CN105713035A - 双环醇磷酸酯化合物、制备方法、制剂及用途 - Google Patents
双环醇磷酸酯化合物、制备方法、制剂及用途 Download PDFInfo
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- CN105713035A CN105713035A CN201510994100.5A CN201510994100A CN105713035A CN 105713035 A CN105713035 A CN 105713035A CN 201510994100 A CN201510994100 A CN 201510994100A CN 105713035 A CN105713035 A CN 105713035A
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- Prior art keywords
- bicyclol
- salt
- phosphate
- phosphate ester
- compound
- Prior art date
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- -1 Bicyclol phosphate ester compound Chemical class 0.000 title claims abstract description 103
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 83
- 239000010452 phosphate Substances 0.000 title claims abstract description 83
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 23
- KXMTXZACPVCDMH-UHFFFAOYSA-N methyl 4-[5-(hydroxymethyl)-7-methoxy-1,3-benzodioxol-4-yl]-7-methoxy-1,3-benzodioxole-5-carboxylate Chemical compound COC(=O)C1=CC(OC)=C2OCOC2=C1C1=C2OCOC2=C(OC)C=C1CO KXMTXZACPVCDMH-UHFFFAOYSA-N 0.000 claims abstract description 112
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 39
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 239000002253 acid Substances 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims abstract description 8
- 239000011230 binding agent Substances 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 22
- 239000001506 calcium phosphate Substances 0.000 claims description 17
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 17
- 235000011010 calcium phosphates Nutrition 0.000 claims description 17
- 239000001488 sodium phosphate Substances 0.000 claims description 17
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 17
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 17
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 13
- 239000011574 phosphorus Substances 0.000 claims description 13
- 229910052698 phosphorus Inorganic materials 0.000 claims description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 230000032050 esterification Effects 0.000 claims description 11
- 238000005886 esterification reaction Methods 0.000 claims description 11
- 238000002347 injection Methods 0.000 claims description 11
- 239000007924 injection Substances 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 7
