JP5439168B2 - ロスバスタチン亜鉛塩 - Google Patents
ロスバスタチン亜鉛塩 Download PDFInfo
- Publication number
- JP5439168B2 JP5439168B2 JP2009504836A JP2009504836A JP5439168B2 JP 5439168 B2 JP5439168 B2 JP 5439168B2 JP 2009504836 A JP2009504836 A JP 2009504836A JP 2009504836 A JP2009504836 A JP 2009504836A JP 5439168 B2 JP5439168 B2 JP 5439168B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- salt
- zinc
- zinc salt
- rosuvastatin
- 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.)
- Active
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- 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 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 51
- 238000000034 method Methods 0.000 claims description 40
- -1 N-methyl-N-methylsulfonylamino Chemical group 0.000 claims description 37
- 239000002904 solvent Substances 0.000 claims description 27
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 25
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 25
- 150000003751 zinc Chemical class 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 229960000672 rosuvastatin Drugs 0.000 claims description 18
- 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 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 13
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 229910052725 zinc Inorganic materials 0.000 claims description 10
- 239000011701 zinc Substances 0.000 claims description 10
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical group [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 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
- 125000001931 aliphatic group Chemical group 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
- 239000000654 additive Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000011592 zinc chloride Substances 0.000 claims description 5
- 235000005074 zinc chloride Nutrition 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 4
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 208000020346 hyperlipoproteinemia Diseases 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 3
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 3
- 230000000996 additive effect Effects 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- 239000004246 zinc acetate Substances 0.000 claims description 3
- OZYYQTRHHXLTKX-UHFFFAOYSA-N 7-octenoic acid Chemical compound OC(=O)CCCCCC=C OZYYQTRHHXLTKX-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000003125 aqueous solvent Substances 0.000 claims description 2
- 229940127557 pharmaceutical product Drugs 0.000 claims description 2
- 150000003752 zinc compounds Chemical class 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 2
- 238000002156 mixing Methods 0.000 claims 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 239000012296 anti-solvent Substances 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- NHXVNEDMKGDNPR-UHFFFAOYSA-N zinc;pentane-2,4-dione Chemical group [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 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 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 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 159000000007 calcium salts Chemical class 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 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
