DE3112566A1 - MONACOLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE DERIVATIVES - Google Patents
MONACOLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE DERIVATIVESInfo
- Publication number
- DE3112566A1 DE3112566A1 DE19813112566 DE3112566A DE3112566A1 DE 3112566 A1 DE3112566 A1 DE 3112566A1 DE 19813112566 DE19813112566 DE 19813112566 DE 3112566 A DE3112566 A DE 3112566A DE 3112566 A1 DE3112566 A1 DE 3112566A1
- Authority
- DE
- Germany
- Prior art keywords
- group
- branched
- bis
- straight
- chain
- 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
- 238000000034 method Methods 0.000 title claims description 29
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 229940126601 medicinal product Drugs 0.000 title 1
- -1 methylenedioxy groups Chemical group 0.000 claims description 95
- JGEXGCWUJFSSPR-VSOKSMTPSA-N n-[(4-amino-2-methylpyrimidin-5-yl)methyl]-n-[(z)-3-[3-(4-chlorophenyl)-3-oxopropyl]sulfanyl-5-hydroxypent-2-en-2-yl]formamide;hydrochloride Chemical compound Cl.C=1C=C(Cl)C=CC=1C(=O)CCSC(/CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N JGEXGCWUJFSSPR-VSOKSMTPSA-N 0.000 claims description 68
- 150000001875 compounds Chemical class 0.000 claims description 31
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 28
- 125000002252 acyl group Chemical group 0.000 claims description 22
- 244000005700 microbiome Species 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000001963 growth medium Substances 0.000 claims description 13
- HVAMZGADVCBITI-UHFFFAOYSA-M pent-4-enoate Chemical compound [O-]C(=O)CCC=C HVAMZGADVCBITI-UHFFFAOYSA-M 0.000 claims description 11
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 10
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 238000005917 acylation reaction Methods 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 230000010933 acylation Effects 0.000 claims description 8
- 150000008065 acid anhydrides Chemical class 0.000 claims description 7
- 150000004820 halides Chemical class 0.000 claims description 7
- 241000031003 Monascus ruber Species 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 241000228347 Monascus <ascomycete fungus> Species 0.000 claims description 5
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 150000005690 diesters Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 2
- 241000597033 Dietes Species 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 238000009833 condensation Methods 0.000 claims 1
- 230000005494 condensation Effects 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 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 160
- WWSNTLOVYSRDEL-UHFFFAOYSA-N desmethylmonacolin J Natural products CC1C=CC2=CCCC(O)C2C1CCC1CC(O)CC(=O)O1 WWSNTLOVYSRDEL-UHFFFAOYSA-N 0.000 description 159
- 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 121
- 239000000047 product Substances 0.000 description 46
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 42
- 238000000921 elemental analysis Methods 0.000 description 39
- 238000002329 infrared spectrum Methods 0.000 description 38
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 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 description 14
- 239000002904 solvent Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- LXZBFUBRYYVRQJ-AXHZAXLDSA-M sodium;(3r,5r)-7-[(1s,2s,6r,8s,8ar)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]-3,5-dihydroxyheptanoate Chemical compound [Na+].C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC([O-])=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C=C21 LXZBFUBRYYVRQJ-AXHZAXLDSA-M 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 235000012000 cholesterol Nutrition 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- REEZZSHJLXOIHL-UHFFFAOYSA-N octanoyl chloride Chemical compound CCCCCCCC(Cl)=O REEZZSHJLXOIHL-UHFFFAOYSA-N 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 5
- 150000007942 carboxylates Chemical class 0.000 description 5
- ISULZYQDGYXDFW-UHFFFAOYSA-N 3-methylbutanoyl chloride Chemical compound CC(C)CC(Cl)=O ISULZYQDGYXDFW-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 239000005662 Paraffin oil Substances 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- YWGHUJQYGPDNKT-UHFFFAOYSA-N hexanoyl chloride Chemical compound CCCCCC(Cl)=O YWGHUJQYGPDNKT-UHFFFAOYSA-N 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- BVHMITOWPMCRLY-HZJYTTRNSA-N (6z,9z)-18-chlorooctadeca-6,9-diene Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCCl BVHMITOWPMCRLY-HZJYTTRNSA-N 0.000 description 3
- 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 3
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 239000001888 Peptone Substances 0.000 description 3
- 108010080698 Peptones Proteins 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 240000008042 Zea mays Species 0.000 description 3
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 3
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 235000005822 corn Nutrition 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- ARBOVOVUTSQWSS-UHFFFAOYSA-N hexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCC(Cl)=O ARBOVOVUTSQWSS-UHFFFAOYSA-N 0.000 description 3
- 229940049918 linoleate Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 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 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- JDKQTIKEGOOXTJ-UHFFFAOYSA-N pent-4-enoyl chloride Chemical compound ClC(=O)CCC=C JDKQTIKEGOOXTJ-UHFFFAOYSA-N 0.000 description 3
- 235000019319 peptone Nutrition 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- AFDXODALSZRGIH-QPJJXVBHSA-N (E)-3-(4-methoxyphenyl)prop-2-enoic acid Chemical compound COC1=CC=C(\C=C\C(O)=O)C=C1 AFDXODALSZRGIH-QPJJXVBHSA-N 0.000 description 2
- JATAKEDDMQNPOQ-UHFFFAOYSA-M 2,4,6-trimethoxybenzoate Chemical compound COC1=CC(OC)=C(C([O-])=O)C(OC)=C1 JATAKEDDMQNPOQ-UHFFFAOYSA-M 0.000 description 2
- GPVDHNVGGIAOQT-UHFFFAOYSA-N 2,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 0.000 description 2
- NYJBTJMNTNCTCP-UHFFFAOYSA-M 2,5-dimethoxybenzoate Chemical compound COC1=CC=C(OC)C(C([O-])=O)=C1 NYJBTJMNTNCTCP-UHFFFAOYSA-M 0.000 description 2
- MBIZFBDREVRUHY-UHFFFAOYSA-N 2,6-Dimethoxybenzoic acid Chemical compound COC1=CC=CC(OC)=C1C(O)=O MBIZFBDREVRUHY-UHFFFAOYSA-N 0.000 description 2
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N 2-Ethylhexanoic acid Chemical compound CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 2
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 2
- UABHETFCVNRGNL-UHFFFAOYSA-N 2-butoxybenzoic acid Chemical compound CCCCOC1=CC=CC=C1C(O)=O UABHETFCVNRGNL-UHFFFAOYSA-N 0.000 description 2
- IKCLCGXPQILATA-UHFFFAOYSA-M 2-chlorobenzoate Chemical compound [O-]C(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-M 0.000 description 2
- XDZMPRGFOOFSBL-UHFFFAOYSA-N 2-ethoxybenzoic acid Chemical compound CCOC1=CC=CC=C1C(O)=O XDZMPRGFOOFSBL-UHFFFAOYSA-N 0.000 description 2
- CGMMPMYKMDITEA-UHFFFAOYSA-N 2-ethylbenzoic acid Chemical compound CCC1=CC=CC=C1C(O)=O CGMMPMYKMDITEA-UHFFFAOYSA-N 0.000 description 2
- NSTREUWFTAOOKS-UHFFFAOYSA-N 2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1F NSTREUWFTAOOKS-UHFFFAOYSA-N 0.000 description 2
- SMNDYUVBFMFKNZ-UHFFFAOYSA-M 2-furoate Chemical compound [O-]C(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-M 0.000 description 2
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 2
- OXOWWPXTTOCKKU-UHFFFAOYSA-N 2-propoxybenzoic acid Chemical compound CCCOC1=CC=CC=C1C(O)=O OXOWWPXTTOCKKU-UHFFFAOYSA-N 0.000 description 2
- GADSJKKDLMALGL-UHFFFAOYSA-N 2-propylbenzoic acid Chemical compound CCCC1=CC=CC=C1C(O)=O GADSJKKDLMALGL-UHFFFAOYSA-N 0.000 description 2
- SJSOFNCYXJUNBT-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1OC SJSOFNCYXJUNBT-UHFFFAOYSA-N 0.000 description 2
- OMHDOOAFLCMRFX-UHFFFAOYSA-N 3-(2-bromophenyl)prop-2-enoic acid Chemical compound OC(=O)C=CC1=CC=CC=C1Br OMHDOOAFLCMRFX-UHFFFAOYSA-N 0.000 description 2
- KJRRTHHNKJBVBO-UHFFFAOYSA-N 3-(2-chlorophenyl)prop-2-enoic acid Chemical compound OC(=O)C=CC1=CC=CC=C1Cl KJRRTHHNKJBVBO-UHFFFAOYSA-N 0.000 description 2
- RSWBWHPZXKLUEX-UHFFFAOYSA-N 3-(2-methylphenyl)prop-2-enoic acid Chemical compound CC1=CC=CC=C1C=CC(O)=O RSWBWHPZXKLUEX-UHFFFAOYSA-N 0.000 description 2
- YEMUSDCFQUBPAL-UHFFFAOYSA-N 3-(3-bromophenyl)prop-2-enoic acid Chemical compound OC(=O)C=CC1=CC=CC(Br)=C1 YEMUSDCFQUBPAL-UHFFFAOYSA-N 0.000 description 2
- FFKGOJWPSXRALK-UHFFFAOYSA-N 3-(3-chlorophenyl)prop-2-enoic acid Chemical compound OC(=O)C=CC1=CC=CC(Cl)=C1 FFKGOJWPSXRALK-UHFFFAOYSA-N 0.000 description 2
- CPDDDTNAMBSPRN-UHFFFAOYSA-N 3-(4-bromophenyl)prop-2-enoic acid Chemical compound OC(=O)C=CC1=CC=C(Br)C=C1 CPDDDTNAMBSPRN-UHFFFAOYSA-N 0.000 description 2
- GXLIFJYFGMHYDY-UHFFFAOYSA-N 3-(4-chlorophenyl)prop-2-enoic acid Chemical compound OC(=O)C=CC1=CC=C(Cl)C=C1 GXLIFJYFGMHYDY-UHFFFAOYSA-N 0.000 description 2
- RURHILYUWQEGOS-UHFFFAOYSA-N 3-(4-methylphenyl)prop-2-enoic acid Chemical compound CC1=CC=C(C=CC(O)=O)C=C1 RURHILYUWQEGOS-UHFFFAOYSA-N 0.000 description 2
- VOIZNVUXCQLQHS-UHFFFAOYSA-N 3-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC(Br)=C1 VOIZNVUXCQLQHS-UHFFFAOYSA-N 0.000 description 2
- DNGXQBZMSWQUKS-UHFFFAOYSA-N 3-butoxybenzoic acid Chemical compound CCCCOC1=CC=CC(C(O)=O)=C1 DNGXQBZMSWQUKS-UHFFFAOYSA-N 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-M 3-chlorobenzoate Chemical compound [O-]C(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-M 0.000 description 2
- DTFQMPQJMDEWKJ-UHFFFAOYSA-N 3-ethoxybenzoic acid Chemical compound CCOC1=CC=CC(C(O)=O)=C1 DTFQMPQJMDEWKJ-UHFFFAOYSA-N 0.000 description 2
- HXUSUAKIRZZMGP-UHFFFAOYSA-N 3-ethylbenzoic acid Chemical compound CCC1=CC=CC(C(O)=O)=C1 HXUSUAKIRZZMGP-UHFFFAOYSA-N 0.000 description 2