- 239000008215 water for injection Substances 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- SUHOOTKUPISOBE-UHFFFAOYSA-N O-phosphoethanolamine Chemical compound NCCOP(O)(O)=O SUHOOTKUPISOBE-UHFFFAOYSA-N 0.000 claims description 5
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 claims description 5
- 125000003368 amide group Chemical group 0.000 claims description 5
- 150000001447 alkali salts Chemical class 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 230000004044 response Effects 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- 229940124899 Biothrax Drugs 0.000 claims description 3
- HDFFVHSMHLDSLO-UHFFFAOYSA-N Dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)(O)OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-N 0.000 claims description 3
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 229910001413 alkali metal ion Inorganic materials 0.000 claims description 3
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 claims description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 3
- SFOQXWSZZPWNCL-UHFFFAOYSA-K bismuth;phosphate Chemical compound [Bi+3].[O-]P([O-])([O-])=O SFOQXWSZZPWNCL-UHFFFAOYSA-K 0.000 claims description 3
- 238000013270 controlled release Methods 0.000 claims description 3
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 3
- UCQFCFPECQILOL-UHFFFAOYSA-N diethyl hydrogen phosphate Chemical compound CCOP(O)(=O)OCC UCQFCFPECQILOL-UHFFFAOYSA-N 0.000 claims description 3
- DLPMOMUTOGVWOH-UHFFFAOYSA-M dihydrogen phosphate;tetraethylazanium Chemical compound OP(O)([O-])=O.CC[N+](CC)(CC)CC DLPMOMUTOGVWOH-UHFFFAOYSA-M 0.000 claims description 3
- WOERBKLLTSWFBY-UHFFFAOYSA-M dihydrogen phosphate;tetramethylazanium Chemical compound C[N+](C)(C)C.OP(O)([O-])=O WOERBKLLTSWFBY-UHFFFAOYSA-M 0.000 claims description 3
- WZPMZMCZAGFKOC-UHFFFAOYSA-N diisopropyl hydrogen phosphate Chemical compound CC(C)OP(O)(=O)OC(C)C WZPMZMCZAGFKOC-UHFFFAOYSA-N 0.000 claims description 3
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 claims description 3
- NFORZJQPTUSMRL-UHFFFAOYSA-N dipropan-2-yl hydrogen phosphite Chemical compound CC(C)OP(O)OC(C)C NFORZJQPTUSMRL-UHFFFAOYSA-N 0.000 claims description 3
- 229940116007 ferrous phosphate Drugs 0.000 claims description 3
