CN101490015A - 瑞舒伐他汀锌盐 - Google Patents
瑞舒伐他汀锌盐 Download PDFInfo
- Publication number
- CN101490015A CN101490015A CNA200780021254XA CN200780021254A CN101490015A CN 101490015 A CN101490015 A CN 101490015A CN A200780021254X A CNA200780021254X A CN A200780021254XA CN 200780021254 A CN200780021254 A CN 200780021254A CN 101490015 A CN101490015 A CN 101490015A
- Authority
- CN
- China
- Prior art keywords
- zinc salt
- formula
- rosuvastatin
- methyl
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- KUQHZGJLQWUFPU-BGRFNVSISA-L zinc;(e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical class [Zn+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O KUQHZGJLQWUFPU-BGRFNVSISA-L 0.000 title claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 41
- 229940126601 medicinal product Drugs 0.000 claims abstract description 24
- 229960000672 rosuvastatin Drugs 0.000 claims abstract description 21
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims abstract description 21
- 238000002360 preparation method Methods 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 10
- 239000011701 zinc Substances 0.000 claims abstract description 10
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000003751 zinc Chemical class 0.000 claims abstract description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 40
- 229910052799 carbon Inorganic materials 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- -1 pyrimidine-5-yl Chemical group 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000005204 segregation Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- FLYIRERUSAMCDQ-UHFFFAOYSA-N 2-azaniumyl-2-(2-methylphenyl)acetate Chemical compound CC1=CC=CC=C1C(N)C(O)=O FLYIRERUSAMCDQ-UHFFFAOYSA-N 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims description 6
- 229960001763 zinc sulfate Drugs 0.000 claims description 6
- 229910000368 zinc sulfate Inorganic materials 0.000 claims description 6
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 5
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 5
- 239000012752 auxiliary agent Substances 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 208000020346 hyperlipoproteinemia Diseases 0.000 claims description 5
- 239000011592 zinc chloride Substances 0.000 claims description 5
- 235000005074 zinc chloride Nutrition 0.000 claims description 5
