IE51478B1 - 6(r)-(2-(8'-acyloxy-2'-methyl-6'-methyl(or hydrogen)-polyhydronaphthyl-1')-ethyl)-4(r)-hydroxy-3,4,5,6-tetrahydro-2h-pyran-2-ones,the hydroxy acid form of said pyranones,the pharmaceutically acceptable salts of said hydroxy acids,and the lower alkyl,and phenyl,dimethylamino or acetylamino substituted lower alkyl esters of said hydroxy acid,processes for preparing the same,and a pharmaceutical antihypercholesterolemic composition containing the same - Google Patents
6(r)-(2-(8'-acyloxy-2'-methyl-6'-methyl(or hydrogen)-polyhydronaphthyl-1')-ethyl)-4(r)-hydroxy-3,4,5,6-tetrahydro-2h-pyran-2-ones,the hydroxy acid form of said pyranones,the pharmaceutically acceptable salts of said hydroxy acids,and the lower alkyl,and phenyl,dimethylamino or acetylamino substituted lower alkyl esters of said hydroxy acid,processes for preparing the same,and a pharmaceutical antihypercholesterolemic composition containing the sameInfo
- Publication number
- IE51478B1 IE51478B1 IE204/81A IE20481A IE51478B1 IE 51478 B1 IE51478 B1 IE 51478B1 IE 204/81 A IE204/81 A IE 204/81A IE 20481 A IE20481 A IE 20481A IE 51478 B1 IE51478 B1 IE 51478B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- acid
- hydroxy
- formula
- ethyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 39
- -1 phenyl,dimethylamino Chemical group 0.000 title claims description 25
- 125000000217 alkyl group Chemical group 0.000 title claims description 22
- 239000000203 mixture Substances 0.000 title claims description 18
- 150000003839 salts Chemical class 0.000 title claims description 13
- 150000001261 hydroxy acids Chemical group 0.000 title claims description 11
- 125000005907 alkyl ester group Chemical group 0.000 title claims description 10
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 title claims description 5
- 230000000326 anti-hypercholesterolaemic effect Effects 0.000 title claims 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 title abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 title abstract description 7
- 239000001257 hydrogen Substances 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 85
- 230000010933 acylation Effects 0.000 claims abstract description 7
- 238000005917 acylation reaction Methods 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims description 37
- 238000002360 preparation method Methods 0.000 claims description 35
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 239000012298 atmosphere Substances 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 10
- 230000020477 pH reduction Effects 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 5
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 125000005059 halophenyl group Chemical group 0.000 claims description 3
- 238000007273 lactonization reaction Methods 0.000 claims description 3
- 239000003586 protic polar solvent Substances 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 229940125810 compound 20 Drugs 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 abstract description 8
- 125000002252 acyl group Chemical group 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 235000012000 cholesterol Nutrition 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- 239000003112 inhibitor Substances 0.000 abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 82
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 44
- 239000000243 solution Substances 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 150000002148 esters Chemical class 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 20
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 229910001868 water Inorganic materials 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 238000000855 fermentation Methods 0.000 description 12