- 239000007902 hard capsule Substances 0.000 claims description 3
- 229910000155 iron(II) phosphate Inorganic materials 0.000 claims description 3
- SDEKDNPYZOERBP-UHFFFAOYSA-H iron(ii) phosphate Chemical compound [Fe+2].[Fe+2].[Fe+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O SDEKDNPYZOERBP-UHFFFAOYSA-H 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 229910001386 lithium phosphate Inorganic materials 0.000 claims description 3
- GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 claims description 3
- 239000004137 magnesium phosphate Substances 0.000 claims description 3
- 229910000157 magnesium phosphate Inorganic materials 0.000 claims description 3
- 229960002261 magnesium phosphate Drugs 0.000 claims description 3
- 235000010994 magnesium phosphates Nutrition 0.000 claims description 3
- 229950002366 nafoxidine Drugs 0.000 claims description 3
- RQKYHDHLEMEVDR-UHFFFAOYSA-N oxo-bis(phenylmethoxy)phosphanium Chemical compound C=1C=CC=CC=1CO[P+](=O)OCC1=CC=CC=C1 RQKYHDHLEMEVDR-UHFFFAOYSA-N 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- 239000008213 purified water Substances 0.000 claims description 3
- VHNQIURBCCNWDN-UHFFFAOYSA-N pyridine-2,6-diamine Chemical class NC1=CC=CC(N)=N1 VHNQIURBCCNWDN-UHFFFAOYSA-N 0.000 claims description 3
- 150000003222 pyridines Chemical class 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 239000007901 soft capsule Substances 0.000 claims description 3
- 230000002459 sustained effect Effects 0.000 claims description 3
- 238000013268 sustained release Methods 0.000 claims description 3
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims description 3
- TWQULNDIKKJZPH-UHFFFAOYSA-K trilithium;phosphate Chemical compound [Li+].[Li+].[Li+].[O-]P([O-])([O-])=O TWQULNDIKKJZPH-UHFFFAOYSA-K 0.000 claims description 3
- JOPDZQBPOWAEHC-UHFFFAOYSA-H tristrontium;diphosphate Chemical compound [Sr+2].[Sr+2].[Sr+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O JOPDZQBPOWAEHC-UHFFFAOYSA-H 0.000 claims description 3
- LRXTYHSAJDENHV-UHFFFAOYSA-H zinc phosphate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O LRXTYHSAJDENHV-UHFFFAOYSA-H 0.000 claims description 3
- 229910000165 zinc phosphate Inorganic materials 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 17
- 230000000694 effects Effects 0.000 abstract description 16