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000005837 enolization reaction Methods 0.000 claims description 4
- 150000002191 fatty alcohols Chemical class 0.000 claims description 4
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 3
- 230000003143 atherosclerotic effect Effects 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- 239000004246 zinc acetate Substances 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052728 basic metal Inorganic materials 0.000 claims description 2
- 150000003818 basic metals Chemical class 0.000 claims description 2
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 150000002196 fatty nitriles Chemical class 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 239000012296 anti-solvent Substances 0.000 claims 1
- 239000002244 precipitate Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 150000003752 zinc compounds Chemical class 0.000 claims 1
- NHXVNEDMKGDNPR-UHFFFAOYSA-N zinc;pentane-2,4-dione Chemical compound [Zn+2].CC(=O)[CH-]C(C)=O.CC(=O)[CH-]C(C)=O NHXVNEDMKGDNPR-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 11
- 239000003814 drug Substances 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000004927 fusion Effects 0.000 description 6
- 239000000377 silicon dioxide Substances 0.000 description 6
- 159000000007 calcium salts Chemical class 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000002349 favourable effect Effects 0.000 description 5
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical class [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 5
- 229960001866 silicon dioxide Drugs 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000000151 deposition Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 238000010936 aqueous wash Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- LMDAGMAWWYVRJZ-UHFFFAOYSA-N ethanol;zinc Chemical compound [Zn].CCO LMDAGMAWWYVRJZ-UHFFFAOYSA-N 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- IZXGZAJMDLJLMF-UHFFFAOYSA-N methylaminomethanol Chemical class CNCO IZXGZAJMDLJLMF-UHFFFAOYSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 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 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
本发明涉及式(I)的瑞舒伐他汀锌盐,其制备方法以及含所述盐的药用产品。根据本发明的瑞舒伐他汀锌盐如下制备:使瑞舒伐他汀与醇化锌、烯醇化锌或无机或有机锌盐反应并将如此获得的瑞舒伐他汀锌盐(2∶1)离析。
Description
发明领域
本发明涉及以下式(I)的(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸的锌盐,
它的水合物,它们的制备方法,含所述盐的药用产品,药用产品的制备方法和所述盐在医药中的用途。
