g,8.95mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.72g,8.95mmol),加毕后于室温下反应。待原料反应完全后,浓缩,再加入水与乙酸乙酯溶解,并用稀盐酸调节pH到5~6,乙酸乙酯萃取2次,有机相合并后,水、饱和食盐水洗涤1次,无水硫酸钠干燥,抽滤,将滤液浓缩,柱层析纯化,得到3.28g中间体4c,收率:93.0%;
ESI-MS:m/z=473(M+H)+。
中间体4d的制备:
将中间体4c(1.94g,4.1mmol)溶解到10mL四氢呋喃中,于冰浴下滴加氢氧化钠(0.5g,12.3mmol)与10mL水的混合溶液,加毕后于室温下反应。待原料反应完全后,浓缩,再加入水与乙酸乙酯溶解,并用稀盐酸调节pH到5~6,乙酸乙酯萃取3次,有机相合并后,水、饱和食盐水洗涤1次,无水硫酸钠干燥,抽滤,将滤液浓缩,得到1.78g中间体4d,收率:92.1%;
ESI-MS:m/z=459(M+H)+。
化合物4的制备
将中间体4d(1.3g,2.84mmol)溶解到10mL乙酸乙酯中,于冰浴下滴加4N盐酸乙酸乙酯溶液(7.6mL,30.4mmol),加毕后于室温下反应。待原料反应完全后,浓缩,再加入水溶解,并用稀氢氧化钠调节pH到6~7,体系中会有大量的白色固体析出,并于室温下搅拌反应30min,抽滤,用石油醚洗涤滤饼,将滤饼旋干得到695mg化合物4,收率:68.1%;
ESI-MS:m/z=359(M+H)+;
1H NMR(400MHz,CF3COOD)δ7.30–7.25(m,3H),7.17–7.05(m,4H),6.87-6.83(m,2H),4.99–4.92(m,1H),4.70–4.39(m,1H),4.00–3.84(m,2H),3.44-3.30(m,1H),3.10–2.89(m,2H).
实施例5:化合物5的制备
中间体5b的制备:
将化合物5a(2.04g,10mmol)溶解到10mL甲醇中,于冰浴下加入二氯亚砜(5.95g,50mmol),加毕后于室温下反应。待原料反应完全后,浓缩,得到2.55g中间体5b,收率:100%。
中间体5c的制备
中间体5b(2.55g,10mmol)溶解到30mL二氯甲烷中,于室温下加入TMSCl(1.09g,10mmol),30度反应4小时,加入三乙胺(2.02g、20mmol)并反应15min,冷却至室温后,加入三苯甲基氯(2.79g,10mmol)、三乙胺(1.01g,10mmol),室温下搅拌2小时,往反应中加入甲醇(150ml)并于室温下搅拌过夜,将反应液浓缩干后加水(50ml)溶解,乙酸乙酯萃取2次,无水硫酸钠干燥,抽滤,滤液浓缩干得4.2g中间体5c,收率:91.1%。
中间体5d的制备
将中间体1b(2.45g,8.29mmol)、中间体5c(4.2g,9.12mmol)溶解到60mL二氯甲烷中,于冰浴下滴加三乙胺(2.51g,24.87mmol)、1-羟基苯并三唑(1.34g,9.95mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(1.91g,9.95mmol),加毕后于室温下反应。待原料反应完全后,浓缩,再加入水与乙酸乙酯溶解,并用稀盐酸调节pH到5~6,乙酸乙酯萃取2次,有机相合并后,水、饱和食盐水洗涤1次,无水硫酸钠干燥,抽滤,将滤液浓缩,柱层析纯化,得到2.14g中间体5d,收率:35.0%;
ESI-MS:m/z=738(M+H)+。
中间体5e的制备
将中间体5d(2.14g,2.9mmol)溶解到20mL乙酸乙酯中,于冰浴下滴加4N盐酸乙酸乙酯溶液(7.6mL,30.4mmol),加毕后于室温下反应。待原料反应完全后,浓缩,再加入水溶解,并用稀氢氧化钠调节pH到6~7,体系中会有大量的白色固体析出,并于室温下搅拌反应30min,抽滤,石油醚洗涤滤饼,将滤饼旋干得到960mg中间体5e,收率:83.7%;
ESI-MS:m/z=396(M+H)+。
化合物5的制备
将中间体17e(960mg,2.43mmol)溶解到5mL四氢呋喃中,于冰浴下滴加氢氧化钠(0.29g,7.27mmol)与5mL水的混合溶液,加毕后于室温下反应。待原料反应完全后,浓缩,再加入水与乙酸乙酯溶解,并用稀盐酸调节pH到5~6,乙酸乙酯萃取3次,有机相合并后,水、饱和食盐水洗涤1次,无水硫酸钠干燥,抽滤,将滤液浓缩,经柱层析纯化得到713mg化合物5,收率:77.1%;
ESI-MS:m/z=382(M+H)+;
1H NMR(400MHz,CF3COOD)δ7.95–7.47(m,1H),7.31–6.91(m,9H),5.16-5.08(m,1H),4.71-4.54(m,1H),4.13-3.92(m,1H),3.76-3.66(m,1H),3.54-3.45(m,1H),3.38-3.51(m,1H),3.06-2.84(m,2H),2.22-2.18(m,1H).