- 230000004151 fermentation Effects 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 150000001298 alcohols Chemical class 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical class O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 239000013587 production medium Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 235000010633 broth Nutrition 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 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 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 150000002009 diols Chemical class 0.000 description 4
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000011573 trace mineral Substances 0.000 description 4
- 235000013619 trace mineral Nutrition 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000538 analytical sample Substances 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 235000011148 calcium chloride Nutrition 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- OZJPLYNZGCXSJM-UHFFFAOYSA-N delta-Valerolactone Natural products O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 3
- 229910003446 platinum oxide Inorganic materials 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 229910001220 stainless steel Inorganic materials 0.000 description 3
- 239000010935 stainless steel Substances 0.000 description 3
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- XNAQEDQKXCHDIW-UHFFFAOYSA-N 2-ethyl-2-methylbutanoyl chloride Chemical compound CCC(C)(CC)C(Cl)=O XNAQEDQKXCHDIW-UHFFFAOYSA-N 0.000 description 2
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 239000003529 anticholesteremic agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- WWSNTLOVYSRDEL-DZSDEGEFSA-N compactin diol lactone Chemical compound C([C@@H]1[C@H]2[C@@H](O)CCC=C2C=C[C@@H]1C)C[C@@H]1C[C@@H](O)CC(=O)O1 WWSNTLOVYSRDEL-DZSDEGEFSA-N 0.000 description 2
- WWSNTLOVYSRDEL-UHFFFAOYSA-N desmethylmonacolin J Natural products CC1C=CC2=CCCC(O)C2C1CCC1CC(O)CC(=O)O1 WWSNTLOVYSRDEL-UHFFFAOYSA-N 0.000 description 2
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 2
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 2
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- 150000002596 lactones Chemical group 0.000 description 2
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- 229910052763 palladium Inorganic materials 0.000 description 2
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- 238000000746 purification Methods 0.000 description 2
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 2
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- 238000003786 synthesis reaction Methods 0.000 description 2
- RZLVQBNCHSJZPX-UHFFFAOYSA-L zinc sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Zn+2].[O-]S([O-])(=O)=O RZLVQBNCHSJZPX-UHFFFAOYSA-L 0.000 description 2
- FHSAZOGISLHXPK-SCSAIBSYSA-N (3r)-3-hydroxyoxan-2-one Chemical class O[C@@H]1CCCOC1=O FHSAZOGISLHXPK-SCSAIBSYSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
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- KJTLQQUUPVSXIM-ZCFIWIBFSA-N (R)-mevalonic acid Chemical class OCC[C@](O)(C)CC(O)=O KJTLQQUUPVSXIM-ZCFIWIBFSA-N 0.000 description 1
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- 229960002023 chloroprocaine Drugs 0.000 description 1
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- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 1
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- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
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- SURQXAFEQWPFPV-UHFFFAOYSA-L iron(2+) sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Fe+2].[O-]S([O-])(=O)=O SURQXAFEQWPFPV-UHFFFAOYSA-L 0.000 description 1
