CN1169433A - 糖类衍生物 - Google Patents
糖类衍生物 Download PDFInfo
- Publication number
- CN1169433A CN1169433A CN97111112A CN97111112A CN1169433A CN 1169433 A CN1169433 A CN 1169433A CN 97111112 A CN97111112 A CN 97111112A CN 97111112 A CN97111112 A CN 97111112A CN 1169433 A CN1169433 A CN 1169433A
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- Prior art keywords
- carbohydrate derivative
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- oso
- solution
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- 238000002360 preparation method Methods 0.000 claims description 20
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- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
本发明涉及式Ⅰ糖类衍生物或其可药用盐:其中R1为H或CH2OSO3 －;R2和R3彼此独立为H,(1－6C)烷基或SO3 －;R4为OSO3 －或NHSO3 －;n为0或1;p为1或2。本发明化合物具有抗凝血酶素活性,并可用于抑制平滑肌细胞增生。
Description
本发明涉及具有抗凝血酶素活性的糖类衍生物，含有它们的药物组合物，以及所述糖类衍生物在制备药物方面的应用。
具有抗凝血酶素活性的糖类衍生物是已知的，例如EP84,999中公开了硫酸化葡糖胺聚糖衍生物。EP529,715中公开了其它与硫酸化葡糖胺聚糖有关的糖类衍生物，它们具有改进的药理学性质。这些糖类衍生物不具有葡糖胺聚糖的特征官能团，即游离羟基，N-硫酸基和N-乙酰基。
现已发现，本发明式I糖类衍生物或其可药用盐具有抗-Xa活性，该活性显著高于在非还原性末端的4-位上无甘油状或二醇状基团的糖类：其中R1为H或CH2OSO3 -；R2和R3彼此独立为H，(1-6C)烷基或SO3 -；R4为OSO3 -或NHSO3 -；n为0或1；p为1或2。
因子Xa在凝血级联系统方面起重要作用。它催化形成能调节凝血级联系统最后步骤的凝血酶。凝血酶的最重要的作用在于裂解血纤蛋白原产生血纤蛋白单体，通过交联它们形成不溶凝胶-血纤蛋白块。
本发明化合物适用于治疗和预防凝血酶介导的和凝血酶相关的疾病。这类疾病包括众多血栓形成和前血栓形成(prothrombotic)病症，其中凝血级联系统被激活，这些病症包括但不限于，深静脉血栓形成，肺栓塞，血栓性静脉炎，血栓形成或栓塞造成的动脉闭塞，血管成形术或血栓溶解期间或之后引起的动脉再闭塞，动脉损伤或心脏病发作过程之后的再狭窄，术后静脉血栓形成或栓塞，急性或慢性动脉粥样硬化，中风，心肌梗塞形成，癌症及其转移，以及神经变性疾病。本发明糖类衍生物也可用作平滑肌细胞增生的抑制剂，并用于治疗血管生成，癌症和逆转录病毒感染，如HIV。
进一步，如果需要，在透析和外科手术方面，本发明化合物可用作抗凝剂和体外血路的抗凝血药膜。
本发明化合物也可用作体内或体外抗凝剂。
优选的本发明糖类衍生物为式I化合物或其可药用盐，其中R2为(1-6C)烷基，R3为SO3 -，R4为OSO3 -，以及R1，n和p的定义同前。
更优选的本发明糖类衍生物为其中R1为甲基的式I化合物。特别优选的糖类衍生物为其中n为1及p为1的式I化合物。最优选其中R1为CH2OSO3 -的式I糖类衍生物。
术语(1-6C)烷基是指具有1至6个碳原子的支链或直链烷基，如甲基，乙基，异丙基，叔丁基，异戊基，己基等。优选的烷基为(1-4C)烷基，如甲基，乙基，(异)丙基，正丁基和叔丁基。最优选的烷基为甲基。
平衡带电部分的抗衡离子为可药用的抗衡离子，如氢，或者更优选碱金属或碱土金属离子，象钠，钙，或镁。
本发明糖类衍生物可通过将被保护的甘油状或二醇状部分偶连到被另外保护的四糖的非还原性末端的4-羟基基团上制备，所述四糖可按照Weserduin P.，生物有机和医学化学(Bioorg.andMed.Chem.)，2，1267-1280，1994中所述方法生产。此后，移去保护基，接着硫酸化化合物，产生式I糖类衍生物。
对于静脉血栓形成的治疗或平滑肌细胞增生的抑制，本发明化合物可经肠或非肠道施用，并其对人而言，优选日剂量为每千克体重0.001-10mg。当口服、向颊或舌下施用本发明化合物时，如标准参考文献，Gennaro等人，Remington’s PharmaceuticalSciences，(18th ed.，Mack Publishing Company，1990，特别是参见第8部分，药物制剂及其制备)中所述，本发明化合物可与药学上适宜的助剂混合，压制成固态剂量单位形式，如丸剂，片剂，或加工成胶囊或栓剂。利用药学上适宜的液体，本发明化合物也可以溶液，悬浮液，乳状液形式的注射制剂形式施用，或以喷雾剂如鼻喷雾剂形式施用。