以下式(II)的(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸以国际非专利名称(INN)瑞舒伐他汀已知。
本发明的技术背景
式(II)的瑞舒伐他汀首次公开在欧洲专利No.521471中。瑞舒伐他汀的钙盐是用于治疗高胆固醇血症、高脂蛋白血症和动脉粥样硬化的药物。
卫生管理机构对药物活性成分设置了严格的质量标准。这些标准中的一些与药物活性成分的化学纯度和稳定性有关。其它官方的要求是以满意的质量制造药用产品并且该药用产品应该具有适当的稳定性。此种标准由药典的相应条款确定并出版。
在式(II)的瑞舒伐他汀的情况下,对打算用于药用产品的活性药物成分的基本要求是高纯度、适当的稳定性和简单配方的可能性。
根据公开的国际专利申请号WO00/042024,根据欧洲专利号521471的方法获得的式(II)的无定形瑞舒伐他汀在制药技术中可能用起来具有较大困难。为了排除这种缺点,制备了比无定形产物具有更有利物理性能的结晶剂型。然而,结晶瑞舒伐他汀钙盐的制造是要求高生产容积的制造方法并且导致较大材料损失。
瑞舒伐他汀钙盐制造中的基本问题在于以下事实:所获得的初次产物不可充分过滤并且不能以容易的方式纯化。公开的国际专利申请WO04/14872公开了具有有利可过滤性的非结晶产物。根据所述申请的方法,使瑞舒伐他汀的碱金属、铵、甲基铵或三(羟甲基)甲基铵盐与氯化钙在水溶液中反应而制备具有有利颗粒尺寸的钙盐。
在公开的国际专利申请号WO01/60804中,公开了式(II)的瑞舒伐他汀的高纯度铵、锂或镁盐以解决在无定形瑞舒伐他汀的制造期间产生的生产问题。从上述盐开始,有可能以适合于药用产品制造的质量制备无定形瑞舒伐他汀。
公开的国际专利申请WO2005/051921公开了一种类似的方法,其中以高纯度制备瑞舒伐他汀的异丙铵或环己铵盐并将所述盐转变成瑞舒伐他汀的钠盐或高纯度无定形钙盐。
公开的国际专利申请号WO2005/040132公开了具有高非对映纯度的无定形瑞舒伐他汀钙盐。根据该公开方法,在第一阶段使初次产物无定形瑞舒伐他汀钙盐结晶,随后将如此获得的产物转变成无定形剂型。
总之,可以断定,根据现有技术,适合于制备药用产品的瑞舒伐他汀钙盐的制造是一种尤其复杂的方法。必须让粗产物经历进一步纯化和结晶步骤以获得在纯度和物理性能方面适合的产物。已知的方法难以按工业规模方法操作并且这些已知方法的使用通常导致显著的材料损失并因此是不经济的。
发明概述
我们研究-开发工作的目标是开发式(II)的[(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸]的具有高稳定性的新型盐,该盐维持或提高他汀类(statins)基团的药理学效果特性并且可以按适合于制造药用产品的质量制备。
上面目的根据本发明解决。
本发明的基础是意外认识到式(I)的(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸的锌盐和其水合形式满足所有上述标准,因为所述盐适合于制备药用产品,对光和热具有优异的稳定性并且可以通过工业上方便的方法以高纯度制备。
发明详述
根据本发明的第一方面,提供了式(I)的瑞舒伐他汀锌盐,其可以按高纯度制备直接地适用于制造药用产品。式(I)的瑞舒伐他汀锌盐是新的。
式(I)的瑞舒伐他汀锌盐与根据现有技术已知的瑞舒伐他汀钙盐相比的优点在于以下事实:该锌盐可以通过简单的方法以高质量制备,该方法可以容易地放大到工业生产。瑞舒伐他汀锌盐的进一步的优点是它可以非常容易地操控并且用于药物配方的初次产物的预处理不要求进一步加工。
式(I)的瑞舒伐他汀锌盐对光和热稳定,这在药物加工、配制期间和在作为药物使用期间是优点。该产物可以有利地用于治疗脂类代谢的病症,例如高胆固醇血症、高脂蛋白血症和动脉粥样硬化。
根据本发明第二方面,提供了式(I)的瑞舒伐他汀锌盐的制备方法,该方法包括使式(II)的瑞舒伐他汀与锌化合物反应。
根据适用于制备式(I)的瑞舒伐他汀锌盐的第一方法变体,使式(II)的(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸与醇化锌起反应并将如此获得的式(I)的瑞舒伐他汀锌离析。
作为醇化锌,式(III)的化合物
R-O-Zn-O-R III
可以按基于式(II)的瑞舒伐他汀的摩尔量计算的0.5-0.6摩尔当量用量使用,其中R代表含1-4个碳原子的直链或支链烷基。
在溶剂中进行该反应。适合的溶剂是具有1-4个碳原子的脂族醇,例如甲醇、乙醇、2-丙醇或1-丁醇;具有3-8个碳原子的脂族酮;具有2-8个碳原子的脂族酯或具有4-8个碳原子的脂族醚或它们的混合物。
该盐的制备在室温和溶剂的沸点温度之间的温度下,优选地在25和50℃之间的温度下进行。
通过蒸发溶剂离析该产物。任选地,在溶剂蒸发之前用硅胶处理该溶液。将蒸发残余物与大量过剩的含4-8个碳原子的醚,优选乙醚一起研碎并过滤如此获得的固体。
将产物离析的第二可能性是将在没有二氧化硅处理的情况下获得的蒸发残余物溶解在具有2-8个碳原子的脂族酯并用二氧化硅处理如此获得的溶液。在重复的过滤之后,部分地蒸发溶剂并将该残余物与大过量的含4-8个碳原子的醚,优选乙醚一起搅拌并过滤沉淀的产物。
根据第二个方法变体,使式(II)的瑞舒伐他汀与式(IV)的烯醇化锌起反应。
按基于式(II)的瑞舒伐他汀的摩尔量计算的0.5-0.6摩尔当量用量使用式(IV)的烯醇化锌。
在溶剂中进行式(II)和(IV)的化合物的反应。适合的溶剂是具有1-4个碳原子的脂族醇。反应可以在室温和溶剂的沸点温度之间的温度下,优选在25-40℃下进行。