- IHCCAYCGZOLTEU-UHFFFAOYSA-M 3-furoate Chemical compound [O-]C(=O)C=1C=COC=1 IHCCAYCGZOLTEU-UHFFFAOYSA-M 0.000 description 2
- IJFXRHURBJZNAO-UHFFFAOYSA-N 3-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC(O)=C1 IJFXRHURBJZNAO-UHFFFAOYSA-N 0.000 description 2
- XHQZJYCNDZAGLW-UHFFFAOYSA-M 3-methoxybenzoate Chemical compound COC1=CC=CC(C([O-])=O)=C1 XHQZJYCNDZAGLW-UHFFFAOYSA-M 0.000 description 2
- IGIDLTISMCAULB-UHFFFAOYSA-N 3-methylvaleric acid Chemical compound CCC(C)CC(O)=O IGIDLTISMCAULB-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 2
- ZMXUPQVAIFGMPS-UHFFFAOYSA-N 3-propoxybenzoic acid Chemical compound CCCOC1=CC=CC(C(O)=O)=C1 ZMXUPQVAIFGMPS-UHFFFAOYSA-N 0.000 description 2
- GIFHXKJTAILWRE-UHFFFAOYSA-N 3-propylbenzoic acid Chemical compound CCCC1=CC=CC(C(O)=O)=C1 GIFHXKJTAILWRE-UHFFFAOYSA-N 0.000 description 2
- ZQVKTHRQIXSMGY-UHFFFAOYSA-N 4-Ethylbenzoic acid Chemical compound CCC1=CC=C(C(O)=O)C=C1 ZQVKTHRQIXSMGY-UHFFFAOYSA-N 0.000 description 2
- TUXYZHVUPGXXQG-UHFFFAOYSA-M 4-bromobenzoate Chemical compound [O-]C(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-M 0.000 description 2
- LAUFPZPAKULAGB-UHFFFAOYSA-N 4-butoxybenzoic acid Chemical compound CCCCOC1=CC=C(C(O)=O)C=C1 LAUFPZPAKULAGB-UHFFFAOYSA-N 0.000 description 2
- XRHGYUZYPHTUJZ-UHFFFAOYSA-M 4-chlorobenzoate Chemical compound [O-]C(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-M 0.000 description 2
- SHSGDXCJYVZFTP-UHFFFAOYSA-N 4-ethoxybenzoic acid Chemical compound CCOC1=CC=C(C(O)=O)C=C1 SHSGDXCJYVZFTP-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 2
- GDFUWFOCYZZGQU-UHFFFAOYSA-N 4-propoxybenzoic acid Chemical compound CCCOC1=CC=C(C(O)=O)C=C1 GDFUWFOCYZZGQU-UHFFFAOYSA-N 0.000 description 2
- ATZHGRNFEFVDDJ-UHFFFAOYSA-N 4-propylbenzoic acid Chemical compound CCCC1=CC=C(C(O)=O)C=C1 ATZHGRNFEFVDDJ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-M pentadecanoate Chemical compound CCCCCCCCCCCCCCC([O-])=O WQEPLUUGTLDZJY-UHFFFAOYSA-M 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- 125000005607 tigloyl group Chemical group 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 125000000297 undecanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Classifications
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
-
- 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
- A61P9/12—Antihypertensives
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- 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
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Die Erfindung betrifft neue Monacolinderivate, die sich von den Verbindungen ML-263A und MB-53OA ableiten und die Cholesterin-Biosynthese hemmen, sowie Verfahren zu ihrer Herstellung und diese Derivate enthaltende Arzneimittel.The invention relates to new monacoline derivatives which are derived from the compounds ML-263A and MB-53OA and which Inhibiting cholesterol biosynthesis, as well as processes for their preparation and pharmaceuticals containing these derivatives.
Die Hyperlipämie, insbesondere die Hypercholesterinämie, sind bekanntlich eine der Hauptursachen für Herzkrankheiten, wie den Herzinfarkt oder die Arteriosclerose. Es sind daher erhebliche Anstrengungen unternommen worden, Verbindungen zu entdecken, die den Lipid- und insbesondere den Cholcsterinspiegel des Blutes senken. Eine Gruppe derartiger Verbindungen ist in der US-PS 3 983 140 beschrieben. Diese Gruppe von Verbindungen wird aus Mikroorganismen des Genus Penicillium isoliert und kollektiv als ML-236 bezeichnet.Hyperlipemia, especially hypercholesterolemia, is known to be one of the main causes of heart disease, like heart attack or arteriosclerosis. Considerable efforts have therefore been made to establish connections to discover the lipid and especially the cholesterol level lower the blood. One group of such compounds is described in US Pat. No. 3,983,140. These Group of compounds is isolated from microorganisms of the genus Penicillium and collectively referred to as ML-236.
In den USSN 121 515 vom 14.02.1980 und 137 821 vom 4.04.1980 (DE-OS 30 06 215 und 30 06 216) ist eine weitere derartige Verbindung beschrieben, die als Monacolin K oder MB-53OB bezeichnet wird und durch Züchten von Mikroorganismen des Genus Monascus, insbesondere den Stämmen Monascus ruber, erhalten wird.In USSN 121 515 of 02/14/1980 and 137 821 of 04/04/1980 (DE-OS 30 06 215 and 30 06 216) describes another such compound, which is referred to as Monacolin K or MB-53OB and by growing microorganisms of the genus Monascus, in particular the strains Monascus ruber, is obtained.
Es wurde nun eine neue Reihe von Verbindungen isoliert, die mit ML-236 und MB-53OB verwandt sind und aufgrund ihrer besseren Absorption bei oraler Verabreichung und ihrer leichteren Verfügbarkeit als pro-Droge. (d.h. Arzneistoff, der nach der Verabreichung durch chemische oder biochemischeA new set of compounds has now been isolated that are related to ML-236 and MB-53OB and because of them better absorption when administered orally and their easier availability than per-drug. (i.e. drug that after administration by chemical or biochemical
- 8 - ■ *■ "■- 8 - ■ * ■ "■
Körperreaktionen in eine aktive oder aktivere Form überführt wird, eine bessere Aktivitätsentwicklung zeigen.Body reactions are converted into an active or more active form, show better activity development.
ML-236A und ML-236B (zwei Verbindungen des in der US-PS 3 983 140 beschriebenen ML-236-Komplexes) haben die FormelnML-236A and ML-236B (two compounds of the ML-236 complex described in U.S. Patent 3,983,140) have the formulas
II bzw. III:II or III:
CHCH
CH3 CH 3
während MB-53OB (oder Monacolin K) die folgende Formel IV hat:while MB-53OB (or Monacolin K) has the following Formula IV Has:
(IV](IV]
Die erfindungsgemäßen Verbindungen haben die Formel IThe compounds according to the invention have the formula I.
1 21 2
in der R und R gleich oder unterschiedlich Wasserstoffatome oder Acylgruppen bedeuten und R ein Wasserstoffatom oder eine Methylgruppe ist, mit der Maßgabe, daß wenn Rin which R and R, identically or differently, denote hydrogen atoms or acyl groups and R denotes a hydrogen atom or a methyl group, with the proviso that when R
2 32 3
ein Wasserstoffatom ist, R und R nicht gleichzeitig Was-is a hydrogen atom, R and R are not water at the same time
serstoffatome sind, und R keine a-Methylbutyrylgruppe darstellt. are hydrogen atoms, and R does not represent an α-methylbutyryl group.
1 21 2
Die erfindungsgemäße Verbindung, bei der R und R beide Wasserstoffatome sind und R eine Methylgruppe ist, d.h. die Verbindung der Formel VThe compound of the invention in which R and R are both Are hydrogen atoms and R is a methyl group, i.e. the Compound of Formula V
(Vj(Previous year
wurde als MB-5 3OA bezeichnet und kann dadurch hergestellt werden, daß man einem ΜΒ-53ΟΛ erzeugenden Mikroorganismus des Genus Monascus in einem geeigneten Kulturmedium züchtetwas designated as MB-5 30A and can be manufactured by it be that one ΜΒ-53ΟΛ producing microorganism of the genus Monascus in a suitable culture medium
- 10 und das produzierte MB-53OA aus dem Kulturmedium gewinnt.- 10 and the MB-53OA produced is recovered from the culture medium.
Die anderen erfindungsgemäßen Verbindungen, die als 3- und/ oder 8'-acylierte Derivate von ML-236A oder ΜΒ-53ΟΆ angesehen werden können, lassen sich durch Acylieren von ML-236A, ML-236B, MB-53OA oder M3-53OB herstellen. Zur Verdeutlichung werden diese acylierten Derivate im folgenden als Ester der Verbindung (ML-236A, ML-236B, MB-53OA oder MB-53OB) bezeichnet, aus der sie durch Acylierung erhalten wurden.The other compounds of the invention that are viewed as 3- and / or 8'-acylated derivatives of ML-236A or ΜΒ-53ΟΆ can be prepared by acylating ML-236A, ML-236B, MB-53OA, or M3-53OB. For clarification these acylated derivatives are hereinafter referred to as esters of the compound (ML-236A, ML-236B, MB-53OA or MB-53OB), from which they are obtained by acylation became.
Bei der Definition der erfindungsgemäßen Verbindungen wird folgende Bezifferung angewandt:When defining the compounds according to the invention, the following numbering was used:
1 21 2
Wenn einer oder beide Reste R und R eine Acylgruppe bedeuten, ist dies vorzugsweise eine gesättigte oder ungesättigte Acylgruppe, eine aromatische Acylgruppe oder eine araliphatische Acylgruppe.If one or both of the radicals R and R are an acyl group, this is preferably a saturated or unsaturated acyl group, an aromatic acyl group or an araliphatic group Acyl group.
Bevorzugte aliphatische Acylgruppen sind Formyl , geradkettiges oder verzweigtes Alkanoyl mit 2 bis 20, vorzugsweise 2 bis 6 Kohlenstoffatomen und geradkettiges oder verzweigtesPreferred aliphatic acyl groups are formyl, straight chain or branched alkanoyl with 2 to 20, preferably 2 to 6 carbon atoms and straight-chain or branched
Alkenoyl mit 3 bis 20, vorzugsweise 2 bis 6 Kohlenstoftatomen. Alkenoyl with 3 to 20, preferably 2 to 6 carbon atoms.
Bevorzugte gesättigte aliphatische Acylgruppen sind Formyl, Acetyl, Propionyl, Butyryl, Isobutyryl, Valeryl, Isovaleryl, Hexanoyl, 2-Methylvaleryl, 3-Methylvaleryl, 4-Methylvaleryl, 2-Ethylbutyryl, Heptanoyl, Octanoyl, 2-rEthylhexanoyl, Nonamoyl, Isononanoyl, Decanoyl, Undecanoyl, Dodecanoyl, Tridecanoyl, Tetradecanoyl, Pentadecanoyl, Palmitoyl, Stearoyl, Isostearoyl, Nonadecanoyl, Eicosanoyl und Pivaloyl.Preferred saturated aliphatic acyl groups are Formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, Isovaleryl, hexanoyl, 2-methylvaleryl, 3-methylvaleryl, 4-methylvaleryl, 2-ethylbutyryl, heptanoyl, octanoyl, 2-rethylhexanoyl, nonamoyl, isononanoyl, decanoyl, undecanoyl, Dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, Palmitoyl, stearoyl, isostearoyl, nonadecanoyl, eicosanoyl and pivaloyl.