- 229940079593 drug Drugs 0.000 abstract description 6
- 210000004185 liver Anatomy 0.000 abstract description 5
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 abstract description 4
- 238000005192 partition Methods 0.000 abstract description 3
- 238000006366 phosphorylation reaction Methods 0.000 abstract description 3
- 230000008685 targeting Effects 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 238000001727 in vivo Methods 0.000 abstract description 2
- 230000014759 maintenance of location Effects 0.000 abstract description 2
- 230000026731 phosphorylation Effects 0.000 abstract description 2
- 206010061218 Inflammation Diseases 0.000 abstract 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 8
- 210000002966 serum Anatomy 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 102000003929 Transaminases Human genes 0.000 description 6
- 108090000340 Transaminases Proteins 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000005696 Diammonium phosphate Substances 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 4
- 229910000388 diammonium phosphate Inorganic materials 0.000 description 4
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- 125000003545 alkoxy group Chemical group 0.000 description 3
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- 125000003118 aryl group Chemical group 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
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Abstract
本发明涉及式(Ⅰ)的双环醇磷酸酯(盐)、其制备方法、制剂以及双环醇磷酸酯(盐)在制备抗炎药物中的用途,其中,M1、M2各自独立地代表H、金属离子、铵离子(NH4 +)或氨基或胺基;双环醇磷酸酯由双环醇和磷酰化试剂在催化剂和缚酸剂存在下发生磷酰化反应制得,使双环醇磷酸酯与碱或盐发生反应,可制得双环醇磷酸酯盐。本发明在双环醇分子结构中引入了磷酸基团,主要依靠磷酸基团的高负电性即亲水性强的特点改善药物的酯水分配系数,从而在不影响双环醇的活性和安全性的前提下提高了药物的水溶性,并且所得到的双环醇磷酸酯(盐)可提高双环醇对肝脏的靶向作用,改善给药途径,并延长药物在体内的保留时间。
Description
技术领域
本发明属于药物制备技术领域,具体涉及双环醇磷酸酯化合物、其制备方法、制剂以及双环醇磷酸酯化合物在制备抗炎药物中的用途。
背景技术
双环醇(Bicyclol),化学名称为4,4'-二甲氧基-5,6,5',6'-双(亚甲二氧基)-2-羟甲基-2'-甲氧羰基联苯。系中国医学科学院药物研究所研制的具有自主知识产权的抗肝炎创新药物,在16个国家和地区获得专利保护,目前上市剂型为口服片剂。双环醇原料及其片剂于2001年获得新药证书和生产批件,由北京协和药厂独家生产。双环醇对四氯化碳、D-氨基半乳糖、扑热息痛引起的小鼠急性肝损伤的氨基转移酶升高、小鼠免疫性肝炎的氨基转移酶升高有降低作用,肝脏组织病理形态学损害有不同程度的减轻。体外试验结果显示双环醇对肝癌细胞转染人乙肝病毒的2.2.15细胞株具有抑制HBeAg、HBVDNA、HB分泌的作用。适用于伴有氨基转移酶异常升高的慢性病毒性肝炎和非病毒性肝病治疗,安全性高,停药后不易反弹。经北京、上海多家医院500多例慢性乙肝、丙肝患者进行临床疗效观察,表明该药不但能降低血清谷丙转氨酶和谷草转氨酶,而且具有一定抑制肝病毒复制的作用,未发现明显副作用。
尽管双环醇对慢性乙型和慢性丙型肝炎均有较好的改善症状和降低血清转氨酶的效果,但是双环醇水溶性不佳,影响药物的成药性,增大制剂研发的难度和投入成本。因此有必要对双环醇分子结构进行优化,以改善其水溶性,提高成药性。