为制备剂量单位形式制剂如片剂，可考虑使用常规添加剂如填料，着色剂，聚合粘合剂等。一般来说，不影响活性化合物作用的任何药学上可接受的添加剂都可使用。
可与组合物一同施用的适当载体包括乳糖，淀粉，纤维素衍生物等，或它们的混合物，它们以适当量使用。
本发明用下述实施例进一步说明。(各实施例请参见流程图1和2，中间体和最终产物用流程图中的相应编号表示)实施例1制备化合物7和8制备2
氮气气氛下，向2-苄氧基乙醇1(2.84ml)和氯甲基甲基硫醚(1.59ml)的乙二醇二甲醚(25ml)冷(0℃)溶液中加入在矿物油中的60％氢化钠分散体(1.2g)，室温搅拌混合物20h。向反应混合物中加入甲醇并续搅拌15分钟。混合物用乙酸乙酯(100ml)稀释，随后用碳酸氢钠水溶液和水洗涤，有机相用硫酸镁干燥并真空浓缩。粗产物通过硅胶柱色谱纯化，得到2.5g的2。制备3
3的合成见生物有机和医学化学，vol 2，no.11，pp1267-1280，1994(P.Westerduin等人)中所述。制备4
将3(125mg)，2(64mg)和粉状分子筛(4埃)的在二氯甲烷(1.5ml)中的混合物在氮气气氛中搅拌15分钟。冷却(5℃)溶液并向其中加入新制备的含有N-碘代琥珀酰亚胺(68mg)和三氟甲磺酸(2.7μl)的1.5ml 1，2-二氯乙烷-二恶烷(1/1，v/v)溶液。10分钟后，过滤红色反应混合物，用二氯甲烷稀释，并依次用硫代硫酸钠水溶液和碳酸氢钠水溶液洗涤。有机层用硫酸镁干燥并真空浓缩。残留物通过悬浮在二氯甲烷-甲醇(2/1，v/v)中的Sep hadex LH-20的筛析色谱法纯化，得到108mg的4。制备5
向4(105mg)的四氢呋喃(7.3ml)冷溶液(-5℃)中加入30％过氧化氢水溶液(3.8ml)，搅拌10分钟后，加入氢氧化锂溶液(1.25M，1.7ml)。混合物于-5℃搅拌2小时，然后将温度升至0℃。搅拌20小时后，将温度升至20℃并续搅拌24小时。冷却反应混合物(0℃)，其后加入甲醇(7.0ml)和氢氧化钠水溶液(4M，2.0ml)。搅拌1小时后，将温度再升至20℃并继续搅拌20小时。冷却混合物(0℃)，用盐酸(2N)酸化至pH3并用二氯甲烷提取。有机层用亚硫酸钠水溶液(5％)洗涤，硫酸镁干燥并真空浓缩。粗产物用硅胶柱色谱纯化，得到80mg的5。制备6
向6(80mg)在水(7ml)和2-甲基-2-丙醇(7ml)混合物中的溶液中加入80mg载于木炭上的钯(10％)。反应混合物在氢气气氛中放置16小时。滤出催化剂并用2-甲基-2-丙醇/水混合物漂洗。将滤液和洗涤液真空浓缩并冻干，得到38mg的6。制备7和8
将6(38mg)的水(0.8ml)溶液通过Dowex 50WX8H+柱用水洗脱，并将收集的各部分蒸发至干。与N，N-二甲基甲酰胺一同蒸发后，将残留物溶于N，N-二甲基甲酰胺(2.5ml)，置于氮气气氛中，加入三乙胺-三氧化硫配合物(287mg)。混合物于50℃搅拌过夜，冷却至0℃，加入碳酸氢钠水溶液(533mg)。混合物于20℃搅拌1小时，浓缩至少量体积，用悬浮在水∶乙腈9∶1(v/v)的Sephadex G-25柱脱盐。粗产物通过Dowex50WX8Na+柱洗脱，并通过阴离子交换柱色谱(HPLC，Mono-Q5/5，氯化钠梯度)纯化，得到12mg的7{[α]20 D＝+31.1(c＝1；水)}和18mg的8{[α]20 D＝34.8(c＝0.93；水)}。实施例2制备化合物16制备10
1小时内，将苯甲酰氯(26.3ml)的无水二恶烷(26ml)溶液滴加到甘油(10g)和吡啶(109ml)的冷混合液(-20℃)中。0℃搅拌所形成的混合物16小时，然后加入水。搅拌15分钟后，浓缩混合物至其体积的1/5，用二氯甲烷稀释，并用水，碳酸氢钠水溶液和水洗涤。有机层用硫酸镁干燥并真空浓缩。所得油通过硅胶柱色谱纯化，得到21g的10。制备11
将二甲硫(1.45ml)加到10(600mg)的乙腈∶二氯甲烷(1∶1，v/v，；8ml)溶液中。冷却反应混合物至0℃，滴加入无水过氧化苯甲酰(3.63g)的乙腈∶二氯甲烷(1∶1，v/v；10ml)混合物。在20℃搅拌16h后，混合物用二氯甲烷稀释并用碳酸氢钠水溶液和水洗涤。有机层用硫酸镁干燥并真空浓缩。在用硅胶柱色谱纯化后，分离到400mg11。制备12
用与P.Westerduin等人在生物有机和医学化学，1994，vol2，no.11，pp.1267-1280中所述类似的方法，制备化合物12。
在产生12的反应步骤过程中，用苯甲酰基代替甲基保护糖醛酸。制备13
用与化合物4所述类似的方法，通过偶联化合物11到化合物12上制得化合物13。制备14