- 239000000872 buffer Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose 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
- 238000009472 formulation Methods 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
- 239000004615 ingredient 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
- 229940126601 medicinal product Drugs 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- BBMFSGOFUHEVNP-UHFFFAOYSA-N 4-hydroxy-2-methylbenzoic acid Chemical compound CC1=CC(O)=CC=C1C(O)=O BBMFSGOFUHEVNP-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 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
- 229940121710 HMGCoA reductase inhibitor Drugs 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
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-O Methylammonium ion Chemical compound [NH3+]C BAVYZALUXZFZLV-UHFFFAOYSA-O 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 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
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 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
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical class NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 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
- 238000005755 formation reaction Methods 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
- 239000008187 granular material Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-O isopropylaminium Chemical compound CC(C)[NH3+] JJWLVOIRVHMVIS-UHFFFAOYSA-O 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
- 229910052744 lithium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- FYFFGSSZFBZTAH-UHFFFAOYSA-N methylaminomethanetriol Chemical class CNC(O)(O)O FYFFGSSZFBZTAH-UHFFFAOYSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- CWMPPVPFLSZGCY-UHFFFAOYSA-N oct-2-enoic acid Chemical compound CCCCCC=CC(O)=O CWMPPVPFLSZGCY-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate 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
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- RGEBGDYYHAFODH-DHMAKVBVSA-M sodium;(e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical class [Na+].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 RGEBGDYYHAFODH-DHMAKVBVSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active 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
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000002560 therapeutic procedure Methods 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
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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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- 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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- 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
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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
Description
R-O-Zn-O-R
(ここで、Rは、炭素数1〜4の直鎖状又は分子状アルキル基である)の化合物を、式(II)のロスバスタチンのモル量基準で算定して0.5〜0.6モル当量の量で使用できる。
(+)-7-[4-(4-フルオロフェニル)-6-イソプロピル-2-(N-メチル-N-メチルスルホニルアミノ)ピリミジン-5-イル]-(3R,5S)-ジヒドロキシ-(E)-6-ヘプテンカルボン酸4.16ミリモルをメタノール70mlに溶解し、この溶液に、室温において、亜鉛アセチルアセトネート・1水和物0.60g(2.13ミリモル)を添加した。反応混合物を、室温において、8時間撹拌した。この時間の経過後、知りか1.0gを添加し、反応混合物を30分間撹拌した。混合物を濾過し、溶媒を蒸発させることによって、濾液を1/10の容積に濃縮した。残渣を20倍容量のジエチルエーテルと混合し、沈殿物を濾取し、ジエチルエーテルにて洗浄し、真空中、40℃において乾燥した。このようにして、生成物2.05gが得られた(93%)。この生成物は、温度137℃において溶融を開始する。