通过结构修饰改善水溶性的策略有:
1)成盐修饰:大部分药物都具有一定的酸碱性,成盐可通过增加离子水合能,促进溶解。如盐酸盐、硫酸盐等。
2)引入极性基团:引入极性基团实际上是增加化合物的水合作用,促进溶解的热力学过程。另外,很多极性基团也是可离子化的基团,离子化过程会提供额外的能量,促进溶解。可供选择的极性基团一般为直链或环状的含有N、O原子的基团,如直链的胺类、醇类、环状的哌嗪、吗啉、氧杂或氮杂环烷烃、酸碱等可离子化片段等。
3)降低脂溶性:在化合物结构中含有数量较多或体积较大的芳香体系时,减少芳香环可以降低晶体中的分子堆积作用,提高化合物的水溶性,另外也常见采用饱和换替代芳香环,利用破坏分子平面性的作用降低晶格能。
4)构象优化:对于平面型分子,特别是含有共轭芳香环的分子,由于分子之间紧密推挤和π-π作用,导致较难溶解。通过化学结构修饰方法干扰分子的平面性,进而影响晶格能,增加化合物的溶解性。方法有增加共轭体系间的位阻、改变稠环体系的电性、引入平米外取代基等。
5)前药修饰:上述几个策略都是直接修饰化合物的结构,但不适当的化学修饰可能会影响化合物的活性或安全性。而前药策略是不是改变原药结构,只靠添加助溶基团来提高水溶性,这是前药策略的一个优势,前药大体有分类有:磷酸化、氨基酸酯、糖基化、羧酸酯化、酰胺化和水溶性聚合物等。
目前对于双环醇进行结构修饰的研究报道也较多,中国专利“双环醇-亮氨酰胺及其制备方法与应用”(申请号201210535804,公开日2013年3月27日)、中国专利“双环醇-硫普罗宁酯及其制备方法与应用”(申请号201210535803,公开日2012年12月13日)、中国专利“双环醇糖苷类化合物及其制备方法和用途“(申请号200510077441,公开日2013年3月27日)、中国专利“双环醇缬氨酸酯及其制备方法和其药物组合物与用途”(申请号201010184424,公开日2010年5月27日)和中国专利“腺嘌呤双环醇酯及其制备方法”(申请号200410024276,公开日2004年6月16日)分别披露了各种通过结构修饰得到的双环醇衍生物,但上述专利中对于是否改善了双环醇的水溶性没有提供明确的实验数据,难以说明改善水溶性的效果。
发明内容
针对现有技术中存在的不足,本发明的第一个目的是提供式(Ⅰ)的化合物,所述化合物亲水性强,具有较高的水溶性,可大大提高双环醇对肝脏的靶向作用,从而可有效改善给药途径。
本发明的第二个目的是提供式(Ⅰ)的化合物的制备方法,该方法工艺简单,成本低,易于工业化。
本发明的第三个目的是提供含式(Ⅰ)的化合物或双环醇磷酸酯盐的制剂。
本发明的第四个目的是提供式(Ⅰ)的化合物或双环醇磷酸酯盐在制备抗炎药物中的用途。
为达到以上目的,本发明采用的技术方案是:式(Ⅰ)的化合物,
其中,M1、M2各自独立地代表H、金属离子、铵离子或氨基或胺基。
进一步,所述金属离子为碱金属离子、碱土金属离子、第ⅡB族金属离子、第ⅢA族金属离子、第ⅤA族金属离子或第Ⅷ族金属离子。
本发明提供的双环醇磷酸酯盐,选自:
双环醇磷酸钠,双环醇磷酸钾,双环醇磷酸锂、双环醇磷酸锶、双环醇磷酸钙、双环醇磷酸镁、双环醇磷酸锌、双环醇磷酸亚铁、双环醇磷酸铝、双环醇磷酸铋、双环醇磷酸乙醇胺、双环醇磷酸异丙胺、双环醇磷酸氨基酸盐、双环醇磷酸葡甲胺盐或双环醇磷酸季铵盐。
进一步,所述双环醇磷酸氨基酸盐为双环醇磷酸丝氨酸盐、双环醇磷酸苏氨酸盐或双环醇磷酸酪氨酸盐;双环醇磷酸季铵盐为双环醇磷酸四甲基铵、双环醇磷酸四乙基铵或双环醇磷酸四丁基铵。
本发明提供的式(Ⅰ)的化合物的制备方法:
当M1、M2分别为H时,所述式(Ⅰ)化合物为式(Ⅱ)的双环醇磷酸酯,
本发明提供的所述式(Ⅱ)的双环醇磷酸酯的制备方法为:
使双环醇溶于有机溶剂,加入磷酰化试剂、催化剂和缚酸剂,使双环醇与磷酰化试剂发生磷酰化反应,反应时间为15-25小时,反应温度为70-130℃,反应完毕后室温静置6-8小时;然后除去反应产物中的有机溶剂,提纯,即得双环醇磷酸酯;
当M1、M2各自独立地代表金属离子、铵离子或有机碱基时,所述式(Ⅰ)化合物为双环醇磷酸酯盐,所述双环醇磷酸酯盐的制备方法选自以下方法A、B:
方法A:使式(Ⅱ)的双环醇磷酸酯与碱A或盐A反应生成相应的双环醇磷酸酯盐;其中,当双环醇磷酸酯与所述的盐A反应时,所述的盐A为碱式盐;
方法B:使双环醇磷酸盐与碱B或盐B发生反应,生成另外的双环醇磷酸酯盐;其中,当双环醇磷酸酯盐与所述的碱B反应时,参与反应的双环醇磷酸酯盐呈酸性,当双环醇磷酸酯盐与所述的盐B反应时,所述盐B的溶解度小于所生成的另外的双环醇磷酸酯盐的溶解度。
进一步,所述磷酰化试剂选自磷酸、五氧化二磷、三氯氧磷、亚磷酸二乙酯、亚磷酸二异丙酯、对甲苯磺酰磷酸二乙酯、对甲苯磺酰磷酸二异丙酯、亚磷酸二苄酯、磷酸二苄酯、磷酸二氢四丁铵、4-硝基苯甲基磷酸中的一种或多种;所述催化剂选自4-二甲氨基吡啶、四氢吡咯基吡啶、2,6-二胺基吡啶、氢化钠和乙酸酐的一种或多种;所述缚酸剂为吡啶和/或三乙胺。
进一步,所述有机溶剂为乙腈、甲醇、乙醇、异丙醇、四氢呋喃、乙酸乙酯或二氯甲烷。
本发明提供的含式(Ⅰ)的化合物的制剂可以是将式(Ⅰ)的化合物或含式(Ⅰ)的化合物的混合物制成的各种形式的固体药物制剂;或者,将式(Ⅰ)的化合物或含式(Ⅰ)的化合物的混合物溶于纯化水或注射用水并灌封于硬胶囊、软胶囊、缓控释胶囊中而得到的各种合适的液体胶囊剂型;或者,将式(Ⅰ)的化合物或含式(Ⅰ)的化合物的混合物溶于注射用水制成的注射液。