Beispiele für geeignete ungesättigte aliphatische Acylgruppen sind Acryloyl, 3-Butenoyl, Methacryloyl, 2-Pentenoyl, 4-Pentenoyl, 2-Undecenoyl, 4-Undecenoyl, 2-Trideceneoyl, 2-Tetradecenoyl, 2-Hexadecenoyl, Linolenoyl, Linoleyl, Arachidonoyl, Propioloyl, Crotonoyl, Tigloyl, Angeloyl, Senecionoyl, 2-Heptenoyl, 2-Octenoyl und 2-Nonenoyl.Examples of suitable unsaturated aliphatic acyl groups are acryloyl, 3-butenoyl, methacryloyl, 2-pentenoyl, 4-pentenoyl, 2-undecenoyl, 4-undecenoyl, 2-trideceneoyl, 2-tetradecenoyl, 2-hexadecenoyl, linolenoyl, linoleyl, Arachidonoyl, propioloyl, crotonoyl, tigloyl, angeloyl, Senecionoyl, 2-heptenoyl, 2-octenoyl and 2-nonenoyl.
1 21 2
Wenn R und/oder R aromatische Acylgruppen sind, ist dies vorzugsweise eine Benzoy!gruppe, die gegebenenfalls am Phenylkern einen oder mehrere Substituenten aufweist. Derartige Substituenten sind vorzugsweise CL-C'-Alkyl, C. -C--Alkoxy, Hydroxy, Methylendioxy, Halogen und/oder Trifluormethyl. Die Substituenten können in der ortho-, meta- oder para-Stellung stehen. Wenn zwei oder mehrere Substituenten vorhanden sind, können diese gleich oder unterschiedlich sein.If R and / or R are aromatic acyl groups, this is preferably a Benzoy! Phenyl nucleus has one or more substituents. Such substituents are preferably CL-C'-alkyl, C. -C - alkoxy, Hydroxy, methylenedioxy, halogen and / or trifluoromethyl. The substituents can be in the ortho, meta or para position. When two or more substituents are present, they can be the same or different.
Beispiele für Benzoylgruppen mit einem Substituenten sind Methylbenzoyl, Ethylbenzoyl, Propylbenzoyl, Bufcylbenzoyl, Methoxybenzoyl, Ethoxybenzoyl, Propoxybenzoyl, Butoxybenzoyl, Hydroxybenzoyl, Chlorbenzoyl, Brombenzoyl und Fluorbenzoyl, wobei die Substituenten in ortho-, meta- oder para-Stellung stehen können. Beispiele für Benzoylgruppen mit zwei oder mehreren Suüstituenten sind 2,3-Dimethoxybenzoyl,Examples of benzoyl groups with a substituent are Methylbenzoyl, ethylbenzoyl, propylbenzoyl, bufcylbenzoyl, Methoxybenzoyl, ethoxybenzoyl, propoxybenzoyl, butoxybenzoyl, Hydroxybenzoyl, chlorobenzoyl, bromobenzoyl and fluorobenzoyl, it being possible for the substituents to be in the ortho, meta or para position. Examples of benzoyl groups with two or several substituents are 2,3-dimethoxybenzoyl,
2,4-Diraethoxybenzoyl, 2,5-Dimethoxybenzoyl, 2,6-Dimethoxybenzoyl, 2,4,6-Trimethoxybenzoyl, 3,4,5-Trimethoxybenzoyl, 3,4-Methylendioxybenzoyl und 2,3-Methylendioxybenzoyl.2,4-diraethoxybenzoyl, 2,5-dimethoxybenzoyl, 2,6-dimethoxybenzoyl, 2,4,6-trimethoxybenzoyl, 3,4,5-trimethoxybenzoyl, 3,4-methylenedioxybenzoyl and 2,3-methylenedioxybenzoyl.
1 21 2
Wenn R und/oder R araliphatische Acylgruppen bedeuten, ist dies vorzugsweise eine Phenylalkanoylgruppe, die gegebenenfalls am Phenylkern einen oder mehrere Substituenten aufweist. Die Alkanoy!gruppe dieser Phenylalkanoylgruppe ist vorzugsweise eine C^-C.-Alkanoylgruppe, vorzugsweise Acetyl, Propionyl oder Butyryl, und die Substituenten sind vorzugsweise Cj-C^-Alkyl, Cj-C.-Alkoxy, Hydroxy, Methylendioxy, Halogen und/oder Trifluormethyl. Diese Substituenten können in der ortho-, meta- oder para-Stellung stehen. Wenn zwei oder mehrere Substituenten vorhanden sind, können diese gleich oder unterschiedlich sein.When R and / or R are araliphatic acyl groups, is this is preferably a phenylalkanoyl group which optionally has one or more substituents on the phenyl nucleus. The alkanoyl group of this phenylalkanoyl group is preferably a C 1-4 alkanoyl group, preferably acetyl, Propionyl or butyryl, and the substituents are preferably Cj-C ^ -alkyl, Cj-C.-alkoxy, hydroxy, methylenedioxy, Halogen and / or trifluoromethyl. These substituents can be in the ortho, meta or para position. If two or several substituents are present, these can be the same or different.
Beispiele für araliphatische Acylgruppen sind Cinnamoyl, Chloreinnamoyl, Bromcinnamoyl, Methoxycinnamoyl, Methy1-cinnamoyl, Phenylacetyl, Phenoxyacetyl und Phenylpropionyl, wobei die Substituenten der Cinnamoylgruppen in ortho-, meta- oder para-Stellung stehen können.Examples of araliphatic acyl groups are cinnamoyl, Chlorinenamoyl, bromocinnamoyl, methoxycinnamoyl, methy1-cinnamoyl, Phenylacetyl, phenoxyacetyl and phenylpropionyl, where the substituents of the cinnamoyl groups can be in the ortho, meta or para position.
Alternativ, wenn auch weniger bevorzugt, können R und/oder R einen heterocyclischen Acylrest bedeuten (z.B. 2-Furoyl, 2-Thenoyl, 3-Thenoyl, Nicotinoyl und Isonicotinoyl)oder einen heterocyclisch-substituierten aliphatischen Acylrest, (z.B. 2-Thienylacetyl, 3-Thienylacetyl, 2-Fury!acetyl, 3-Furylacetyl, 2-Thienylacryloyl, 3-Thienylacryloyl, 2-Furylacryloyl und 3-Furylacryloyl) oder einen alicycüschen Acylrest (vorzugsweise Cyclopropancarbonyl, Cyclobutancarbonyl, Cyclopentancarbonyl, Cyclohexancarbonyi, Cyclohoptancarbonyl, Cyclooctancarbonyl, Cyclohexanacetyl, 3-Cyclohexanpropionyl, 4-Cyclohexanbutyryl und 1-Adamantancarbonyl). Alternatively, although less preferred, R and / or R can represent a heterocyclic acyl radical (e.g. 2-furoyl, 2-thenoyl, 3-thenoyl, nicotinoyl and isonicotinoyl) or a heterocyclically substituted aliphatic acyl radical, (e.g. 2-thienylacetyl, 3-thienylacetyl, 2-Fury! acetyl, 3-furylacetyl, 2-thienylacryloyl, 3-thienylacryloyl, 2-Furylacryloyl and 3-Furylacryloyl) or an alicyclic Acyl radical (preferably cyclopropane carbonyl, cyclobutane carbonyl, cyclopentane carbonyl, cyclohexane carbonyi, cyclohoptane carbonyl, Cyclooctanecarbonyl, Cyclohexanacetyl, 3-cyclohexane propionyl, 4-cyclohexane butyryl and 1-adamantane carbonyl).
- 13 Beispiele für erfindungsgemäße Verbindungen sind:- 13 examples of compounds according to the invention are:
ML-236A und MB-53OA-3,8'-diformiat ML-236A und MB-53OA-3,8'-diacetat ML-236A und MB-53OA-3,8'-dipropionat ML-236A und MB-53OA-3,8'-dibutyrat ML-236A und MB-5 3OA-3,8'-diisobutyrat ML-236A und MB-53OA-3,8'-divalerat ML-236A und MB-53OA-3,8'-diisovalerat ML-236A und MB-53OA-3,8'-dipivalat ML-236A und MB-5 3OÄ-3,8'-dihexanoat ML-236A und MB-53OA-3,8'-diheptanoat ML-236A und MB-5 3OA-3,8'-bis(2-methylvalerat) ML-236A und MB-53OA-3,8'-bis(3-methylvalerat) ML-236A und MB-53OA-3,8'-bis(2-ethylbutyrat) ML-236A und MB-5 3OA-3,8'-dioctanoat ML-236A und MB-53OA-3,8'-bis(2-ethylhexanoat) ML-236A und MB-5 3OA-3,8'-dinonanoat M1-236A und MB-53OA-3,8'-diisononanoat ML-236A und MB-53OA-3,8'-diundecanoat ML-236A und MN-530A-3,8'-ditetradecanoat ML-236A und MB-53OA-3,8'-dipentadecanoat ML-236A und MB-53OA-3,8'-dipalmitat ML-236A und MB-5 3OA-3,8'-distearat ML-236A und MB-53OA-3,8'-diisostearat ML-236A und MB-53OA-3,8'-dinonadecanoat ML-236A und MB-53OA-3,8'-dieicosanoat ML-236A und MB-53OA-3,8'-bis(1-adamantancarboxylat) ML-236A und MB-53OA-3,8'-dicyclopropancarboxylat ML-236A und MB-53OA-3,8'-dicyclobutancarboxylat ML-236A und MB-53OA-3,8'-dicyclopentancarboxylat ML-236A und MB-53OA-3,8'-dicyclohexancarboxylat ML-236A und MB-5 3OA-3,8'-dicyeloheptancarboxylat ML-236A und MB-53OA-3,8'-dicyclooctancarboxylat ML-236A und MB-53OA-3,8'-bis(cyclohexanacetat) ML-236A und MB-5 3OA-3 ,8 ' -bis (3-cyclohaxanprop i.onat)ML-236A and MB-53OA-3,8'-diformiate ML-236A and MB-53OA-3,8'-diacetate ML-236A and MB-53OA-3,8'-dipropionate ML-236A and MB-53OA-3,8'-dibutyrate ML-236A and MB-5 3OA-3,8'-diisobutyrate ML-236A and MB-53OA-3,8'-divalerate ML-236A and MB-53OA-3,8'-diisovalerate ML-236A and MB-53OA-3,8'-dipivalate ML-236A and MB-5 30E-3,8'-dihexanoate ML-236A and MB-53OA-3,8'-diheptanoate ML-236A and MB-5 3OA-3,8'-bis (2-methylvalerate) ML-236A and MB-53OA-3,8'-bis (3-methylvalerate) ML-236A and MB-53OA-3,8'-bis (2-ethylbutyrate) ML-236A and MB-5 3OA-3,8'-dioctanoate ML-236A and MB-53OA-3,8'-bis (2-ethylhexanoate) ML-236A and MB-5 3OA-3,8'-dinonanoate M1-236A and MB-53OA-3,8'-diisononanoate ML-236A and MB-53OA-3,8'-diundecanoate ML-236A and MN-530A-3,8'-ditetradecanoate ML-236A and MB-53OA-3,8'-dipentadecanoate ML-236A and MB-53OA-3,8'-dipalmitate ML-236A and MB-5 3OA-3,8'-distearate ML-236A and MB-53OA-3,8'-diisostearate ML-236A and MB-53OA-3,8'-dinonadecanoate ML-236A and MB-53OA-3,8'-dieicosanoate ML-236A and MB-53OA-3,8'-bis (1-adamantane carboxylate) ML-236A and MB-53OA-3,8'-dicyclopropanecarboxylate ML-236A and MB-53OA-3,8'-dicyclobutane carboxylate ML-236A and MB-53OA-3,8'-dicyclopentanecarboxylate ML-236A and MB-53OA-3,8'-dicyclohexane carboxylate ML-236A and MB-5 3OA-3,8'-dicyeloheptane carboxylate ML-236A and MB-53OA-3,8'-dicyclooctane carboxylate ML-236A and MB-53OA-3,8'-bis (cyclohexane acetate) ML-236A and MB-5 3OA-3, 8 '-bis (3-cyclohaxane propionate)