如下离析产物:用二氧化硅处理该溶液,过滤,通过蒸发溶剂将该溶液浓缩并通过添加大量过剩的含4-8个碳原子的醚,优选通过添加乙醚使产物沉淀。
根据式(I)的瑞舒伐他汀锌盐的第三个制备变体,使式(II)的(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸的碱金属盐与无机或有机锌盐起反应并将如此获得的式(I)的产物离析。
在该方法中,可以使用无机或有机酸的锌盐。优选的锌盐是氯化锌、硫酸锌或乙酸锌。
起始物质优选是式(II)的化合物的钠盐。
该反应可以在水中使用水溶性锌盐,例如氯化锌、硫酸锌或乙酸锌进行。该反应也可以在有机溶剂中,例如在具有1-4个碳原子的脂族醇;在含3-10个碳原子的酮(包括丙酮)或在脂族腈,例如乙腈中进行。上述溶剂可以呈彼此的或与水的混合物形式使用。
根据该方法的一个优选的实施方案,使用溶于乙醇或水的氯化锌或溶于水的硫酸锌并且在25-50℃的温度下进行反应。
根据本发明尤其优选的实施方案,使式(II)的瑞舒伐他汀的钠盐在水溶液中在25-40℃的温度下与0.5摩尔当量用量硫酸锌起反应。如下将产物与反应混合物水溶液离析:过滤或使用水不混溶性溶剂从该水溶液中洗出产物。随后,分离有机相,浓缩到小体积并离析式(I)的瑞舒伐他汀锌盐。
用于萃取式(I)的瑞舒伐他汀锌盐的有利的水不混溶性溶剂是具有2-8个碳原子的脂族酯,它们是瑞舒伐他汀锌盐的良溶剂,例如甲酸乙酯、乙酸乙酯或乙酸甲酯。如下离析式(I)的瑞舒伐他汀锌盐:将萃取物浓缩到小体积并通过添加含4-8个碳原子的醚,优选乙醚使瑞舒伐他汀锌盐沉淀。
根据本发明的瑞舒伐他汀锌盐与根据现有技术已知的其它瑞舒伐他汀盐,例如钙盐在它们都不具有明确熔化温度的方面相似。因此,根据本发明的瑞舒伐他汀锌盐在实施例中以熔融的起始温度为特征。
另外,已经发现根据本发明的瑞舒伐他汀的锌盐可以按无水以及水合形式获得。当在制备期间使用的溶剂是含水溶剂或溶剂混合物时,式(I)的瑞舒伐他汀锌盐一般以水合物形式获得。然而,当在盐形成反应期间使用有机溶剂时,产生无水剂型。
根据本发明的另一个方面,提供了药用产品,其包含与一种或多种药学上可接受的载体或助剂混合的式(I)的瑞舒伐他汀锌盐。
根据本发明的药用产品一般以0.1-95wt%,优选1-50wt%,最有利5-30wt%的浓度包含该活性药物成分。
根据本发明的药用产品可以口服(例如以粉末、片剂、包衣片剂、嚼用片、胶囊、微胶囊、颗粒、糖衣丸、锭剂、溶液、悬浮液或乳液形式),肠胃外(例如作为静脉内、肌内或腹膜内注射剂或以灌输剂形式),直肠(作为栓剂或保留性灌肠剂),经皮(例如作为贴剂),以植入物形式给药或可以局部给药(例如以软膏、乳膏或贴剂形式)。包含式(I)的瑞舒伐他汀锌盐的固态、半固态或液态药用制剂可以根据现有技术已知的药物技术方法制备。
包含式(I)的瑞舒伐他汀锌盐的准备口服的固态药用产品可以包含载体或填充剂(例如乳糖、葡萄糖、淀粉、磷酸钙、微晶纤维素),粘结剂(例如明胶、山梨糖醇、聚乙烯吡咯烷酮),崩解剂(例如交联羧甲纤维素、羧甲基纤维素钠、交联聚维酮)、压片助剂(例如硬脂酸镁、滑石、聚乙二醇、硅酸、硅石、二氧化硅)和表面活性剂(例如十二烷基硫酸钠)。
包含式(I)的瑞舒伐他汀锌盐的适合于口服的液态药用产品可以以溶液、糖浆、悬浮液或乳液形式制备并且可以包含悬浮剂(例如明胶、羧甲基纤维素),乳化剂(山梨醇一油酸酯),溶剂(例如水、油、甘油、丙二醇、乙醇),缓冲剂(例如乙酸盐、磷酸盐、柠檬酸盐缓冲剂)或稳定剂(例如甲基-4-羟基-苯甲酸酯)。
包含式(I)的瑞舒伐他汀锌盐的准备非肠道使用的液态药用产品是无菌等渗溶液,其除溶剂之外还可以包含防腐剂和缓冲剂。
包含式(I)的瑞舒伐他汀锌盐的半固态药用产品,例如栓剂包含均匀分散在该制剂载体(例如聚乙二醇或可可油)中的活性成分。
包含根据本发明的瑞舒伐他汀锌盐作为活性成分的药用产品包含作为单位剂型的所述化合物。
本发明的另一个方面是式(I)的瑞舒伐他汀锌盐用于制造药物的用途。
包含根据本发明的瑞舒伐他汀锌盐的药用产品可以使用现有技术中已知的药物技术方法制备。将活性成分与固态或液态药学上可接受的载体或助剂混合并使该混合物形成药物剂型。所述方法和药学上可接受的载体或助剂从文献(Remington′s Pharmaceutical Sciences,Edition 18,Mack Publishing Co.,Easton,USA,1990)获知。
本发明的另一个方面是治疗高脂蛋白血症、高胆固醇血症和动脉粥样硬化的方法,该方法包括按临床有效剂量为需要此种治疗的病人施用根据本发明的瑞舒伐他汀锌盐。
以下实施例公开了本发明的更多细节,但不希望将本发明本身限制到所述实施例。
实施例1
(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸锌盐(2:1)
将4.16mmol(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸溶于70ml甲醇并在室温下将0.60g(2.13mmol)乙酰丙酮化锌一水合物添加到这一溶液中。在室温下搅拌该反应混合物8小时。此后,添加1.0g二氧化硅并搅拌该反应混合物30分钟。过滤该混合物并通过蒸发溶剂将该滤液浓缩到十分之一体积。将残余物与20倍体积的乙醚混合,过滤沉淀,用乙醚洗涤并在40℃下在真空中干燥。因此,获得2.05g(93%)产物,该产物在137℃的温度下开始熔融。
IR(KBr):3423,1546,1381,1156cm-1.