IR(KBr):3423, 1546, 1381, 1156 cm-1
HNMR(DMSO-d6, 500 MHz):δ7.72(dd, J=5.9 Hz, 7.7 Hz, 2H), 7.27(t, J=8.5 Hz, 2H), 6.52(d, J=15.9 Hz, 1H), 5.54(dd, J=5.1 Hz, 15.9 Hz, 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=13.7 Hz, 1H), 2.16(dd, J=7.7 Hz, 14.5 Hz, 1H), 1.52(m, 1H), 1.38(m, 1H), 1.22(d, J=6.4 Hz, 6H) ppm
(+)-7-[4-(4-フルオロフェニル)-6-イソプロピル-2-(N-メチル-N-メチルスルホニルアミノ)ピリミジン-5-イル]-(3R,5S)-ジヒドロキシ-(E)-6-ヘプテンカルボン酸3.85 g(8.0ミリモル)を酢酸エチル40mlに溶解し、この溶液に、亜鉛エチラート0.62g(4.0ミリモル)のエタノール(40ml)溶液を添加した。反応混合物を2時間還流した。反応混合物を冷却し、濾過し、溶媒を蒸発させた。残渣をジエチルエーテル50mlで抽出した。懸濁液を濾過し、固体を酢酸エチル50mlに溶解し、溶液を、シリカゲル2gと共に3時間撹拌した。シリカゲルを濾去し、溶媒の容積の2/3を蒸発させ、残渣を10倍容量のジエチルエーテル中で撹拌した。沈殿した亜鉛塩を濾取し、ジエチルエーテルにて洗浄し、乾燥した。このようにして、ロスバスタチン亜鉛塩2.8gが得られた(68%)。この生成物は、温度137℃において溶融を開始する。
実施例1に記載の操作を行った。ただし、反応混合物を室温において16時間撹拌することによって、反応を実施した。このようにして、ロスバスタチン亜鉛塩3.0gが得られた(73%)。
(+)-7-[4-(4-フルオロフェニル)-6-イソプロピル-2-(N-メチル-N-メチルスルホニルアミノ)ピリミジン-5-イル]-(3R,5S)-ジヒドロキシ-(E)-6-ヘプテンカルボン酸4.16ミリモルを酢酸エチル70mlに溶解し、この溶液に、新たに調製したナトリウムエチラートエタノール溶液4.2ml(1.0ミリモル/ml)を、室温において添加した。連続撹拌条件下、塩化亜鉛2.0ミリモルのエタノール(10ml)溶液を30分間で添加した。反応混合物を、50℃において、2時間撹拌し、ついで、室温に冷却し、濾過した。濾液を蒸発によって1/10の容積とし、10倍容量のジエチルエーテルにて生成物を沈殿させた。続いて、生成物を濾取し、50℃において乾燥した。このようにして、ロスバスタチン亜鉛塩1.8gが得られた(86%)。この生成物は、温度136℃において溶融を開始する。
実施例4の操作に従って、ただし、反応を室温において行い、題記化合物を調製した。このようにして、題記化合物1.65gが得られた(77%)。この生成物は、温度137℃において溶融を開始する。
実施例4の操作に従って、ただし、試薬として、水に溶解した硫酸亜鉛2.0ミリモルを使用し、反応を室温において行い、題記化合物を調製した。水相の分離後、溶媒の2/3を蒸発させ、残渣を10倍容量のジエチルエーテルにて抽出することによって生成物を単離した。沈殿した固体を濾取し、温度50℃において乾燥した。このようにして、題記化合物1.76gが得られた(81%)。この生成物は、温度138℃において溶融を開始する。
Claims (21)
- 式(II)の(+)-7-[4-(4-フルオロフェニル)-6-イソプロピル-2-(N-メチル-Nメチル-スルホニルアミノ)ピリミジン-5-イル]-(3R,5S)-ジヒドロキシ-(E)-6-ヘプテンカルボン酸を、式(III)
R-O-Zn-O-R
(ここで、アルコラート残基は、炭素数1〜4のアルキル基を含有する)の亜鉛アルコラートと反応させ、ついで、式(I)のロスバスタチン亜鉛塩を単離する請求項2記載の製法。 - 亜鉛エノラートが亜鉛アセチルアセトネートである請求項4記載の製法。
- (+)-7-[4-(4-フルオロフェニル)-6-イソプロピル-2-(N-メチル-N-メチルスルホニルアミノ)ピリミジン-5-イル]-(3R,5S)-ジヒドロキシ-(E)-6-ヘプテンカルボン酸のアルカリ金属塩を、無機又は有機亜鉛塩と反応させ、式(I)のロスバスタチン亜鉛塩を単離することを特徴とする請求項2記載の製法。
- (+)-7-[4-(4-フルオロフェニル)-6-イソプロピル-2-(N-メチル-N-メチルスルホニルアミノ)ピリミジン-5-イル]-(3R,5S)-ジヒドロキシ-(E)-6-ヘプテンカルボン酸のアルカリ金属塩がナトリウム塩であり、無機又は有機亜鉛塩が、塩化亜鉛、硫酸亜鉛又は酢酸亜鉛である、請求項6記載の方法。
- 塩の形成を、室温〜溶媒の沸点の温度において行うことを特徴とする請求項2〜6のいずれかに記載の製法。
- 塩の形成を、室温〜50℃の温度において行うことを特徴とする請求項8記載の製法。
- 塩の形成を、水、炭素数1〜4の脂肪族アルコール、炭素数3〜8の脂肪族ケトン、炭素数3〜8の脂肪族エステル、炭素数2〜5の脂肪族ニトリル、又は炭素数4〜8の脂肪族エーテルから選ばれる溶媒中で行うことを特徴とする請求項2〜6のいずれかに記載の製法。
- 塩の形成を、エタノール、アセトン、アセトニトリル、酢酸エチル又はジオキサン中で行うことを特徴とする請求項10記載の製法。
- 塩の形成に使用する亜鉛アルコラート、亜鉛エノラート又は無機又は有機亜鉛塩を、式(II)のロスバスタチン又はその塩のモル量基準で算定して0.5〜0.6モル当量で使用することを特徴とする請求項2〜6のいずれかに記載の製法。
- 式(I)のロスバスタチン亜鉛塩を、沈殿又は抽出によって、反応混合物から単離することを特徴とする請求項2〜6のいずれかに記載の製法。
- 抽出を、炭素数2〜8の脂肪族エステルを使用して行うことを特徴とする請求項13記載の製法。
- 沈殿を、任意に、炭素数4〜8の脂肪族エーテル又は炭素数4〜8のエーテルのアンチ溶媒と混合した炭素数2〜8の脂肪族エステル溶媒を使用して行うことを特徴とする請求項13記載の製法。
- 式(I)の粗製ロスバスタチン亜鉛塩の抽出液からの単離を、抽出液を炭素数4〜8の脂肪族エーテル溶媒と混合し、沈殿した式(I)のロスバスタチン亜鉛塩を単離することによって行う請求項14記載の製法。
- 式(I)のロスバスタチン亜鉛塩を、非晶質形、結晶形又は一部結晶形で得ることを特徴とする請求項2〜6のいずれかに記載の製法。
- 請求項1記載の(+)-7-[4-(4-フルオロフェニル)-6-イソプロピル-2-(N-メチル-N-メチルスルホニルアミノ)ピリミジン-5-イル]-(3R,5S)-ジヒドロキシ-(E)-6-ヘプテンカルボン酸の亜鉛塩(2:1)の、医薬品の製造における使用。
- 請求項1記載の式(I)の(+)-7-[4-(4-フルオロフェニル)-6-イソプロピル-2-(N-メチル-N-メチルスルホニルアミノ)ピリミジン-5-イル]-(3R,5S)-ジヒドロキシ-(E)-6-ヘプテンカルボン酸の亜鉛塩(2:1)を、薬学上許容される1以上のビヒクル又は添加剤との混合物として含有する医薬品。
- 請求項19記載の医薬品を製造する方法であって、請求項1記載のロスバスタチン亜鉛塩を、薬学上許容されるビヒクル又は添加剤と混合し、混合物を製剤することを含んでなる医薬品の製法。