将碳酸氢钠(142mg)的水(2ml)悬浮液和Pd/C(400mg)加到13(480mg)的2-甲基-2-丙醇(60ml)溶液中。混合物在氢气气氛中放置16小时。滤出催化剂并用2-甲基-2-丙醇/水混合液洗涤。合并的滤液和洗涤液经真空浓缩，得到315mg14，该产物未经进一步纯化直接使用。制备15
取化合物14(315mg)溶于0.35N氢氧化钠水溶液(10ml)。搅拌反应混合物过夜，然后用1N盐酸调节pH至8.5。混合物用悬浮在水∶乙腈∶三乙胺90∶10∶0.1(v/v/v)的Sephadex G-25柱脱盐。收集合适部分并真空浓缩。按与化合物14所述类似的方式，再氢解产物。经处理和浓缩滤液及洗涤液后，混合物用悬浮在水∶乙腈∶三乙胺90∶10∶0.1(v/v/v)的Sephadex G-25柱脱盐。收集合适部分并真空浓缩，并于Dowex 50WX8Na+柱上用水洗脱，最后冻干，得到165mg15。制备16
将15(165mg)的溶液与N，N-二甲基甲酰胺一同蒸发，并溶于N，N-二甲基甲酰胺(11.0ml)。向反应混合物中加入三乙胺三氧化硫配合物(1.31g)。在50℃搅拌16小时后，冷却混合物(0℃)，加入碳酸氢钠(2.43g)水溶液并于20℃继续搅拌1小时，然后真空浓缩溶液。残留物用悬浮在水-乙腈9∶1(v/v)的Sephadex G-25柱脱盐，收集合适部分并真空浓缩。在Dowex 50WX8Na+洗脱后，产物通过Q-Sepha rose Hing Load柱纯化，采用氯化钠梯度，得到160mg16{[α]20 D＝+24.0(c＝0.77；H2O)}。
Claims (8)
1.式I糖类衍生物或其可药用盐：其中R1为H或CH2OSO3 -；R2和R3彼此独立为H，(1-6C)烷基或SO3 -；R4为OSO3 -或NHSO3 -；n为0或1；p为1或2。
2.权利要求1的糖类衍生物，其中R2为(1-6C)烷基，R3为SO3 -，R4为OSO3 -，以及R1、n和p的定义同上。
3.权利要求2的糖类衍生物，其中R2为甲基。
4.权利要求2或3的糖类衍生物，其中n为1和p为1。
5.权利要求2-4任一项所述的糖类衍生物，其中R1为CH2OSO3
6.一种药物组合物，它包括权利要求1-5任一项所述的糖类衍生物和药学上合适的助剂。
7.在治疗方面应用的权利要求1-5任一项所述的糖类衍生物。
8.权利要求1-5任一项所述的糖类衍生物在制备治疗或预防血栓形成或抑制平滑肌细胞增生的药物方面的应用。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134554A (zh) * | 2017-06-15 | 2019-01-04 | 南京正大天晴制药有限公司 | 抗凝血的五糖类化合物及其制备方法和医药用途 |
| CN109134555A (zh) * | 2017-06-15 | 2019-01-04 | 南京正大天晴制药有限公司 | 抗凝血的五糖类化合物及其制备方法和医药用途 |
| CN109134553A (zh) * | 2017-06-15 | 2019-01-04 | 南京正大天晴制药有限公司 | 抗凝血的五糖类化合物及其制备方法和医药用途 |
Families Citing this family (7)
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| DE69832066T2 (de) * | 1997-05-27 | 2006-07-13 | Sanofi-Aventis | Verwendung eines oligosaccharids zur vorbeugung von blutgerinnung in extrakorporalen kreisläufen |
| ES2312210T3 (es) | 1998-06-17 | 2009-02-16 | N.V. Organon | Composiciones antitromboticas. |
| HUP0201712A3 (en) * | 1999-06-30 | 2003-03-28 | Weitz Jeffrey I Ancaster | Clot associated coagulation factors inhibiting heparin compositions |
| MXPA02004741A (es) * | 1999-11-12 | 2003-12-11 | Emisphere Tech Inc | Formulacion liquida de heparina. |
| US8600783B2 (en) * | 2000-08-18 | 2013-12-03 | The Crawford Group, Inc. | Business to business computer system for communicating and processing rental car reservations using web services |
| AU2001291549A1 (en) * | 2000-09-08 | 2002-03-22 | Hamilton Civic Hospitals Research Development Inc. | Antithrombotic compositions |