ML-236A und MB-53OA-3,8'-bis(4-cyclohexanbutyrat ML-236A und MB-53OA-3,8'-diacrylat ML-236A und MB-5 3OA-3,8'-dipropiolat ML-236A und MB-53OA-3,8'-dicrotonat ML-236A und MB-53OA-3,8'-bis(3-butenoat) ML-236A und MB-5 3OA-3,8'-dimethacrylat ML-236A und MB-53OA-3,8'-bis(2-pentenoat) ML-236A und MB-53OA-3,8'-bis(4-pentenoat) ML-236A und MB-5 3OA-3,8'-ditiglat ML-236A und MB-5 3Oa-3,8'-diangelat ML-236A und MB-53OA-3,8'-disenecionat ML-236A und MB-53OA-3,8'-bis(2-heptenoat) ML-236A und MB-53OA-3,8'-bis(2-octenoat) ML-236A und MB-53OA-3,8'-bis(2-nonenoat) ML-236A und MB-53OA-3,8'-dilinoleat ML-236A und MB-53OA-3,8'-dioleat ML-236A und MB-53OA-3,8'-dilinolenat ML-236A und MB-53OA-3,8'-dicinnamat ML-236A und MB-5 3OA-3,8'-bis(o-chlorcinnamat) ML-236A und MB-5 3OA-3,8'-bis(m-chlorcinnamat) ML-236A und MB-5 3OA-3,8'-bis(p-chlorcinnamat) ML-236A und MB-53OA-3,8'-bis(o-bromcinnamat) ML-236A und MB-53OA-3,8'-bis(m-bromcinnamat) ' ML-236A und MB-53OA-3,8'-bis(p-bromcinnamat) ML-236A und MB-53OA-3 ,8 '-bis (o-iuethoxycinnamat) ML-236A und MB-53OA-3,8'-bis(m-raethoxycinnamat) ML-236A und MB-53OÄ-3,8'-bis(p-methoxycinnamat) ML-236A und MB-53OA-3,8'-bis(o-methylcinnamat) ML-236A und MB-53OA-3,8'-bis(ra-methylcinnamat) ML-236A und MB-53OA-3,8'-bis(p-methylcinnamat) ML-236A und MB-5 3QA-3,8'-bis(phenylacetat) ML-236A und MB-5 3OA-3 , 8 '-bis (phenoxyacet.it) ML-236A und MB-5 3OA-3,8'-bis(3-phenylpropionat) ML-236A und MB-53OA-3,8'-bis(2-thienylacetat) ML-236A und MB-53OA-3,8'-bis(2-furylacetat) ML-236A und MB-53OA-3,8'-bis(2-thiophencarboxylat)ML-236A and MB-53OA-3,8'-bis (4-cyclohexane butyrate ML-236A and MB-53OA-3,8'-diacrylate ML-236A and MB-5 3OA-3,8'-dipropiolate ML-236A and MB-53OA-3,8'-dicrotonate ML-236A and MB-53OA-3,8'-bis (3-butenoate) ML-236A and MB-5 3OA-3,8'-dimethacrylate ML-236A and MB-53OA-3,8'-bis (2-pentenoate) ML-236A and MB-53OA-3,8'-bis (4-pentenoate) ML-236A and MB-5 3OA-3,8'-digiglate ML-236A and MB-5 3Oa-3,8'-diangelate ML-236A and MB-53OA-3,8'-disenecionate ML-236A and MB-53OA-3,8'-bis (2-heptenoate) ML-236A and MB-53OA-3,8'-bis (2-octenoate) ML-236A and MB-53OA-3,8'-bis (2-nonenoate) ML-236A and MB-53OA-3,8'-dilinoleate ML-236A and MB-53OA-3,8'-dioleate ML-236A and MB-53OA-3,8'-dilinolenate ML-236A and MB-53OA-3,8'-dicinnamate ML-236A and MB-5 3OA-3,8'-bis (o-chlorocinnamate) ML-236A and MB-5 3OA-3,8'-bis (m-chlorocinnamate) ML-236A and MB-5 3OA-3,8'-bis (p-chlorocinnamate) ML-236A and MB-53OA-3,8'-bis (o-bromocinnamate) ML-236A and MB-53OA-3,8'-bis (m-bromocinnamate) ' ML-236A and MB-53OA-3,8'-bis (p-bromocinnamate) ML-236A and MB-53OA-3, 8 '-bis (o-iuethoxycinnamate) ML-236A and MB-53OA-3,8'-bis (m-raethoxycinnamate) ML-236A and MB-53OÄ-3,8'-bis (p-methoxycinnamate) ML-236A and MB-53OA-3,8'-bis (o-methylcinnamate) ML-236A and MB-53OA-3,8'-bis (ra-methylcinnamate) ML-236A and MB-53OA-3,8'-bis (p-methylcinnamate) ML-236A and MB-5 3QA-3,8'-bis (phenyl acetate) ML-236A and MB-5 3OA-3, 8 '-bis (phenoxyacet.it) ML-236A and MB-5 3OA-3,8'-bis (3-phenylpropionate) ML-236A and MB-53OA-3,8'-bis (2-thienyl acetate) ML-236A and MB-53OA-3,8'-bis (2-furylacetate) ML-236A and MB-53OA-3,8'-bis (2-thiophenecarboxylate)
ML-236A und MB-53OA-3,81-bis(2-furoat) ML-236A und MB-53OA-3,8'-bis(2-thienylacrylat) ML-236A und MB-53OA-3,8'-bis(2-furylacrylat) ML-236A und MB-53OA-3,8'-bis(3-furoat) ML-236A und MB-53OA-3,8'-dinicotinat ML-236A und MB-53OA-3,8'-diisonicotinat ML-236A und MB-53OA-3,8'-dibenzoat ML-236A und MB-53OA-3,8'-bis(o-methylbenzoat) ML-236A und MB-53OA-3,8'-bis(m-methylbenzoat) ML-236A und MB-53OA-3,8'-bis(p-methylbenzoat) ML-236A und MB-53OA-3,8'-bis(o-ethylbenzoat) ML-236A und MB-53OA-3,8'-bis(m-ethylbenzoat) ML-236A und MB-53OA-3,8'-bis(p-ethylbenzoat) ML-236A und MB-53OA-3,8'-bis(o-propylbenzoat) ML-236A und MB-53OA-3,8'-bis(m-propylbenzoat) ML-236A und MB-53OA-3,8'-bis(p-propylbenzoat) ML-236A und MB-53OA-3,8'-bis(o-butylbenzoat) ML-236A und MB-5 3OA-3,8'-bis(m-butylbenzoat) ML-236A und MB-53OA-3,8'-bis(p-butylbenzoat) ML-236A und MB-53OA-3,8'-bis(o-methoxybenzoat) ML-236A und MB-53OA-3,8'-bis(m-methoxybenzoat) ML-236A und MB-53OA-3,8'-bis(p-methoxybenzoat) ML-236A und MB-53OA-3,8'-bis(o-ethoxybenzoat) ML-236A und MB-53OA-3,8'-bis(m-ethoxybenzoat) ML-236A und MB-53OA-3,8'-bis(p-ethoxybenzoat) ML-236A und MB-53OA-3,8'-bis(o-propoxybenzoat) ML-236A und MB-53OA-3,8'-bis(m-propoxybenzoat) ML-236A und MB-53OA-3,8'-bis(p-propoxybenzoat) ML-236A und MB-53OA-3,8'.bis(o-butoxybenzoat) ML-236A und MB-53OA-3,8'.bis(m-butoxybenzoat) ML-236A und MB-53OA-3,8'-bis(p-butoxybenzoat) ML-236A und MB-53OA-3,8'-bis(o-hydroxybenzoat) ML-236A und MB-5 3OA-3,8'-bis(m-hydroxybenzoat) ML-23()A und MB-53OA-3 , 8 ' -bis (p-hydroxybenzoat:) ML-23f")A und MB-53OA-3 , 8 ' -bis (2 , 3-dirnel:hoxyberr.:oat)ML-236A and MB-53OA-3,8 1 -bis (2-furoate) ML-236A and MB-53OA-3,8'-bis (2-thienyl acrylate) ML-236A and MB-53OA-3,8 ' -bis (2-furylacrylate) ML-236A and MB-53OA-3,8'-bis (3-furoate) ML-236A and MB-53OA-3,8'-dinicotinate ML-236A and MB-53OA-3, 8'-diisonicotinate ML-236A and MB-53OA-3,8'-dibenzoate ML-236A and MB-53OA-3,8'-bis (o-methylbenzoate) ML-236A and MB-53OA-3,8'- bis (m-methylbenzoate) ML-236A and MB-53OA-3,8'-bis (p-methylbenzoate) ML-236A and MB-53OA-3,8'-bis (o-ethylbenzoate) ML-236A and MB- 53OA-3,8'-bis (m-ethylbenzoate) ML-236A and MB-53OA-3,8'-bis (p-ethylbenzoate) ML-236A and MB-53OA-3,8'-bis (o-propylbenzoate ) ML-236A and MB-53OA-3,8'-bis (m-propylbenzoate) ML-236A and MB-53OA-3,8'-bis (p-propylbenzoate) ML-236A and MB-53OA-3,8 '-bis (o-butyl benzoate) ML-236A and MB-5 3OA-3,8'-bis (m-butyl benzoate) ML-236A and MB-53OA-3,8'-bis (p-butyl benzoate) ML-236A and MB-53OA-3,8'-bis (o-methoxybenzoate) ML-236A and MB-53OA-3,8'-bis (m-methoxybenzoate) ML-236A and MB-53OA-3,8'-bis ( p-methoxybenzoate) ML-236A and MB-53OA-3,8'-bis (o-ethoxybenzoate) ML-236A and MB-53OA-3,8'-bis (m-ethoxybenzoate) ML-236A and MB-53OA-3,8'-bis (p-ethoxybenzoate) ML-236A and MB-53OA -3,8'-bis (o-propoxybenzoate) ML-236A and MB-53OA-3,8'-bis (m-propoxybenzoate) ML-236A and MB-53OA-3,8'-bis (p-propoxybenzoate) ML-236A and MB-53OA-3,8'.bis (o-butoxybenzoate) ML-236A and MB-53OA-3,8'.bis (m-butoxybenzoate) ML-236A and MB-53OA-3,8 ' -bis (p-butoxybenzoate) ML-236A and MB-53OA-3,8'-bis (o-hydroxybenzoate) ML-236A and MB-5 3OA-3,8'-bis (m-hydroxybenzoate) ML-23 ( ) A and MB-53OA-3, 8 '-bis (p-hydroxybenzoate :) ML-23f ") A and MB-53OA-3, 8' -bis (2, 3-dirnel: hoxyberr.: Oat)