本发明采用磷酰化的修饰策略对双环醇分子进行结构修饰和优化,引入了磷酸基团,主要依靠磷酸基团的高负电性即亲水性强的特点改善药物的酯水分配系数,从而在不影响双环醇的活性和安全性的前提下,提高了药物的水溶性:同时,采用这种结构修饰方式所得到的双环醇磷酸酯(盐)可提高双环醇对肝脏的靶向作用,改善给药途径,并延长药物在体内的保留时间。
双环醇磷酸钙、双环醇磷酸钠和双环醇在水中的溶解度见下表1。
表1
通常认为,当药物的水溶性<1mg/ml时,其水溶性可能成为药物吸收的限速步骤。如表1所示,双环醇在水中的溶解度仅为0.03mg/ml,但根据本发明,将双环醇转化为双环醇磷酸钙后水溶性可提高100倍以上,转化为双环醇磷酸钠后水溶性可提高约2000倍,显著提高了成药性,为制成其他制剂尤其是注射剂提供了便利。
附图说明
图1为本发明制得的双环醇磷酸钙的ESI-MS的鉴定结果;ESI-MS:m/z[M-H]=509.0;
图2为本发明制得的双环醇磷酸钙的1H-NMR的结果;HNMR(D2O,500MHZ)δ3.708(s,3H);3.984,3.990(d,6H);5.921,5.946,6.060,6.125(s,4H);4.534-4.653(q,3H);7.016(s,1H);7.444(s,1H);
图3为本发明制得的双环醇磷酸钠的ESI-MS的鉴定结果;ESI-MS:m/z[M-H]=515.1。
具体实施方式
下面结合附图和具体实施方式对本发明作进一步描述。
本发明涉及式(Ⅰ)的化合物,
其中,M1、M2各自独立地代表H、金属离子、铵离子(NH4 +)或氨基(-NH2)或胺基(-NR2或-NHR),其中R代表烷基、烷基羰基、烷氧基。显然,本发明的式(Ⅰ)的化合物包括双环醇磷酸酯和双环醇磷酸酯盐。
优选情况下,所述金属离子为碱金属离子、碱土金属离子、第ⅡB族金属离子、第ⅢA族金属离子、第ⅤA族金属离子或第Ⅷ族金属离子。
也就是说,双环醇磷酸酯盐包括常用碱的盐,例如碱金属盐(碱金属选自锂、钠、钾所组成的组)、碱土金属盐(碱土金属选自铍、镁、钙所组成的组)以及由其他金属离子(如第ⅡB族金属离子、第ⅢA族金属离子、第ⅤA族金属离子或第Ⅷ族金属离子)所得到的金属盐,其中,第ⅡB族金属如锌,第ⅢA族金属离子如铝,第ⅤA族金属如铋离子,第Ⅷ族金属如铁等。
双环醇磷酸酯盐还包括从氨或有机胺得到的铵盐,例证性的和优选的有机胺为乙胺、二乙胺、三乙胺、乙基二异丙基胺、单乙醇胺、二乙醇胺、三乙醇胺、葡甲胺、二甲基氨基乙醇、正甲基吗啉、正甲基哌啶或乙烯二胺。
此外,双环醇磷酸酯盐还包括双环醇磷酸氨基酸盐,其中,双环醇磷酸氨基酸盐中的氨基酸选自甘氨酸、L-丙氨酸、D-丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酸、谷氨酰胺、组氨酸、异亮氨酸、亮氨酸、赖氨酸、蛋氨酸、鸟氨酸、脯氨酸、苯丙氨酸、硒半胱氨酸、丝氨酸、酪氨酸、苏氨酸、色氨酸、牛磺酸或缬氨酸所组成的组。
另外,双环醇磷酸酯盐包括双环醇磷酸季铵盐,其中,双环醇磷酸季铵盐为双环醇磷酸四甲基铵、双环醇磷酸四乙基铵或双环醇磷酸四丁基铵。
式(I)的化合物的一些例子如下所示:
双环醇磷酸钠;
双环醇磷酸钾;
双环醇磷酸锂;
双环醇磷酸锶;
双环醇磷酸钙;
双环醇磷酸镁;
双环醇磷酸锌;
双环醇磷酸亚铁;
双环醇磷酸铝;
双环醇磷酸铋;
双环醇磷酸乙醇胺;
双环醇磷酸异丙胺。
尽管已用选择的化合物描述了本发明,本发明包括所有的式(I)的化合物。上述典型化合物的制备在下面的实施例中描述。
式(I)、式(Ⅱ)的化合物的合成
在本领域中,通常使双环醇与磷酰化试剂在催化剂和缚酸剂作用下磷酰化得到式(Ⅱ)的双环醇磷酸酯,如方案A中第一步所示。具体步骤如下:
使双环醇溶于有机溶剂,加入磷酰化试剂、催化剂和缚酸剂,使双环醇与磷酰化试剂发生磷酰化反应,反应时间为15-25小时,反应温度为70-130℃;反应完毕后,室温静置6-8小时,除去反应产物中的有机溶剂,提纯,即得双环醇磷酸酯。
除去有机溶剂后,可采用溶剂萃取法去除反应产物中的杂质,然后采用柱分离法从萃取后的水层中分离出含双环醇磷酸酯的产物,将产物浓缩干燥,即得纯的双环醇磷酸酯。
所述磷酰化试剂选自磷酸、五氧化二磷、三氯氧磷、亚磷酸二乙酯、亚磷酸二异丙酯、对甲苯磺酰磷酸二乙酯、对甲苯磺酰磷酸二异丙酯、亚磷酸二苄酯、磷酸二苄酯、磷酸二氢四丁铵、4-硝基苯甲基磷酸中的一种或多种;所述催化剂选自4-二甲氨基吡啶、四氢吡咯基吡啶、2,6-二胺基吡啶、氢化钠和乙酸酐的一种或多种;所述缚酸剂为吡啶和/或三乙胺;所述有机溶剂为乙腈、甲醇、乙醇、异丙醇、四氢呋喃、乙酸乙酯或二氯甲烷等。
本发明中,采用方案A第二步所示的方法A可制备双环醇磷酸酯盐:
方案A
其中式(Ⅰ)中的M1、M2各自独立地代表H、金属离子、铵离子(NH4 +)或氨基(-NH2)或胺基(-NR2或-NHR),其中R代表烷基、烷基羰基、烷氧基。
方法A具体如下:
方法A:使式(Ⅱ)的双环醇磷酸酯与碱A或盐A反应生成相应的双环醇磷酸酯盐;其中,当双环醇磷酸酯与所述的盐A反应时,所述盐A为碱式盐。
另外,采用方案B所示的方法B也可制备双环醇磷酸酯盐:
方案B
式(Ⅰ)的M1、M2以及式(Ⅰ′)中M1′、M2′各自独立地代表H、金属离子、铵离子(NH4 +)或氨基(-NH2)或胺基(-NR2或-NHR),其中R代表烷基、烷基羰基、烷氧基。