HNMR(DMSO-d6,500MHz):δ 7.72(dd,J=5.9Hz,7.7Hz,2H),7.27(t,J=8.5Hz,2H),6.52(d,J=15.9Hz,1H),5.54(dd,J=5.1Hz,15.9Hz,1H),4.94(b,2H),4.21(m,1H),3.84(m,1H),3.55(s,3H),3.46(s,3H),3.40(m,1H),2.26(d,J=13.7Hz,1H),2.16(dd,J=7.7Hz,14.5Hz,1H),1.52(m,1H),1.38(m,1H),1.22(d,J=6.4Hz,6H)ppm.
实施例2
(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸锌盐(2:1)
将3.85g(8.0mmol)(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸溶于40ml乙酸乙酯并向这一溶液中添加在40ml乙醇中的0.62g(4.0mmol)乙醇锌。将该反应混合物回流2小时。将该反应混合物冷却,过滤并蒸发溶剂。将该残余物与50ml乙醚一起研制。过滤该悬浮液,将固体溶于50ml乙酸乙酯并将该溶液与2g硅胶一起搅拌3小时。滤出硅胶,蒸发该溶剂的三分之二体积并将残余物与10倍体积的乙醚一起搅拌。过滤沉淀的锌盐,用乙醚洗涤并干燥。因此,获得2.8g(68%)瑞舒伐他汀锌盐,其在137℃开始熔融。
实施例3
(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸锌盐(2:1)
遵循实施例2中公开的方法,不同在于通过在室温下搅拌反应混合物16小时进行反应。如此获得3.0g(73%)瑞舒伐他汀锌盐。
实施例4
(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸锌盐(2:1)
将4.16mmol(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸溶于70ml乙酸乙酯并在室温下向这一溶液添加4.2ml(1.0mmol/ml)刚制备的乙醇钠乙醇(ethanolic sodium ethylate)溶液。在持续不断的搅拌下,在30分钟的期间内添加在10ml乙醇中制备的2.0mmol氯化锌的溶液。在50℃下搅拌该反应混合物2小时,然后冷却到室温并过滤。蒸发该滤液到十分之一体积并用10倍体积的乙醚沉淀该产物。随后,过滤产物并在50℃下干燥。如此获得1.8g(86%)瑞舒伐他汀锌盐,其在136℃开始熔融。
实施例5
(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸锌盐(2:1)
根据实施例4的方法制备该主题化合物,改变是在室温下进行反应。如此获得1.65g(77%)主题化合物,其在137℃下开始熔融。
实施例6
(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸锌盐(2:1)
根据实施例4的方法制备主题化合物,不同在于使用2.0mmol溶于水的硫酸锌作为反应试剂并且在室温下进行反应。在水层分离之后,通过蒸发三分之二的溶剂并在10倍体积的乙醚中研制残余物离析产物。在50℃的温度下过滤和干燥沉淀的固体。如此获得1.76g(81%)瑞舒伐他汀锌盐,其在138℃开始熔融。
Claims (18)
3.根据权利要求2的方法,特征在于使式(II)的(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸与式(III)的醇化锌起反应
R-O-Zn-O-R III
其中该醇化物残基包含具有1-4个碳原子的烷基,然后离析式(I)的瑞舒伐他汀锌盐。
5.根据权利要求2的方法,特征在于使(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸与碱金属,优选与钠的盐与无机或有机锌盐,优选与氯化锌、硫酸锌或乙酸锌起反应并离析式(I)的瑞舒伐他汀锌盐。
6.根据权利要求2-5中任一项的方法,特征在于在室温到该溶剂的沸点温度之间的温度下,优选在室温到50℃之间的温度下进行该盐形成。
7.根据权利要求2-5中任一项的方法,特征在于该盐形成在选自以下的溶剂中进行:水,具有1-4个碳原子的脂族醇,具有3-8个碳原子的脂族酮,具有3-8个碳原子的脂族酯,具有2-5个碳原子的脂族腈或具有4-8个碳原子的脂族醚,优选乙醇,丙酮,乙腈,乙酸乙酯或二氧杂环己烷。