试验例1抗淋巴水肿实验
1.材料与方法
1.1实验动物:昆明小鼠,全雄性,体重18-22g。
1.2实验试剂:生理盐水,水合氯醛。
1.3供试品配制:使用生理盐水分别将各化合物配制成0.4mg/mL的供试品溶液。
1.4淋巴水肿建模:试验在无菌环境下进行,小鼠用水合氯醛麻醉后,测量距尾根部2cm处尾巴直径并记录。在距尾根部1.6cm处环行切除尾巴皮肤0.3cm。从尾尖皮下注射0.1mL10%的蓝墨水显色淋巴干,将显露的淋巴管切除,断端与创缘皮肤均进行烧灼以防止淋巴管再通。手术创口以凡士林纱布包扎,定期观察愈合情况以及尾部水肿情况。
1.5分组、给药及测量:术后第三天,挑选肿胀程度超过10-15%的成模动物进行分组,每天腹腔注射给药,共计21天。开始给药后第1、5、10、15、21天对小鼠尾巴进行拍照并称重。最后一天,取材甲醛固定,石蜡包埋切片(5μm),进行组织学检测。
1.6实验结果
分析计算小鼠距尾跟部2cm-4cm范围内尾巴面积变化、病理切片中尾巴的水肿程度。尾部水肿面积为测量日与给药第一天小鼠尾巴距尾跟部2cm-4cm范围内面积的比值。病理结果尾巴水肿程度以像素值表示,试验结果如下:
药效筛选小鼠尾巴面积变化比值(%)
组别 | Day5 | Day10 | Day15 | Day21 |
模型组 | 115.13±15.17 | 127.75±16.92 | 120.26±17.62 | 101.37±7.36 |
乌苯美司 | 115.20±17.15 | 122.31±16.56 | 103.70±9.39 | 87.29±8.76** |
化合物1 | 103.07±19.17 | 102.21±23.88 | 95.75±9.08* | 86.28±9.00** |
注:与模型组比,*P<0.05,**P<0.01;
由试验结果可见:
(1)化合物1组在给药第15天时,小鼠尾巴距尾跟部2cm-4cm范围内面积变化与模型组相比有显著性差异(p<0.05),而乌苯美司组与模型组相比没有显著性差异。
(2)化合物1组和乌苯美司组在给药第21天时,小鼠尾巴距尾跟部2cm-4cm范围内面积变化与模型组相比均有显著性差异(p<0.01)。
由此可见,化合物1组在给药15天时效果比乌苯美司组效果好,乌苯美司组在连续给药21天时达到与化合物1组相当的效果。因此化合物1组相较于乌苯美司组起效快,更有利于消除水肿。
本发明提供的化合物在小鼠体内表现出良好的抗水肿活性,为填补该领域临床空白提供了可能性,具有重要意义。
根据上述结果表明本发明化合物显示出一定的抗水肿活性,对于本领域的普通技术人员而言明显的是在不偏离本发明的精神或者范围,可对本发明化合物、组合物以及方法进行的多种修饰和变化,因此,本发明包含对本发明的修饰和变化,只要在权利要求和其等同的范围内。
Claims (4)
3.根据权利要求1的化合物或其药学上可接受的盐在制备抗淋巴水肿药物中的用途。
4.根据权利要求1所述的化合物或其药学上可接受的盐在制备适用于肿瘤或外科手术引起的淋巴水肿药物中的用途。
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