方法B具体如下:
方法B:使双环醇磷酸盐与另外的碱B或盐B发生反应,生成另外的双环醇磷酸酯盐;其中,当双环醇磷酸酯盐与所述的碱B反应时,参与反应的双环醇磷酸酯盐呈酸性,当双环醇磷酸酯盐与所述的盐B反应时,参与反应的双环醇磷酸酯盐为酸式盐,所述盐B的溶解度小于所生成的另外的双环醇磷酸酯盐的溶解度。
制剂
本发明中,根据需要,可将式(Ⅰ)的化合物或含式(Ⅰ)的化合物的混合物制成各种形式的固体药物制剂,或者,将式(Ⅰ)的化合物或含式(Ⅰ)的化合物的混合物溶于纯化水或生理盐水并灌封于硬胶囊、软胶囊、缓控释胶囊中,得到各种合适的液体胶囊剂型;或者,将所述式(Ⅰ)的化合物或含式(Ⅰ)的化合物的混合物溶于注射用水,制成注射液。
在制备制剂的过程中,必要时可加入赋形剂。所述赋形剂可包括填充剂、稀释剂、崩解剂、润滑剂等。
实施例
实施例1双环醇磷酸酯的制备
取磷酸(56ml,0.96mol)溶于乙腈(800ml)中,室温水浴搅拌下缓慢加入吡啶(320ml)、三乙胺(224ml)、乙酸酐(152ml)、双环醇(80g,0.205mol),回流条件下反应至原料消失(约20小时),室温静置6-8小时,向反应液中加水(100ml),继续回流2h后,减压浓缩去溶剂,浓缩物加水和乙酸乙酯萃取,水层过LSA-21大孔树脂(1kg)柱,用水和乙醇梯度洗脱,产品洗脱液浓缩干燥,得双环醇磷酸酯(44g,45.6%)。
实施例2双环醇磷酸钙的制备
将双环醇磷酸酯(16g,0.034mol)用500ml甲醇溶解,缓慢滴加醋酸钙(8g,0.051mol)水(32ml)溶液,室温搅拌反应30min,过滤得白色固体,将此固体加入到10%的甲醇水溶液(2000ml)中,回流搅拌4h,热过滤,滤液用乙酸乙酯萃取三次,水层减压浓缩至200ml,静置析晶2h,过滤干燥,得双环醇磷酸钙(10g,57.6%)。
ESI-MS:m/z[M-H]=509.0
HNMR(D2O,500MHZ)δ3.708(s,3H);3.984,3.990(d,6H);5.921,5.946,6.060,6.125(s,4H);4.534-4.653(q,3H);7.016(s,1H);7.444(s,1H)。
实施例3双环醇磷酸钠的制备
取双环醇磷酸钙(3g,0.006mol)、碳酸钠(0.6g,0.006mol)、水(50ml),室温搅拌反应2h,过滤,滤液用乙酸乙酯萃取三次,水层减压浓缩干,加入无水甲醇(80ml),50℃水浴搅拌30min,滤除不溶物,滤液减压浓缩干,加入无水乙醇(50ml)),80℃水浴搅拌溶解,冷冻析晶,过滤干燥,得双环醇磷酸钠(2.0g,64.5%)。
ESI-MS:m/z[M-H]=515.1
实施例4双环醇磷酸铝的制备
将双环醇磷酸酯(4.7g,0.01mol)用150mlDMF溶解,加入碱式醋酸铝(1.6g,0.01mol),80℃搅拌反应4h,滤除不溶物,滤液80℃减压浓缩干得油状物,加入50ml无水乙醇,回流搅拌1h,冷却至室温滤出固体,再用乙酸乙酯室温搅拌1h,过滤干燥,得双环醇磷酸铝(3.2g,65.8%)。
实施例5双环醇磷酸乙醇胺的制备
将双环醇磷酸酯(5g,0.011mol)用甲醇(50ml)室温搅拌溶解,缓慢滴加乙醇胺(2ml,0.033mol),室温搅拌反应5h,将反应液45℃减压浓缩干,加入20ml无水甲醇溶解,搅拌下加入100ml乙酸乙酯,过滤,滤液室温静置析晶24h,过滤干燥,得双环醇磷酸乙醇胺(3.2g,54.8%)。
实施例6双环醇磷酸L-丝氨酸的制备
将双环醇磷酸酯(5g,0.011mol)用甲醇(50ml)室温搅拌溶解,加入L-丝氨酸(2.3g,0.022mol),室温搅拌反应5h,将反应液45℃减压浓缩干,加入20ml无水甲醇溶解,搅拌下加入80ml乙酸乙酯,过滤,滤液室温静置析晶20h,过滤干燥,得双环醇磷酸L-丝氨酸(2.9g,38.7%)。
实施例7双环醇磷酸二铵的制备
将双环醇磷酸酯(3.2g,0.007mol)用甲醇(50ml)室温搅拌溶解,缓慢通入氨气,室温搅拌反应2h,过滤得白色固体,过滤干燥,得双环醇磷酸二铵(2g,57.1%)。
实施例8双环醇磷酸钙片的制备
片剂处方:
制备方法:
将双环醇磷酸钙及上述辅料分别过80目筛,用等量递加法充分混匀后,用2%的羟丙基甲基纤维素水溶液制软材,20目筛制粒;湿颗粒在60℃干燥约2h,用20目筛整粒,干颗粒加硬脂酸镁混合均匀压片即得。
实施例9双环醇磷酸钠注射液的制备
注射液配方:
制备工艺:
量取90ml的注射用水,加入0.2g枸橼酸钠,搅拌溶解,用1%的枸橼酸溶液调节溶液的pH值为6.0;加入0.1%(W/V)药用炭,搅拌吸附20min,脱炭,加入1g的双环醇磷酸钠,搅拌溶解,加入注射用水至100ml,用“0.45μm+0.22μm”串联的除菌过滤器精滤,每支按照1.0ml进行灌装于安剖瓶中,封口,采用121℃湿热蒸汽灭菌15min,灯检,得到双环醇磷酸钠注射液。
药理实验例1
下面给出了本发明化合物(Ⅰ)静脉注射用于小鼠四氯化碳肝损伤治疗的药效试验研究数据。
试验方法:
将动物随机分为7组,每组10只,分别为正常对照组,CCl4模型组,及5组受试药物给药组(3组双环醇磷酸钠给药组和2组双环醇磷酸钙给药组)。在给予CCl4前24h、8h、1h,5组受试药物组动物尾静脉分别注射溶于生理盐水的实施例3的双环醇磷酸钠(20mg/kg、40mg/kg、80mg/kg)、实施例2的双环醇磷酸钙(25mg/kg、50mg/kg),共给药三次,正常对照组和CCl4模型组动物给予同体积赋形剂。除正常对照组外,各组均腹腔注射0.2%CCl4花生油,体积为10ml/kg。禁食过夜。给予CCl416h后将动物断头处死,取血,测定血清中ALT和AST酶活力。