ML-2 36A und MB-53OA-3,8'-bis(2,4-dimethoxybenzoat) ML-236A und MB-53OA-3,8'-bis(2,5-dimethoxybenzoat) ML-236A und MB-5 3OA-3,8'-bis(2,6-dimethoxybenzoat) ML-236A und MB-53OA-3,8'-bis(2,4,6-trimethoxybenzoat) ML-236A und MB-53OA-3,8'-bis(3,4,5-trimethoxybenzoat) ML-236A und MB-53OA-3,8'-bis(3,4-methylendioxybenzoat) ML-236A und MB-53OA-3,8'-bis(2,3-methylendioxybenzoat) ML-236A und MB-53OA-3,8'-bis(o-chlorbenzoat) ML-236A und MB-53OA-3,8'-bis(m-chlorbenzoat) ML-236A und MB-53OA-3,8'.bis(p-chlorbenzoat) ML-236A und MB-53OA-3,8'-bis(o-brombenzoat) ML-236A und MB-5 3OA-3,8'-bis(m-brombenzoat) ML-236A und MB-53OA-3,8'-bis(p-brombenzoat) ML-236A und MB-53OA-3,8'-bis(o-fluorbenzoat) ML-236A und MB-53OA-3,8'-bis(m-fluorbenzoat) ML-236A und MB^53OA-3v, 8'-bis.(p-f luorbenzoat) ML-2 36B und MB-5 3OB-acetatML-2 36A and MB-53OA-3,8'-bis (2,4-dimethoxybenzoate) ML-236A and MB-53OA-3,8'-bis (2,5-dimethoxybenzoate) ML-236A and MB-5 3OA-3,8'-bis (2,6-dimethoxybenzoate) ML-236A and MB-53OA-3,8'-bis (2,4,6-trimethoxybenzoate) ML-236A and MB-53OA-3,8'-bis (3,4,5-trimethoxybenzoate) ML-236A and MB-53OA-3,8'-bis (3,4-methylenedioxybenzoate) ML-236A and MB-53OA-3,8'-bis (2,3-methylenedioxybenzoate) ML-236A and MB-53OA-3,8'-bis (o-chlorobenzoate) ML-236A and MB-53OA-3,8'-bis (m-chlorobenzoate) ML-236A and MB-53OA-3,8'.bis (p-chlorobenzoate) ML-236A and MB-53OA-3,8'-bis (o-bromobenzoate) ML-236A and MB-5 3OA-3,8'-bis (m-bromobenzoate) ML-236A and MB-53OA-3,8'-bis (p-bromobenzoate) ML-236A and MB-53OA-3,8'-bis (o-fluorobenzoate) ML-236A and MB-53OA-3,8'-bis (m-fluorobenzoate) ML-236A and MB ^ 53OA-3v, 8'-bis. (P-f luorbenzoate) ML-2 36B and MB-5 3OB acetate
ML-236B und MB-530B-propionat ML-2 36B und MB-5 3OB-butyrat ML-238B und MB-530B-isobutyrat ML-236B und MB-5 3OB-valerat ML-236B und MB-530B-isovalerat ML-236B und MB-5 3OB-pivalat ML-236B und MB-530B-hexanoat ML-236B und MB-530B-heptanoat ML-236B und MB-53OB-(2-iaethylvalerat) ML-236B und MB-53OB-(3-methylvalerat) ML-236B und MB-53OB-(2-ethylbutyrat) ML-236B und MB-530B-octanoat ML-236B und MB-530B-{2-ethylhexanoat) ML-236B und MB-530B-nonanoat ML-236B und MB-5 30B-isononanoat ML-236B und MB-5 30B-ündecanoat ML-236B und MB-5 30B-tetradecanoat ML-2 36B und MB-530B-pentadecanoat ML-236B und MB-5 3OB-palmitat ML-236B und MB-5 3OB-stearat ML-236B und Mß-530B-isostearatML-236B and MB-530B propionate ML-2 36B and MB-5 3OB butyrate ML-238B and MB-530B isobutyrate ML-236B and MB-5 3OB-valerate ML-236B and MB-530B-isovalerate ML-236B and MB-5 3OB-pivalate ML-236B and MB-530B-hexanoate ML-236B and MB-530B-heptanoate ML-236B and MB-53OB- (2-ethylvalerate) ML-236B and MB-53OB- (3-methylvalerate) ML-236B and MB-53OB- (2-ethylbutyrate) ML-236B and MB-530B-octanoate ML-236B and MB-530B- {2-ethylhexanoate) ML-236B and MB-530B nonanoate ML-236B and MB-5 30B isononanoate ML-236B and MB-5 30B undecanoate ML-236B and MB-5 30B tetradecanoate ML-2 36B and MB-530B pentadecanoate ML-236B and MB-5 3OB palmitate ML-236B and MB-5 3OB stearate ML-236B and Mß-530B isostearate
ML-236B und MB-530B-nonadecanoat ML-236B und MB-530B-eicosanoat ML-236B und MB-53OB-(1-adamantancarboxylat) ML-236B und MB-SSOB-cyclopropancarboxylat ML-236B und MB-S.SOB-cyclobutancarboxylat ML-2 36B und MB-SSOB-cyclopentancarboxylat ML-236B und MB-SSOB-cyclohexancarboxylat ML-236B~und MB-SSOB-cycloheptancarboxylat ML-236B und MB-SSOB-cyclooctancarboxylat ML-236B und MB-530B-cyclohexanacetat ML-236B und MB-53OB-(3-cyclohexanpropionat) ML-236B und MB-53OB-acrylat ML-236B und MB-530B-propiolat ML-236B und MB-530B-crotonat ML-236B und MB-SSOB-inethacrylat ML-2 36B und MB-53OB-tiglat ML-236B und MB-53OB-angelat ML-236B und MB-530B-senecionat ML-236B und MB-53OB-(3-butenoat) ML-236B und MB-53OB-(2-pentenoat) ML-236B und MB-530B-linoleat ML-236B und MN-530B-oleat ML-236B und MB-530B-linolenat ML-236B und MB-5 3OB-cinnamat ML-2368 und MB-53OB-(o-chlorcinnamat) ML-236B und MB-53OB-(m-chlorcinnamat) ML-236B und MB-53OB-(p-chlorcinnamat) ML-236B und MB-53OB-(o-bromcinnamat) ML-236B und MB-53OB-(m-bromcinnamat) ML-236B und MB-53OB-(p-bromcinnamat) ML-236B und MB-53OB-(o-methoxycinnamat) ML-236B und MB-5 3OB-(m-methoxycinnamat) ML-236B und MB-53OB-(p-methoxycinnamat) ML-236B und MB-53OB-(o-methylcinnamat) ML-23bB und MB-53OB-(m-methylcinnamat) ML-236B und MB-53OB-(p-methylcinnamat)ML-236B and MB-530B-nonadecanoate ML-236B and MB-530B-eicosanoate ML-236B and MB-53OB- (1-adamantane carboxylate) ML-236B and MB-SSOB-cyclopropanecarboxylate ML-236B and MB-S.SOB cyclobutane carboxylate ML-2 36B and MB-SSOB cyclopentane carboxylate ML-236B and MB-SSOB cyclohexane carboxylate ML-236B ~ and MB-SSOB-cycloheptane carboxylate ML-236B and MB-SSOB cyclooctane carboxylate ML-236B and MB-530B-cyclohexane acetate ML-236B and MB-53OB- (3-cyclohexane propionate) ML-236B and MB-53OB acrylate ML-236B and MB-530B propiolate ML-236B and MB-530B crotonate ML-236B and MB-SSOB-inethacrylate ML-2 36B and MB-53OB-tiglat ML-236B and MB-53OB-angelat ML-236B and MB-530B-senecionate ML-236B and MB-53OB- (3-butenoate) ML-236B and MB-53OB (2-pentenoate) ML-236B and MB-530B linoleate ML-236B and MN-530B oleate ML-236B and MB-530B linolenate ML-236B and MB-5 3OB-cinnamate ML-2368 and MB-53OB- (o-chlorocinnamate) ML-236B and MB-53OB- (m-chlorocinnamate) ML-236B and MB-53OB- (p-chlorocinnamate) ML-236B and MB-53OB- (o-bromocinnamate) ML-236B and MB-53OB- (m-bromocinnamate) ML-236B and MB-53OB- (p-bromocinnamate) ML-236B and MB-53OB- (o-methoxycinnamate) ML-236B and MB-5 3OB- (m-methoxycinnamate) ML-236B and MB-53OB- (p-methoxycinnamate) ML-236B and MB-53OB- (o-methylcinnamate) ML-23bB and MB-53OB- (m-methylcinnamate) ML-236B and MB-53OB- (p-methylcinnamate)
ML-236B und MB-53OB-phenylacetat ML-236B und MB-530B-phenoxyacetat ML-236B und MB-5 3OB-(3-phenylpropionat) ML-236B und MB-53OB-(2-thienylacetat) ML-236B und MB-5 3OB-(2-furylacetat) ML-236B und MB-53OB-(2-thiophencarboxylat) ML-236B und MB-5 3OB-(2-furoat) ML-2 36B und MB-5 3OB-(2-thienylacrylat) ML-236B und MB-5 3OB-(2-furylacrylat) ML-236B und MB-53OB-(3-furoat) ML-236B und MB-5 30B-nicotinat ML-236B und MB-530B-isonicotinat ML-236B und MB-5 30B-benzoat ML-236B und MB-5 3OB-(o-methylbenzoat) ML-236B und MB-53OB-(m-methylbenzoat) ML-236B und MB-53OB-(p-methylbenzoat) ML-236B und MB-5 3OB-(o-ethylbenzoat) ML-236B und MB-53OB-(m-ethylbenzoat) ML-236B und MB-5 3OB-(p-ethylbenzoat) ML-236B und MB-53OB-(o-propylbenzoat) ML-236B und MB-53OB-(m-propylbenzoat) ML-236B und MB-53OB-(p-propylbenzoat) ML-236B und MB-5 30B-{o-butylbenzoat) ML-236B und MB-53OB-(m-butylbenzoat) ML-236B und MB-5 3OB-(p-butylbenzoat) ML-236B und MB-53OB-(o-methoxybenzoat) ML-2 36B und MB-530B-(m-methoxybenzoat) ML-236B und MB-53OB-(p-m.ethoxybenzoat) ML-236B und MB-5 3OB-(o-ethoxybenzoat) ML-236B und MB-5 3OB-(m-ethoxybenzoat) ML-236B und MB-53OB-(p-ethoxybenzoat) ML-236B und MB-53OB-(o-propoxybenzoat) ML-236B und MB-53OB-(m-propoxybenzoat) ML-2 36B und MB-5 3OB-(p-propoxybenzoat) ML-236B und MB-53OB-(o-butoxybenzoat) ML-236B und MB-53OB-(m-butoxybenzoat)ML-236B and MB-53OB-phenyl acetate ML-236B and MB-530B phenoxyacetate ML-236B and MB-5 3OB- (3-phenylpropionate) ML-236B and MB-53OB- (2-thienyl acetate) ML-236B and MB-5 3OB- (2-furylacetate) ML-236B and MB-53OB- (2-thiophene carboxylate) ML-236B and MB-5 3OB- (2-furoate) ML-2 36B and MB-5 3OB- (2-thienyl acrylate) ML-236B and MB-5 3OB- (2-furylacrylate) ML-236B and MB-53OB- (3-furoate) ML-236B and MB-5 30B-nicotinate ML-236B and MB-530B isonicotinate ML-236B and MB-5 30B-benzoate ML-236B and MB-5 3OB- (o-methylbenzoate) ML-236B and MB-53OB- (m-methylbenzoate) ML-236B and MB-53OB- (p-methylbenzoate) ML-236B and MB-5 3OB- (o-ethylbenzoate) ML-236B and MB-53OB- (m-ethylbenzoate) ML-236B and MB-5 3OB- (p-ethylbenzoate) ML-236B and MB-53OB- (o-propylbenzoate) ML-236B and MB-53OB- (m-propylbenzoate) ML-236B and MB-53OB- (p-propylbenzoate) ML-236B and MB-5 30B- {o-butylbenzoate) ML-236B and MB-53OB- (m-butylbenzoate) ML-236B and MB-5 3OB- (p-butylbenzoate) ML-236B and MB-53OB- (o-methoxybenzoate) ML-2 36B and MB-530B- (m-methoxybenzoate) ML-236B and MB-53OB- (p-m.ethoxybenzoate) ML-236B and MB-5 3OB- (o-ethoxybenzoate) ML-236B and MB-5 3OB- (m-ethoxybenzoate) ML-236B and MB-53OB- (p-ethoxybenzoate) ML-236B and MB-53OB- (o-propoxybenzoate) ML-236B and MB-53OB- (m-propoxybenzoate) ML-2 36B and MB-5 3OB- (p-propoxybenzoate) ML-236B and MB-53OB- (o-butoxybenzoate) ML-236B and MB-53OB- (m-butoxybenzoate)
