CN103772277B - 羟氯喹亚麻酸酯及其合成方法 - Google Patents
羟氯喹亚麻酸酯及其合成方法 Download PDFInfo
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- CN103772277B CN103772277B CN201310744461.5A CN201310744461A CN103772277B CN 103772277 B CN103772277 B CN 103772277B CN 201310744461 A CN201310744461 A CN 201310744461A CN 103772277 B CN103772277 B CN 103772277B
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- oxychloroquine
- linolenate
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- 229960004171 hydroxychloroquine Drugs 0.000 title claims abstract description 57
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 229940040452 linolenate Drugs 0.000 title claims abstract description 29
- DTOSIQBPPRVQHS-PDBXOOCHSA-M linolenate Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC([O-])=O DTOSIQBPPRVQHS-PDBXOOCHSA-M 0.000 title claims abstract description 29
- 238000010189 synthetic method Methods 0.000 title description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 21
- 229960004488 linolenic acid Drugs 0.000 claims abstract description 15
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 claims abstract description 14
- 235000020661 alpha-linolenic acid Nutrition 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000004440 column chromatography Methods 0.000 claims abstract description 11
- 238000000926 separation method Methods 0.000 claims abstract description 10
- ZAVJTSLIGAGALR-UHFFFAOYSA-N 2-(2,2,2-trifluoroacetyl)cyclooctan-1-one Chemical compound FC(F)(F)C(=O)C1CCCCCCC1=O ZAVJTSLIGAGALR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960002927 hydroxychloroquine sulfate Drugs 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000012141 concentrate Substances 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 239000003480 eluent Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 230000005526 G1 to G0 transition Effects 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical group CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 6
- 239000000741 silica gel Substances 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000010792 warming Methods 0.000 claims description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical group OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 claims description 2
- 239000006166 lysate Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 7
- 210000004881 tumor cell Anatomy 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 5
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- 239000000470 constituent Substances 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
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- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
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- 230000000694 effects Effects 0.000 description 2
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- 230000005764 inhibitory process Effects 0.000 description 2
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- 201000004792 malaria Diseases 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FQYRLEXKXQRZDH-UHFFFAOYSA-N 4-aminoquinoline Chemical class C1=CC=C2C(N)=CC=NC2=C1 FQYRLEXKXQRZDH-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 108700016171 Aspartate ammonia-lyases Proteins 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102000003952 Caspase 3 Human genes 0.000 description 1
- 108090000397 Caspase 3 Proteins 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 239000012822 autophagy inhibitor Substances 0.000 description 1
- 125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000006195 histone acetylation Effects 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
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- 230000001868 lysosomic effect Effects 0.000 description 1
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- 238000001819 mass spectrum Methods 0.000 description 1
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- 230000002438 mitochondrial effect Effects 0.000 description 1
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- 230000035699 permeability Effects 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
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- 229960004418 trolamine Drugs 0.000 description 1
- 230000002476 tumorcidal effect Effects 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
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CN201310744461.5A CN103772277B (zh) | 2013-12-31 | 2013-12-31 | 羟氯喹亚麻酸酯及其合成方法 |
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CN201310744461.5A CN103772277B (zh) | 2013-12-31 | 2013-12-31 | 羟氯喹亚麻酸酯及其合成方法 |
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CN103772277A CN103772277A (zh) | 2014-05-07 |
CN103772277B true CN103772277B (zh) | 2016-03-30 |
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CN104165850A (zh) * | 2014-08-13 | 2014-11-26 | 四川省人民医院 | 一种羟氯喹亚麻酸酯治疗肿瘤的有效性体外评价方法 |
CN110974831A (zh) * | 2019-10-21 | 2020-04-10 | 四川省人民医院 | 提高氟尿嘧啶敏感性的药物组合及其药物组合的应用 |
CN110974829A (zh) * | 2019-10-21 | 2020-04-10 | 四川省肿瘤医院 | 羟氯喹亚麻酸酯提高5-Fu敏感性的应用及评价方法 |
CN116041259A (zh) * | 2023-01-13 | 2023-05-02 | 武汉科技大学 | 一种羟氯喹的衍生物及其制备方法 |
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CN101768195B (zh) * | 2008-12-31 | 2012-05-23 | 复旦大学附属华东医院 | 碘化亚油酸去氧氟脲苷酯及其制备方法和用途 |
CN102050781B (zh) * | 2010-12-21 | 2012-07-25 | 重庆康乐制药有限公司 | 一种硫酸羟氯喹的工业化制备方法 |
CN103172577B (zh) * | 2012-01-13 | 2015-10-07 | 沈阳药科大学 | 4-氨基喹唑啉及4-氨基喹啉类化合物及其用途 |
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Address after: 610072, No. two, section 32, West Ring Road, Chengdu, Sichuan Applicant after: SICHUAN PROVINCIAL PEOPLE'S Hospital Address before: 610072 Chengdu City, Qingyang Province, Sichuan District, West Ring Road, No. two, No. 32 Applicant before: SICHUAN ACADEMY OF MEDICAL SCIENCES & SICHUAN PROVINCIAL PEOPLE'S Hospital |
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Address after: 610072, No. two, section 32, West Ring Road, Qingyang District, Sichuan, Chengdu Patentee after: Sichuan Academy of Medical Sciences. Sichuan Provincial People's Hospital Address before: 610072, No. two, section 32, West Ring Road, Chengdu, Sichuan Patentee before: SICHUAN PROVINCIAL PEOPLE'S Hospital |
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Effective date of registration: 20230216 Address after: 273400 Shandong city of Linyi province Feixian County North Ring Road No. 1 Patentee after: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Address before: 610072, No. two, section 32, West Ring Road, Qingyang District, Sichuan, Chengdu Patentee before: Sichuan Academy of Medical Sciences. Sichuan Provincial People's Hospital |