- 125000000686 lactone group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- CDUFCUKTJFSWPL-UHFFFAOYSA-L manganese(II) sulfate tetrahydrate Chemical compound O.O.O.O.[Mn+2].[O-]S([O-])(=O)=O CDUFCUKTJFSWPL-UHFFFAOYSA-L 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 1
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
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- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
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- 230000000717 retained effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 230000035040 seed growth Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 235000015113 tomato pastes and purées Nutrition 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11805180A | 1980-02-04 | 1980-02-04 | |
| US11804980A | 1980-02-04 | 1980-02-04 | |
| US17546080A | 1980-08-05 | 1980-08-05 | |
| US06/175,232 US4293496A (en) | 1980-02-04 | 1980-08-05 | 6(R)-[2-(8-Hydroxy-2,6-dimethylpolyhydronaphthyl-1)-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE810204L IE810204L (en) | 1981-08-04 |
| IE51478B1 true IE51478B1 (en) | 1987-01-07 |
Family
ID=27494171
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE204/81A IE51478B1 (en) | 1980-02-04 | 1981-02-03 | 6(r)-(2-(8'-acyloxy-2'-methyl-6'-methyl(or hydrogen)-polyhydronaphthyl-1')-ethyl)-4(r)-hydroxy-3,4,5,6-tetrahydro-2h-pyran-2-ones,the hydroxy acid form of said pyranones,the pharmaceutically acceptable salts of said hydroxy acids,and the lower alkyl,and phenyl,dimethylamino or acetylamino substituted lower alkyl esters of said hydroxy acid,processes for preparing the same,and a pharmaceutical antihypercholesterolemic composition containing the same |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP0033538B1 (OSRAM) |
| AU (1) | AU548996B2 (OSRAM) |
| CA (1) | CA1199322A (OSRAM) |
| CY (1) | CY1404A (OSRAM) |
| DD (1) | DD155989A5 (OSRAM) |
| DE (1) | DE3173042D1 (OSRAM) |
| DK (1) | DK157292C (OSRAM) |
| ES (1) | ES499079A0 (OSRAM) |
| FI (1) | FI78082C (OSRAM) |
| GR (1) | GR74798B (OSRAM) |
| HK (1) | HK16488A (OSRAM) |
| IE (1) | IE51478B1 (OSRAM) |
| IL (1) | IL62044A (OSRAM) |
| MA (1) | MA19054A1 (OSRAM) |
| MY (1) | MY8700745A (OSRAM) |
| NL (1) | NL930009I2 (OSRAM) |
| NO (2) | NO154229C (OSRAM) |
| NZ (1) | NZ196172A (OSRAM) |
| PT (1) | PT72441B (OSRAM) |
| RO (1) | RO82367B (OSRAM) |
| SG (1) | SG61087G (OSRAM) |
| YU (1) | YU28181A (OSRAM) |
Families Citing this family (54)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0692381B2 (ja) * | 1980-03-31 | 1994-11-16 | 三共株式会社 | Ｍｂ−５３０ａ誘導体 |
| US4343814A (en) * | 1980-11-17 | 1982-08-10 | Merck & Co., Inc. | Hypocholesterolemic fermentation products |
| US4432996A (en) * | 1980-11-17 | 1984-02-21 | Merck & Co., Inc. | Hypocholesterolemic fermentation products and process of preparation |
| EP0094443A1 (en) * | 1982-05-17 | 1983-11-23 | Merck & Co. Inc. | 6(R)-(2-(8(S) (2,2-dimethylbutyryloxy)-2(S),6(S)-dimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S))ethyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, process for preparing and pharmaceutical composition containing the same |
| US4503072A (en) * | 1982-12-22 | 1985-03-05 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
| ES8609193A1 (es) * | 1983-01-24 | 1986-07-16 | Sandoz Ag | Procedimiento para preparar analogos de mevalonolactona y derivados de los mismos |
| EP0137445B1 (en) * | 1983-10-11 | 1990-01-03 | Merck & Co. Inc. | Process for c-methylation of 2-methylbutyrates |
| DE3481190D1 (de) * | 1983-10-11 | 1990-03-08 | Merck & Co Inc | Verfahren zur herstellung von 6(r)-(2-(8(s)(2,2-dimethylbutyryloxy)-2(s),6(s)-dimethyl-1,2,3,4,4a(s),5,6,7,8,8a(s)-decahydronaphthyl-1(s))ethyl)-4(r)-hydroxy-3,4,5,6-tetrahydro-2h-pyran-2-on. |
| US4668699A (en) * | 1985-08-05 | 1987-05-26 | Merck & Co., Inc. | Novel HMG-CoA reductase inhibitors |