8.根据权利要求2-5中任一项的方法,特征在于用于盐形成的醇化锌、烯醇化锌或无机或有机锌盐按基于式(II)的瑞舒伐他汀或其盐的摩尔量计算的0.5-0.6摩尔当量用量使用。
9.根据权利要求2-5中任一项的方法,特征在于通过沉淀或萃取从反应混合物中离析式(I)的瑞舒伐他汀锌盐。
10.根据权利要求9的方法,其特征在于使用含2-8个碳原子的脂族酯进行萃取。
11.根据权利要求9的方法,其特征在于使用任选与含4-8个碳原子的脂族醚和具有4-8个碳原子的醚型反溶剂混合的具有2-8个碳原子的脂族酯型溶剂进行沉淀。
12.根据权利要求10的方法,特征在于如下从萃取物中离析式(I)的粗瑞舒伐他汀锌盐∶将该萃取物与具有4-8个碳原子的脂族醚型溶剂混合并离析式(I)的沉淀的瑞舒伐他汀锌盐。
13.根据权利要求2-5中任一项的方法,特征在于式(I)的瑞舒伐他汀锌盐以无定形、结晶或部分结晶形式获得。
14.(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸锌盐(2∶1)用于制备药用产品的用途。
15.药用产品,包含与一种或多种药学上可接受的载体或助剂混合的式(I)的(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸锌盐(2:1)。
16.根据权利要求15的药用产品的制备方法,该方法包括将根据权利要求1的瑞舒伐他汀锌盐与药学上可接受的载体或助剂混合并将该混合物转化成药物剂型。
17.式(I)的(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸锌盐(2:1)用于制备适合于预防或治疗高胆固醇血症、高脂蛋白血症或动脉粥样硬化的药用产品的用途。
18.高胆固醇血症、高脂蛋白血症或动脉粥样硬化的治疗方法,该方法包括为需要此种治疗的病人施用药理学有效量的根据权利要求1的(+)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)嘧啶-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸锌盐(2:1)。
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CN102357096A (zh) * | 2011-09-09 | 2012-02-22 | 北京阜康仁生物制药科技有限公司 | 一种含有他汀类药物锌盐的降血脂组合物 |
CN102558016A (zh) * | 2012-02-14 | 2012-07-11 | 北京阜康仁生物制药科技有限公司 | 一种新型具有高度降脂活性的化合物及其制备方法 |
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CN103328450A (zh) * | 2010-11-16 | 2013-09-25 | 埃吉斯药物股份公开有限公司 | 晶体药物活性成分 |
CN102548971B (zh) * | 2009-07-24 | 2015-09-16 | 埃吉斯药物股份公开有限公司 | 罗苏伐他汀锌盐的晶型i |
CN105722505A (zh) * | 2013-09-30 | 2016-06-29 | 埃吉斯药物私人有限公司 | 含有胆固醇吸收抑制剂和胆固醇生物合成抑制剂的药物组合物 |
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CN102357096A (zh) * | 2011-09-09 | 2012-02-22 | 北京阜康仁生物制药科技有限公司 | 一种含有他汀类药物锌盐的降血脂组合物 |
CN102558016A (zh) * | 2012-02-14 | 2012-07-11 | 北京阜康仁生物制药科技有限公司 | 一种新型具有高度降脂活性的化合物及其制备方法 |
CN105722505A (zh) * | 2013-09-30 | 2016-06-29 | 埃吉斯药物私人有限公司 | 含有胆固醇吸收抑制剂和胆固醇生物合成抑制剂的药物组合物 |
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