ML-236B und MB-53OB-(p-butoxybenzoat) ML-236B und MB-236B-(o-hydroxybenzoat) ML-236B und MB-53OB-(m-hydroxybenzoat) ML-236B und MB-53OB-(p-hydroxybenzoat) ML-236B und MB-53OB-(2,3-dimethoxybenzoat) ML-236B und MB-53OB-(2,4-dimethoxybenzoat) ML-236B und MB-53OB-(2,5-dimethoxybenzoat) ML-236B und MB-5 3OB-(2,6-dimethoxybenzoat) ML-236B und MB-53OB-(2,4,6-trimethoxybenzoat) ML-236B und MB-53OB-(3,4,5-trimethoxybenzoat) ML-236B und MB-53OB-(3,4-methylendioxybenzoat) ML-2 36B und MB-53OB-(2,3-methyledioxybenzoat) ML-236B und MB-53OB-(o-chlorbenzoat) ML-236B und MB-53OB-(m-chlorbenzoat) ML-236B und MB-53OB-(p-chlorbenzoat) ML-236B und MB-53OB-(o-brombenzoat) ML-236B und MB-53OB-(m-brombenzoat) ML-236B und MB-53OB-(p-brombenzoat) ML-236B und MB-53OB-(o-fluorbenzoat) ML-236B und MB-53OB-(ra-fluorbenzoat) ML-236B und MB-53OB-(p-fluorbenzoat)ML-236B and MB-53OB- (p-butoxybenzoate) ML-236B and MB-236B- (o-hydroxybenzoate) ML-236B and MB-53OB- (m-hydroxybenzoate) ML-236B and MB-53OB- (p-hydroxybenzoate) ML-236B and MB-53OB- (2,3-dimethoxybenzoate) ML-236B and MB-53OB- (2,4-dimethoxybenzoate) ML-236B and MB-53OB- (2,5-dimethoxybenzoate) ML-236B and MB-5 3OB- (2,6-dimethoxybenzoate) ML-236B and MB-53OB- (2,4,6-trimethoxybenzoate) ML-236B and MB-53OB- (3,4,5-trimethoxybenzoate) ML-236B and MB-53OB- (3,4-methylenedioxybenzoate) ML-2 36B and MB-53OB- (2,3-methyledioxybenzoate) ML-236B and MB-53OB- (o-chlorobenzoate) ML-236B and MB-53OB- (m-chlorobenzoate) ML-236B and MB-53OB- (p-chlorobenzoate) ML-236B and MB-53OB- (o-bromobenzoate) ML-236B and MB-53OB- (m-bromobenzoate) ML-236B and MB-53OB- (p-bromobenzoate) ML-236B and MB-53OB- (o-fluorobenzoate) ML-236B and MB-53OB- (ra-fluorobenzoate) ML-236B and MB-53OB- (p-fluorobenzoate)
Vorstehend sind nur die Diester von ML-236A und MB-5 3OA aufgeführt, jedoch umfaßt die Erfindung auch die entsprechenden 3-Monoester und 8'-Monoester. Von diesen Verbindungen sind die folgenden besonders bevorzugt:The above are only the diesters of ML-236A and MB-5 30A listed, but the invention also includes the corresponding 3-monoesters and 8'-monoesters. From these connections the following are particularly preferred:
ML-236A - δ'-butyratML-236A - δ'-butyrate
ML-2 36A - 8'-isobutyrat ML-236A - δ'-isovalerat MB-53OB - 8'-butyratML-2 36A - 8'-isobutyrate ML-236A - δ'-isovalerate MB-53OB - 8'-butyrate
MB-53OB - 8'-isovalerat ML-236A - 8'-(4-pentenoat) ML-236A - 3,8'-diacetat ML-236A - 3,8'-dibutyrat und ML-2:ö6A - 3,8'-di (4-pentenoat) .MB-53OB - 8'-isovalerate ML-236A - 8 '- (4-pentenoate) ML-236A - 3,8'-diacetate ML-236A - 3,8'-dibutyrate and ML-2: 6A - 3,8'-di (4-pentenoate).
MB-53OA, eine der erfindungsgemäßen Verbindungen, kann durch Züchten eines MB-53OA erzeugenden Mikroorganismus des Genus Monascus, vorzugsweise eines Stammes Monascus ruber und insbesondere Monascus ruber SANK 15177 hergestellt werden. Dieser Stamm wurde am 27.04.1979 unter der Eingangs-Nr. FERM 4956 beim Fermentation Research Institute, Agency of Industrial Science and Technology, Ministry of International Trade and Industry, Japan, sowie am 25.01.1980 unter der Eingangs-Nr. NRRL 12081 beim Agricultural Research Service Culture Collection, Northern Regional Research Laboratory, Peoria, Illinois, USA , hinterlegt. Die Morphologie und Physiologie dieses Stammes sind im einzelnen in der USSN 137 821 vom 4.04.1980 beschrieben.MB-53OA, one of the compounds of the invention, can by cultivating an MB-53OA producing microorganism belonging to the genus Monascus, preferably a strain Monascus ruber and in particular Monascus ruber SANK 15177 can be produced. This strain was registered on April 27, 1979 under the entry no. FERM 4956 at the Fermentation Research Institute, Agency of Industrial Science and Technology, Ministry of International Trade and Industry, Japan, as well as on January 25, 1980 under the entrance no. NRRL 12081 at the Agricultural Research Service Culture Collection, Northern Regional Research Laboratory, Peoria, Illinois, USA. The morphology and physiology of this strain are detailed described in USSN 137 821 of April 4, 1980.
Das gewünschte MB-53OA kann durch Züchten des gewählten Mikroorganismus unter aeroben Bedingungen in einer Kulturbrühe nach an sich bekannten Methoden der Züchtung von Fungi und anderen Mikroorganismen hergestellt werden. Beispielsweise kann man zunächst den gewählten Monascus-Stamm in einem geeigneten Medium züchten, dann die gezüchteten Mikroorganismen sammeln und in ein anderes Kulturmedium überimpfen und dort weiter-zuchten, um das gewünschte MB-5 3OA zu erhalten. Das für die Vermehrung des Mikroorganismus und das für die Produktion von MB-5 3OA verwendete Kulturmedium können gleich oder unterschiedlich sein. Es können beliebige, für die Züchtung von Fungi bekannte Kulturmedien angewandt werden, sofern es die bekannten notwendigen Nährstoffe enthält, insbesondere assimilierbare Kohlenstoff- und Stickstoffquellen. Beispiele für geeignete assimilierbare Kohlenstoffquellen sind Glucose, Maltose, Dextrin, Stärke, Lactose, Sucrose und Glycerin. Hiervon sind zur Produktion von MB-53OA Glucose, Glycerin und Stärke besonders bevorzugt. Beispiele für geeignete assimilierbare Stickstoffquellen sind Pepton, Fleischextrakt, Hefe, Hefeextrakt, Sojamehl, Erdnußmehl, Maisquellflüssigkeit, Reiskleie und anorganische Stickstoffquellen,Hiervon sind Maisquellflüssigkeit undThe desired MB-53OA can be obtained by growing the selected one Microorganism under aerobic conditions in a culture broth according to methods known per se for cultivating fungi and other microorganisms. For example, you can first see the selected Monascus strain in culture in a suitable medium, then collect the cultured microorganisms and inoculate them into another culture medium and continue breeding there to obtain the desired MB-5 3OA to obtain. The culture medium used for the multiplication of the microorganism and the culture medium used for the production of MB-5 30A can be the same or different. Any culture media known for cultivating fungi can be used be used, provided it contains the known necessary nutrients, especially assimilable carbon and Nitrogen sources. Examples of suitable assimilable carbon sources are glucose, maltose, dextrin, starch, Lactose, sucrose and glycerin. Of these, glucose, glycerin and starch are particularly preferred for the production of MB-53OA. Examples of suitable assimilable nitrogen sources are peptone, meat extract, yeast, yeast extract, soy flour, Peanut meal, corn steep liquor, rice bran and inorganic nitrogen sources, of which are corn steep liquor and
112566112566
Pepton besonders bevorzugt. Für die Herstellung von MB-5 3OA können dem Kulturmedium gegebenenfalls anorganische SaIae und/oder Metallsalze zugesetzt werden. Ferner können gegebenenfalls geringe Schwermetallmengen zugegeben werden.Peptone is particularly preferred. For the production of MB-5 3OA Inorganic SaIae can optionally be added to the culture medium and / or metal salts are added. In addition, small amounts of heavy metals can optionally be added.
Der Mikroorganismus wird vorzugsweise unter aeroben Bedingungen unter Anwendung bekannter Kulturmethoden gezüchtet, z.B. als Festkultur, Schüttelkultur oder belüftete Rührkultur. Die Mikroorganismen wachsen über einen breiten Temperaturbereich, z.B. etwa 7 bis 40 C, jedoch ist für die Produktion von MB-53OA eine Züchtungstemperatur von 20 bin 30°C besonders bevorzugt.The microorganism is preferably grown under aerobic conditions using known culture methods, e.g. as a festival culture, shaking culture or aerated stirring culture. The microorganisms grow over a wide temperature range, e.g. about 7 to 40 C, but for the production of MB-53OA a growth temperature of 20 am is required 30 ° C is particularly preferred.