| US4833258A (en) * | 1987-02-17 | 1989-05-23 | Merck & Co., Inc. | Intermediates useful in the preparation of HMG-COA reductase inhibitors |
| US4997848A (en) | 1987-10-27 | 1991-03-05 | Sankyo Company, Limited | Octahydronaphthalene oxime derivatives for cholesterol synthesis inhibition |
| US5021451A (en) * | 1988-11-14 | 1991-06-04 | Hoffman-La Roche Inc. | Method for inhibiting hyperproliferative diseases |
| GB8915280D0 (en) * | 1989-07-04 | 1989-08-23 | British Bio Technology | Compounds |
| US5110825A (en) * | 1989-12-28 | 1992-05-05 | Shionogi & Co., Ltd. | Benzofuran derivative |
| GB9100174D0 (en) * | 1991-01-04 | 1991-02-20 | British Bio Technology | Compounds |
| NZ250609A (en) * | 1992-12-28 | 1995-07-26 | Sankyo Co | Hexahydronaphthalene esters and ring closed lactones; preparation and medicaments |
| US6642268B2 (en) | 1994-09-13 | 2003-11-04 | G.D. Searle & Co. | Combination therapy employing ileal bile acid transport inhibiting benzothipines and HMG Co-A reductase inhibitors |
| US6268392B1 (en) | 1994-09-13 | 2001-07-31 | G. D. Searle & Co. | Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors |
| NZ286920A (en) * | 1995-07-03 | 1997-06-24 | Sankyo Co | Use of combination of hmg-coa reductase inhibitors and of insulin sensitizers for the prevention/treatment of arteriosclerosis or xanthoma |
| DE69614571T2 (de) * | 1995-12-06 | 2002-06-27 | Balkanpharma-Razgard Ad, Razgard | Verfahren zur herstellung von lovastatin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5612114B2 (OSRAM) * | 1974-06-07 | 1981-03-18 | ||
| US4049495A (en) * | 1974-06-07 | 1977-09-20 | Sankyo Company Limited | Physiologically active substances and fermentative process for producing the same |
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| JPS5925599B2 (ja) * | 1979-02-20 | 1984-06-19 | 三共株式会社 | 新生理活性物質モナコリンｋおよびその製造法 |
| US4231938A (en) * | 1979-06-15 | 1980-11-04 | Merck & Co., Inc. | Hypocholesteremic fermentation products and process of preparation |
| AU535944B2 (en) * | 1979-06-15 | 1984-04-12 | Merck & Co., Inc. | Hypocholestermic fermentation products from aspergillus |
| PT72394B (en) | 1980-02-04 | 1982-09-06 | Merck & Co Inc | Process for preparing dihydro and tetrahydromevinoline hypocholesterolimics |
-
1981
- 1981-01-23 AU AU66573/81A patent/AU548996B2/en not_active Expired
- 1981-01-29 MA MA19255A patent/MA19054A1/fr unknown
- 1981-02-02 GR GR64028A patent/GR74798B/el unknown
- 1981-02-02 EP EP81100729A patent/EP0033538B1/en not_active Expired
- 1981-02-02 IL IL62044A patent/IL62044A/xx not_active IP Right Cessation
- 1981-02-02 FI FI810287A patent/FI78082C/fi not_active IP Right Cessation
- 1981-02-02 DE DE8181100729T patent/DE3173042D1/de not_active Expired
- 1981-02-02 CY CY140481A patent/CY1404A/xx unknown
- 1981-02-03 PT PT72441A patent/PT72441B/pt unknown
- 1981-02-03 CA CA000369992A patent/CA1199322A/en not_active Expired
- 1981-02-03 NO NO810358A patent/NO154229C/no unknown
- 1981-02-03 YU YU00281/81A patent/YU28181A/xx unknown
- 1981-02-03 NZ NZ196172A patent/NZ196172A/en unknown
- 1981-02-03 DK DK046181A patent/DK157292C/da active
- 1981-02-03 ES ES499079A patent/ES499079A0/es active Granted
- 1981-02-03 IE IE204/81A patent/IE51478B1/en not_active IP Right Cessation
- 1981-02-03 DD DD81227405A patent/DD155989A5/de unknown
- 1981-02-04 RO RO103303A patent/RO82367B/ro unknown
-
1987
- 1987-07-27 SG SG610/87A patent/SG61087G/en unknown
- 1987-12-30 MY MY745/87A patent/MY8700745A/xx unknown
-
1988
- 1988-03-03 HK HK164/88A patent/HK16488A/en not_active IP Right Cessation
-
1993
- 1993-02-09 NL NL930009C patent/NL930009I2/nl unknown
-
1994
- 1994-07-01 NO NO1994001C patent/NO1994001I1/no unknown
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