- 請求項1記載の式(I)の(+)-7-[4-(4-フルオロフェニル)-6-イソプロピル-2-(N-メチル-N-メチルスルホニルアミノ)ピリミジン-5-イル]-(3R,5S)-ジヒドロキシ-(E)-6-ヘプテンカルボン酸の亜鉛塩(2:1)の、高コレステロール血症、高リポタンパク血症及びアテローム性動脈硬化症の予防又は治療に好適な医薬品の製造における使用。
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HU0600293A HU227696B1 (en) | 2006-04-13 | 2006-04-13 | Zinc salt of rosuvastatin, process for its preparation and pharmaceutical compositions containing it |
HUP0600293 | 2006-04-13 | ||
PCT/HU2007/000030 WO2007119085A1 (en) | 2006-04-13 | 2007-04-12 | Rosuvastatin zinc salt |
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HUP0900285A2 (en) | 2009-05-07 | 2011-01-28 | Egis Gyogyszergyar Nyilvanosan Mukoedoe Reszvenytarsasag | Rosuvastatin salts and preparation thereof |
WO2011010174A1 (en) * | 2009-07-24 | 2011-01-27 | Egis Gyógyszergyár Nyilvánosan Működő | Crystalline form i rosuvastatin zinc salt |
HU230737B1 (hu) | 2010-11-16 | 2018-01-29 | EGIS Gyógyszergyár Nyrt | Eljárás rosuvastatin só előállítására |
HU229260B1 (en) * | 2010-11-29 | 2013-10-28 | Egis Gyogyszergyar Nyrt | Process for preparation of rosuvastatin salts |
WO2012073256A1 (en) | 2010-11-29 | 2012-06-07 | Cadila Healthcare Limited | Salts of rosuvastatin |
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GB0312896D0 (en) * | 2003-06-05 | 2003-07-09 | Astrazeneca Ab | Chemical process |
AU2003269477A1 (en) * | 2003-08-26 | 2005-03-10 | Biocon Limited | Novel process for preparation of 7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1h-indol-2-yl)-3, 5-dihydroxy-6-heptenoic acid sodium salt |
EP1682518A4 (en) * | 2003-10-24 | 2007-08-01 | Univ North Carolina | DIKATIONAL TRIARYLANALOGA AS MEANS AGAINST PROTOZOEN |
CA2546701C (en) * | 2003-11-24 | 2010-07-27 | Teva Pharmaceutical Industries Ltd. | Crystalline ammonium salts of rosuvastatin |
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CN1709257A (zh) * | 2004-06-16 | 2005-12-21 | 鲁南制药集团股份有限公司 | 治疗高血脂症的组合物 |
CA2576196A1 (en) * | 2004-08-06 | 2006-02-16 | Transform Pharmaceuticals, Inc. | Novel statin pharmaceutical compositions and related methods of treatment |
CN100436428C (zh) * | 2005-08-22 | 2008-11-26 | 鲁南制药集团股份有限公司 | 瑞舒伐他汀及其盐的制备方法 |
WO2009157014A2 (en) | 2008-01-30 | 2009-12-30 | Cadila Healthcare Limited | A process for preparing hmg-coa reductase inhibitors and intermediates |
CN102317267A (zh) * | 2009-01-15 | 2012-01-11 | 埃吉斯药物股份公开有限公司 | 制备罗苏伐他汀盐的方法 |
HU230987B1 (hu) * | 2010-11-29 | 2019-08-28 | Egis Gyógyszergyár Nyrt. | Eljárás nagy tisztaságú gyógyszeripari intermedierek előállítására |
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HUP0600293A3 (en) | 2008-04-28 |
EP2013188B1 (en) | 2016-09-07 |
CA2649219A1 (en) | 2007-10-25 |
ES2605579T3 (es) | 2017-03-15 |
US9174945B2 (en) | 2015-11-03 |
EA016141B1 (ru) | 2012-02-28 |
KR20080109088A (ko) | 2008-12-16 |
CA2649219C (en) | 2014-12-23 |
WO2007119085A1 (en) | 2007-10-25 |
EP2013188A1 (en) | 2009-01-14 |
HUP0600293A2 (en) | 2007-12-28 |
HU227696B1 (en) | 2011-12-28 |
EA200802142A1 (ru) | 2009-02-27 |
JP2009533412A (ja) | 2009-09-17 |
CN101490015B (zh) | 2013-06-12 |
IL194674A (en) | 2013-10-31 |
US20090306117A1 (en) | 2009-12-10 |
UA95287C2 (en) | 2011-07-25 |
CN101490015A (zh) | 2009-07-22 |
HU0600293D0 (en) | 2006-05-29 |
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