实验结果:实验过程中所有受试动物均无任何异常反应,也无一只动物死亡,具体实验结果见表2。
表2
注:与模型组比较,*P<0.05,**P<0.01,***P<0.001。
结论:
小鼠腹腔注射CCl4后,血清转氨酶水平明显升高,与正常组比较有显著性差异;小鼠静脉注射双环醇磷酸钠(20mg/kg、40mg/kg、80mg/kg)及双环醇磷酸钙(25mg/kg、50mg/kg)可明显降低CCl4诱发的小鼠血清ALT的升高,与模型组比较有显著性差异。
药理实验例2
下面给出了本发明化合物(Ⅰ)口服用于小鼠四氯化碳肝损伤治疗的药效试验研究数据。
试验方法:
将动物随机分为8组,每组8只,分别为正常对照组,CCl4模型组、4组双环醇磷酸钠给药组及4组双环醇磷酸钙给药组。在给予CCl4前24,8和1小时,给药组动物分别口服溶于生理盐水的实施例3的双环醇磷酸钠及实施例2的双环醇磷酸钙(50、100、200mg/kg),共给药三次,正常对照组和CCl4模型组动物给予同体积赋形剂。除正常对照组外,各组均腹腔注射0.2%CCl4花生油,体积为10ml/kg。禁食过夜。给予CCl416小时后将动物断头处死,取血,测定血清中ALT和AST水平。
实验结果:实验数据见表3。
表3
注:与模型组比较,*P<0.05,**P<0.01,***P<0.001。
结论:
小鼠腹腔注射CCl4后,血清转氨酶水平明显升高,与正常组比较有显著性差异。双环醇磷酸钠、双环醇磷酸钙(100、200mg/kg)可明显降低CCl4诱发的小鼠血清ALT的升高,与模型组比较有显著性差异。
上述实施例只是对本发明的举例说明,本发明也可以以其它的特定方式或其它的特定形式实施,而不偏离本发明的要旨或本质特征。因此,描述的实施方式从任何方面来看均应视为说明性而非限定性的。本发明的范围应由附加的权利要求说明,任何与权利要求的意图和范围等效的变化也应包含在本发明的范围内。
Claims (9)
1.式(Ⅰ)的化合物,
其中,M1、M2各自独立地代表H、金属离子、铵离子或氨基或胺基。
2.根据权利要求1所述的化合物,其特征在于,所述金属离子为碱金属离子、碱土金属离子、第ⅡB族金属离子、第ⅢA族金属离子、第ⅤA族金属离子或第Ⅷ族金属离子。
3.双环醇磷酸酯盐,选自:
双环醇磷酸钠,双环醇磷酸钾,双环醇磷酸锂、双环醇磷酸锶、双环醇磷酸钙、双环醇磷酸镁、双环醇磷酸锌、双环醇磷酸亚铁、双环醇磷酸铝、双环醇磷酸铋、双环醇磷酸乙醇胺、双环醇磷酸异丙胺、双环醇磷酸氨基酸盐、双环醇磷酸葡甲胺盐或双环醇磷酸季铵盐。
4.根据权利要求3所述的双环醇磷酸酯盐,其特征在于,所述双环醇磷酸氨基酸盐为双环醇磷酸丝氨酸盐、双环醇磷酸苏氨酸盐或双环醇磷酸酪氨酸盐;双环醇磷酸季铵盐为双环醇磷酸四甲基铵、双环醇磷酸四乙基铵或双环醇磷酸四丁基铵。
5.权利要求1所述的式(Ⅰ)的化合物的制备方法:
当M1、M2分别为H时,所述式(Ⅰ)化合物为式(Ⅱ)的双环醇磷酸酯,
所述式(Ⅱ)的双环醇磷酸酯的制备方法为:
使双环醇溶于有机溶剂,加入磷酰化试剂、催化剂和缚酸剂,使双环醇与磷酰化试剂发生磷酰化反应,反应时间为15-25小时,反应温度为70-130℃,反应完毕后室温静置6-8小时;然后除去反应产物中的有机溶剂,提纯,即得双环醇磷酸酯;
当M1、M2各自独立地代表金属离子、铵离子或有机碱基时,所述式(Ⅰ)化合物为双环醇磷酸酯盐,所述双环醇磷酸酯盐的制备方法选自以下方法A、B:
方法A:使式(Ⅱ)的双环醇磷酸酯与碱A或盐A反应生成相应的双环醇磷酸酯盐;其中,当双环醇磷酸酯与所述的盐A反应时,所述的盐A为碱式盐;
方法B:使双环醇磷酸盐与碱B或盐B发生反应,生成另外的双环醇磷酸酯盐;其中,当双环醇磷酸酯盐与所述的碱B反应时,参与反应的双环醇磷酸酯盐呈酸性,当双环醇磷酸酯盐与所述的盐B反应时,所述盐B的溶解度小于所生成的另外的双环醇磷酸酯盐的溶解度。
6.根据权利要求5所述的制备方法,其特征在于,所述磷酰化试剂选自磷酸、五氧化二磷、三氯氧磷、亚磷酸二乙酯、亚磷酸二异丙酯、对甲苯磺酰磷酸二乙酯、对甲苯磺酰磷酸二异丙酯、亚磷酸二苄酯、磷酸二苄酯、磷酸二氢四丁铵、4-硝基苯甲基磷酸中的一种或多种;所述催化剂选自4-二甲氨基吡啶、四氢吡咯基吡啶、2,6-二胺基吡啶、氢化钠和乙酸酐的一种或多种;所述缚酸剂为吡啶和/或三乙胺。
7.根据权利要求5所述的制备方法,其特征在于,所述有机溶剂为乙腈、甲醇、乙醇、异丙醇、四氢呋喃、乙酸乙酯或二氯甲烷。
8.含权利要求1-2任一所述的式(Ⅰ)的化合物或权利要求3-4任一所述的双环醇磷酸酯盐的制剂,其特征在于,所述制剂为将所述式(Ⅰ)的化合物或双环醇磷酸酯盐制成的各种形式的固体药物制剂;或者,将所述式(Ⅰ)的化合物或双环醇磷酸酯盐溶于纯化水或注射用水并灌封于硬胶囊、软胶囊、缓控释胶囊中而得到的各种合适的液体胶囊剂型;或者,将所述式(Ⅰ)的化合物或双环醇磷酸酯盐溶于注射用水制成的注射液。
9.权利要求1-2任一所述的式(Ⅰ)的化合物或权利要求3-4任一所述的双环醇磷酸酯盐在制备抗炎药物中的用途。
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