Während der Züchtung des Mikroorganismus kann die Produktion von MB—5 3OA durch Probenentnahme aus dem Kulturmedium und Messen der physiologischen Aktivität des Mediums nach bekannten Methoden überwacht werden. Die Kultur kann dann fortgesetzt werden, bis sich in dem Kulturmedium ausreichend MB-53OA angesammelt hat, worauf man das MB-53OA durch eine geeignete Kombination von Isoliertechniken, die im Hinblick auf seine physikalischen und chemischen Eigenschaften ausgewählt werden, aus dem Kulturmedium und den Geweben (Mycel) des Mikroorganismus isoliert und gewinnt. Beispielsweise können eine oder mehrere der folgenden Isoliermethoden angewandt werden:During the cultivation of the microorganism, the production of MB-5 3OA can be determined by taking samples from the culture medium and measuring the physiological activity of the medium can be monitored by known methods. The culture can then be continued until sufficient MB-53OA has accumulated in the culture medium, whereupon the MB-53OA can be removed by a appropriate combination of insulation techniques, considering its physical and chemical properties are selected, isolated from the culture medium and the tissues (mycelium) of the microorganism and recovered. For example one or more of the following isolation methods can be used:
Extraktion der Flüssigkeit aus der Kulturbrühe mit einem hydrophilen Lösungsmittel (z.B. Diethylether, Ethylacetat, Chloroform oder Benzol); Extraktion des Organismus mit einem hydrophilen Lösungsmittel (z.B. Aceton oder einem Alkohol); Konzentrieren, z.B. teilweises oder gesamtes Abdampfen des Lösungsmittels unter vermindertem Druck; Auflösen in einem polareren Lösungsmittel (z.B. Aceton oder einem Alkohol); Abtrennen der Verunreinigungen mit einem weniger polaren Lösungsmittel (z.B. Petrolether oder Hexan); Gelfiltration, z.B. mit Sephadex (Produkt der Pharmacia Co. Limited, USA ) ;Extraction of the liquid from the culture broth with a hydrophilic solvent (e.g. diethyl ether, ethyl acetate, Chloroform or benzene); Extraction of the organism with a hydrophilic solvent (e.g. acetone or an alcohol); Concentration, e.g., evaporation of part or all of the solvent under reduced pressure; Dissolve in one more polar solvents (e.g. acetone or an alcohol); Separate the impurities with a less polar one Solvents (e.g. petroleum ether or hexane); Gel filtration, for example with Sephadex (product of Pharmacia Co. Limited, USA);
Absorptionschromatographie mit Aktivkohle oder Silikagelr
und ähnliche Methoden. Durch Anwendung einer geeigneten Kombination dieser Methoden läßt sich das gewünschte MB-53OA
aus der Kulturbrühe als Reinsubstanz isolieren.Absorption chromatography with activated carbon or silica gel
and similar methods. By using an appropriate combination of these methods, the desired MB-53OA
isolate from the culture broth as a pure substance.
Auf ähnliche Weise können die anderen bekannten Ausgangsmaterialien
des erfindungsgemäßen Acylierungsverfahrens, d.h.
ML-236A, ML-236B und MB-53OB, aus' Kulturmedien, die den jeweiligen
Mikroorganismus enthalten, nach den vorstehenden Methoden erhalten werden oder aber nach den in der US-PS
3 983 140, der USSN 121 515 vom 14.02.1980 oder der
USSN 137 821 vom 4.04.1980 beschriebenen Methoden.In a similar manner, the other known starting materials of the acylation process according to the invention, ie ML-236A, ML-236B and MB-53OB, can be obtained from culture media containing the respective microorganism by the above methods or by the methods described in US Pat
3 983 140, USSN 121 515 dated 02/14/1980 or the
USSN 137 821 of 04/04/1980 described methods.
Die erfindungsgemäßen acylierten Derivate können aus ML-236A, ML-236B, MB-5 3OA oder MB-5 3OB nach einem der folgenden Verfahren hergestellt werden.The acylated derivatives according to the invention can be prepared from ML-236A, ML-236B, MB-5 3OA, or MB-5 3OB using one of the following methods getting produced.
Verfahren 1Procedure 1
ML-236A, ML-236B, MB-53OA oder ML-53OB werden mit einem geeigneten
Säurechlorid oder Säureanhydrid zu dem gewünschten Acylderivat umgesetzt. Die Umsetzung erfolgt vorzugsweise in
Gegenwart einer Base (die die Säure bindet), vorzugsweise
einem organischen Aitiin, wie Pyridin, Triethylamin, N,N-Dimethylaminopyridin,
N-Methylpyrrolidon oder N-Methylmorpholin.
Die Reaktion wird vorzugsweise in Gegenwart eines Lösungsmittels durchgeführt, dessen Auswahl nicht kritisch ist,
solange es die Reaktion nicht negativ beeinflußt. Geeignete Lösungsmittel sind z.B. Chloroform, Methylenchlorid und Dimethylether.
In einigen Fällen ist es möglich, die Reaktion unter Verwendung eines Überschusses eines der Reaktanten
oder der Base als Lösungsmittel durchzuführen. Die Reaktion erfolgb über einen breiten Temperaturbereich, normalerweise
ist es jedoch für die Reaktionssteuerung bevorzugt, eine relativ
niedrige Temperatur anzuwenden, z.B. -20 C bis Raumtemperatur,
insbesondere -20 bis O0C. Falls erwünscht, können .
jedoch auch höhere Temperaturen angewandt werden.ML-236A, ML-236B, MB-53OA or ML-53OB are reacted with a suitable acid chloride or acid anhydride to give the desired acyl derivative. The reaction is preferably carried out in the presence of a base (which binds the acid), preferably
an organic alkali such as pyridine, triethylamine, N, N-dimethylaminopyridine, N-methylpyrrolidone or N-methylmorpholine. The reaction is preferably carried out in the presence of a solvent, the choice of which is not critical as long as it does not adversely affect the reaction. Suitable solvents are, for example, chloroform, methylene chloride and dimethyl ether. In some cases it is possible to carry out the reaction using an excess of one of the reactants
or the base as a solvent. The reaction succeeds over a wide temperature range, but it is usually preferred for reaction control to use a relatively low temperature, for example -20 ° C. to room temperature, especially -20 ° C. to 0 ° C. If desired, can. however, higher temperatures can also be used.
- 23 Verfahren 2 - 23 Procedure 2
Eine Carbonsäure wird mit einem Chlorkohlensäureester oder einem Sulfonsäurechlorid in Gegenwart einer Base, z.B. einem der vorstehend genannten organischen Amine, zu einem gemischten Säureanhydrid umgesetzt, das man dann mit ML-236A, ML-236B, MB-53OA oder MB-53OB umsetzt. Die Reaktion erfolgt vorzugsweise in Gegenwart eines Lösungsmittels, dessen Auswahl nicht kritisch ist, solange es die Reaktion nicht negativ beeinflußt. Geeignete Lösungsmittel sind z.B. Diethylether, Benzol, Chloroform und Methylenchlorid. Die Umsetzung erfolgt innerhalb eines breiten Temperaturbereichs, z.B. -20°C bis Raumtemperatur, insbesondere -20 bis 0 C.A carboxylic acid is reacted with a chlorocarbonic acid ester or a sulfonic acid chloride in the presence of a base, e.g. of the organic amines mentioned above, converted to a mixed acid anhydride, which can then be mixed with ML-236A, ML-236B, MB-53OA or MB-53OB implements. The reaction takes place preferably in the presence of a solvent, the choice of which is not critical, as long as it does not adversely affect the reaction influenced. Suitable solvents are, for example, diethyl ether, benzene, chloroform and methylene chloride. The implementation takes place within a wide temperature range, e.g. -20 ° C to room temperature, in particular -20 to 0 C.
Verfahren 3Procedure 3
ML-236A, ML-236B, MB-53OA oder MB-53OB werden mit einer Carbonsäure und einem Diazoalkyldicarboxylat in Gegenwart von z.B. Dicyclohexylcarbodiimid, Triphenylphosphin oder Dimethy!phosphorsäureamid umgesetzt. Die Reaktion erfolgt vorzugsweise in Gegenwart eines Lösungsmittels, dessen Auswahl nicht kritisch ist, solange es die Reaktion nicht negativ beeinflußt. Geeignete Lösungsmittel sind z.B. Chloroform, Methylenchlorid, Benzol und Diethylether.ML-236A, ML-236B, MB-53OA or MB-53OB are mixed with a carboxylic acid and a diazoalkyl dicarboxylate in the presence of, for example, dicyclohexylcarbodiimide, triphenylphosphine or dimethyl phosphoric acid amide implemented. The reaction is preferably carried out in the presence of a solvent, the selection thereof is not critical as long as it does not adversely affect the reaction. Suitable solvents are e.g. chloroform, Methylene chloride, benzene and diethyl ether.
Die vorstehenden Reaktionen sind normalerweise innerhalb 30 Minuten bis 5 Stunden vollständig, jedoch hängt die jeweils erforderliche Reaktionszeit von den Reaktanten und der Reaktionstemperatur ab. Nach beendeter Umsetzung wird das gewünschte Produkt auf übliche Weise aus dem Reaktionsgemisch abgetrennt, z.B. durch Abdampfen des Lösungsmittels aus einer Lösung des gewünschten Produkts (diese Lösung kann einfach das Reaktionsgemisch sein oder eine Lösung, die durch Extraktion des Reaktionsgemischs mit einem organischen Lösungsmittel erhalten wurde), wobei die Lösung gegebenen fall κ vorher gewaschen und getrocknet wurde. Hierauf kann das Pro-The above reactions are usually complete within 30 minutes to 5 hours, however each depends required reaction time depends on the reactants and the reaction temperature. After the implementation is complete, the the desired product is separated off from the reaction mixture in the usual way, e.g. by evaporating off the solvent a solution of the desired product (this solution can simply be the reaction mixture or a solution created by Extraction of the reaction mixture with an organic solvent was obtained), the solution given case κ was washed and dried beforehand. The pro-
dukt auf übliche Weise gereinigt werden, z.B. durch Säalenchromatographie, Dünnschichtchromatographie und/oder Umkristallisieren .the product can be cleaned in the usual way, e.g. by column chromatography, Thin layer chromatography and / or recrystallization.