| CN111057115B (zh) * | 2019-12-17 | 2022-03-22 | 广东海洋大学 | 一种从贵妃蚌中提取的抗血栓类肝素及其制备方法和应用 |
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| EP0300099A1 (en) * | 1987-07-20 | 1989-01-25 | Akzo N.V. | New pentasaccharides |
| ES2060284T3 (es) * | 1990-04-23 | 1994-11-16 | Sanofi Elf | Un procedimiento para la preparacion de un derivado de carbohidrato que comprende una unidad de trisacarido. |
| US5378829A (en) * | 1990-04-23 | 1995-01-03 | Akzo N.V. | Sulfated glycosaminoglycanoid derivatives of the heparin and heparan sulfate type |
| US5707973A (en) * | 1991-04-23 | 1998-01-13 | Rhone-Poulenc Rorer S.A. | Sulfated polysaccharids for treatment or prevention of thromboses |
| IL102758A (en) * | 1991-08-23 | 1997-03-18 | Akzo Nv | Glycosaminoglycanoid derivatives, their preparation and pharmaceutical compositions comprising them |
| FR2704226B1 (fr) * | 1993-04-22 | 1995-07-21 | Sanofi Elf | 3-desoxy oligosaccharides, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent. |
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- 1997-05-07 NO NO972120A patent/NO308251B1/no not_active IP Right Cessation
- 1997-05-08 TR TR97/00354A patent/TR199700354A2/xx unknown
- 1997-05-08 AR ARP970101915A patent/AR007052A1/es active IP Right Grant
- 1997-05-08 BR BRPI9703099 patent/BRPI9703099B8/pt not_active IP Right Cessation
- 1997-05-19 TW TW086106674A patent/TW498078B/zh not_active IP Right Cessation
- 1997-05-27 SG SG1997001743A patent/SG46779A1/en unknown
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1998
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134554A (zh) * | 2017-06-15 | 2019-01-04 | 南京正大天晴制药有限公司 | 抗凝血的五糖类化合物及其制备方法和医药用途 |
| CN109134555A (zh) * | 2017-06-15 | 2019-01-04 | 南京正大天晴制药有限公司 | 抗凝血的五糖类化合物及其制备方法和医药用途 |
| CN109134553A (zh) * | 2017-06-15 | 2019-01-04 | 南京正大天晴制药有限公司 | 抗凝血的五糖类化合物及其制备方法和医药用途 |
| CN109134555B (zh) * | 2017-06-15 | 2021-09-28 | 南京正大天晴制药有限公司 | 抗凝血的五糖类化合物及其制备方法和医药用途 |
| CN109134554B (zh) * | 2017-06-15 | 2021-09-28 | 南京正大天晴制药有限公司 | 抗凝血的五糖类化合物及其制备方法和医药用途 |
| CN109134553B (zh) * | 2017-06-15 | 2021-09-28 | 南京正大天晴制药有限公司 | 抗凝血的五糖类化合物及其制备方法和医药用途 |
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