Wenn das Ausgangsmaterial für die Acylierungsreaktion zwei Hydroxylgruppen enthält, d.h. im Falle-von ML-236A oder MB-53OA, können die vorstehenden Reaktionen den 3-Monoester, den 3,8'-Diester, den 8'-Monoester oder deren Gemische ergeben. Die Art des erhaltenen Produkts kann über die Mengen der Reaktanten, die Reaktionstemperatur und andere Reaktionsbedingungen beeinflußt werden, wobei aus bisher nicht geklärten Gründen angenommen wird, daß der 3-Monoester bevorzugt gebildet wird, gefolgt von dem 3,8'-Diester und dem 8'-Monoester. Bei jeder einzelnen Reaktion kann der Fachmann jedoch leicht die optimalen Bedingungen zur Herstellung des jeweils gewünschten Produkts bestimmen. Im allgemeinen wird folgendes Ergebnis erhalten:When the starting material for the acylation reaction contains two hydroxyl groups, i.e. in the case of ML-236A or MB-53OA, the above reactions can give the 3-monoester, the 3,8'-diester, the 8'-monoester, or mixtures thereof. The nature of the product obtained may depend on the amounts of the reactants, the reaction temperature and other reaction conditions are influenced, it being assumed, for reasons not yet cleared, that the 3-monoester is preferred is formed, followed by the 3,8'-diester and the 8'-monoester. For each individual reaction, the person skilled in the art can however, it is easy to determine the optimal conditions for producing the particular desired product. Generally will get the following result:
Der 3-Monoester und/oder 8'-Monoester werden hauptsächlich gebildet, wenn man die Reaktion unter Verwendung eines Säureanhydrids oder -halogenids als Acylierungsmittels in Gegenwart einer organischen Base bei einer Temperatur von -20 bis 00C durchführt. Die Menge des Acylierungsmittels, vorzugsweise des Säurehalogenids, beträgt vorzugsweise etwa 1 Äquivalent pro Äquivalent ML-236A, ML-236B, MB-5 3OA oder MB-53OB.The 3-Monoester and / or 8'-Monoester are mainly formed when halide carrying out the reaction using an acid anhydride as acylating agent or in the presence of an organic base at a temperature of -20 to 0 0 C. The amount of the acylating agent, preferably the acid halide, is preferably about 1 equivalent per equivalent of ML-236A, ML-236B, MB-5 30A, or MB-53OB.
Der 3,8'-Diester wird hauptsächlich gebildet, wenn man als Acylierungsmittel ein Säureanhydrid oder -halogenid in einer Menge von mindestens 2 Äquivalenten pro Äquivalent ML-236A, ML-2 36B, MB-5 3OA oder MB-53OB einsetzt und die Acylierung in Gegenwart einer organischen Base bei einer Temperatur über Raumtemperatur durchführt.The 3,8'-diester is mainly formed when one is used as Acylating agent an acid anhydride or halide in an amount of at least 2 equivalents per equivalent of ML-236A, ML-2 36B, MB-5 30A or MB-53OB begins and the acylation carried out in the presence of an organic base at a temperature above room temperature.
Die erfindungsgemäßen Verbindungen haben eine spezifische Hemmwirkung gegen die 2-Hydroxy-3-methylglutaryl-Coenzym A-Reduktase (HMG-CoA-Reductase), die das geschwindigkeitsbestimmende Enzym bei der Biosynthese von Cholesterin darstellt. Die Hemmwirkung einiger erfindungsgemäßer Verbindungen bei der Cholesterin-Biosynthese ist in der folgenden Tabelle anhand ihrer I1. -Werte (Konzentration in μΐη/πιΐ, die eine 50prozentige Hemmung der Cholesterin-Biosynthese bewirkt) gezeigt. Die Messung erfolgt nach der Methode von Knaus et al., J. Biol.Chem. Bd. 234, S. 2835 (1959).The compounds according to the invention have a specific inhibitory effect against 2-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), which is the rate-limiting enzyme in the biosynthesis of cholesterol. The inhibiting action of some compounds according to the invention in cholesterol biosynthesis is shown in the table below based on their I 1 . Values (concentration in μΐη / πιΐ, which causes a 50 percent inhibition of cholesterol biosynthesis). The measurement is carried out according to the method of Knaus et al., J. Biol.Chem. Vol. 234, p. 2835 (1959).
Die Herstellung der erfindungsgemäßen Verbindungen ist in den folgenden Beispielen erläutert. Die Herstellung und die Eigenschaften von MB-53OB (Monacolin K), das als Ausgangsmaterial in einigen Beispielen verwendet wird, sind im einzelnen in der USSN 121 515 vom 14.02.1980 und der USSN 137 821 vom 4.O4.198O beschrieben. Die Herstellung und die Eigenschaften von ML-236A und ML-236B sind in der US-PS 3 983 140 beschrieben.The preparation of the compounds according to the invention is in explained in the following examples. The manufacture and properties of MB-53OB (Monacolin K) used as the starting material Used in some examples are detailed in USSN 121 515 dated 02/14/1980 and US Pat USSN 137 821 of 04.04.198O described. The manufacture and the properties of ML-236A and ML-236B are in the U.S. Patent 3,983,140.
Beispiel 1
Herstellung von MB-53OA example 1
Manufacture of MB-53OA
300 Liter eines Kulturmediums, das vor der Sterilisation einen pH von 5,5 hat und 5 % G/V Glucose, 0,5 % G/V Maisque.llflüssigkeit, 2 % G/V Pepton (Marke Kyokuto von der Kyokuto Seiyaku KK, Japan )und 0,5 % Ammoniumchlorid enthält, werden in einen 600 Liter-Fermenter eingebracht und mit einer Kultur von Monascus ruber SANK 15177 (FERM 49 56, NRRL 12081) beimpft. Der Mikroorganismus wird 120 Stunden bei 270C mit einer Belüftungsrate von 300 Liter/min und unter Rühren mit 190 U/min gezüchtet.300 liters of a culture medium that has a pH of 5.5 before sterilization and contains 5% w / v glucose, 0.5% w / v corn squeegee liquid, 2% w / v peptone (Kyokuto brand from Kyokuto Seiyaku KK, Japan) and containing 0.5% ammonium chloride are placed in a 600 liter fermenter and inoculated with a culture of Monascus ruber SANK 15177 (FERM 49 56, NRRL 12081). The microorganism is grown for 120 hours at 27 ° C. with an aeration rate of 300 liters / min and with stirring at 190 rpm.
Anschließend wird die Kulturbrühe durch eine Filterpresse filtriert, wobei ein FiItrat und ein Filterkuchen erhalten werden, der aus feuchten Mikroorganismenzellen besteht. Das Filtrat wird durch Zusatz von 6 N Salzsäure auf einen pH von 3,0 eingestellt und dann mit 400 Liter Ethylacetat extrahiert. Der Extrakt (etwa 400 Liter) wird unter vermindertem Druck eingedampft, über Natriumsulfat getrocknet und hierauf zur Trockene eingedampft, wobei etwa 60 g eines öligen Produkts erhalten werden. Dieses wird mit Ethylcyclohexan und mit Hexan gewaschen, worauf man den Rückstand (20 g) chromatographisch unter Verwendung eines Flüssig-Chromatographen für große Volumenproben (System 500 für die Flussig-Chromatogruphie von der Waters Co., USA.) und KIu Loren rail:The culture broth is then filtered through a filter press, a filtrate and a filter cake being obtained which consists of moist microorganism cells. The filtrate is adjusted to pH by adding 6N hydrochloric acid set of 3.0 and then extracted with 400 liters of ethyl acetate. The extract (about 400 liters) is evaporated under reduced pressure, dried over sodium sulfate and then added evaporated to dryness to give about 60 g of an oily product. This is done with ethylcyclohexane and washed with hexane, whereupon the residue (20 g) is chromatographed using a liquid chromatograph for large volume samples (System 500 for liquid chromatography from Waters Co., USA.) and KIu Loren rail:
60 % V/V wäßrigem Methanol auftrennt. Die Fraktionen mit einer chromatographischen Retentionszeit von 6 Minuten werden gesammelt und unter vermindertem Druck eingedampft, wobei 100 mg des gewünschten MB-53OA als Öliges Produkt erhalten werden. Das ölige MB-53OA wird aus -Aceton/Die thy lether umkristallisiert und ergibt hierbei 57 mg des gewünschten Produkts in Form von farblosen Nadeln mit den folgenden Eigenschaften:60% v / v aqueous methanol separates. The fractions with a chromatographic retention time of 6 minutes will be collected and evaporated under reduced pressure to give 100 mg of the desired MB-53OA as an oily product will. The oily MB-53OA is made from acetone / The thy lether recrystallized to give 57 mg of the desired product in the form of colorless needles with the following Characteristics:
1. Schmelzpunkt: 92 - 93°C.1. Melting point: 92-93 ° C.
2. Elementaranalyse für CigK „0.: C H2. Elemental analysis for C ig K "0 .: CH
ber.: ■ 69,76 %; 8,68 % gef.: 71,22 %; 8,81 %.calc .: ■ 69.76%; 8.68% found: 71.22%; 8.81%.
3. Molekulargewicht: 320 {Massenanalyse)3. Molecular weight: 320 (mass analysis)
4. Summenformel·: C. „!!„„O. .4. Molecular formula ·: C. "!!" "O. .
5. UV-Absorptionsspektrum: siehe Figur 1.5. UV absorption spectrum: see Figure 1.
6. IR-Absorptionsspektrum: siehe Figur 26. IR absorption spectrum: see Figure 2
7. NMR-Spektrum: siehe Figur 37. NMR spectrum: see FIG. 3
8. Löslichkeit: Leicht löslich in Methanol, Ethanol, Aceton, Ethylacetat, Chloroform und Kohlenstofftetrachlorid; löslich in Benzol; unlöslich in Hexan und Petrolether.8. Solubility: Easily soluble in methanol, ethanol, acetone, ethyl acetate, chloroform and carbon tetrachloride; soluble in benzene; insoluble in hexane and petroleum ether.
9. Färbungsreaktion: Bei der Dünnschichtchromatographie auf Silikagel tritt bei der Entwicklung mit 50 % V/V Schwefelsäure eine Rosafärbung auf.9. Coloring reaction: In thin layer chromatography on silica gel, development occurs at 50% v / v Sulfuric acid turns pink.
10. Hemmwirkung bei der Cholesterin-Biosynthese: Bei einer Konzentration von 0,04 μΐη/ml wird eine 50%ige Hemmung der Cholesterin-Synthese in der Rattenleber beobachtet.10. Inhibitory effect in cholesterol biosynthesis: With a Concentration of 0.04 μΐη / ml will result in 50% inhibition of cholesterol synthesis was observed in the rat liver.
Beispiel 2
ML-236A-3-acetat Example 2
ML-236A-3-acetate
918 mg ML-236A und 0,36 ml Pyridin werden in 10 ml Methylenchlorid gelöst und tropfenweise bei einer Temperatur von -20 bis -100C mit 1,0 ml Acetanhydrid versetzt. Nach beendeter Umsetzung versetzt man das Reaktionsgemisch mit Wasser, trennt die Methylenchloridschicht ab, wäscht sie mit Wasser und trocknet über Natriumsulfat. Der durch Abdampfen des Mothylenchlorids erhaltene Rückstand wird durch Säulenchromatographie an Silikagel (10 g) getrennt und aus Diethylether umkristallisiert, wobei 780 mg des gewünschten Produkts erhalten werden, F. 138 bis 1390C.918 mg of ML-236A and 0.36 ml of pyridine are dissolved in 10 ml of methylene chloride and treated dropwise at a temperature from -20 to -10 0 C with 1.0 ml of acetic anhydride. When the reaction has ended, water is added to the reaction mixture, the methylene chloride layer is separated off, washed with water and dried over sodium sulfate. The residue obtained by evaporating the methylene chloride is separated by column chromatography on silica gel (10 g) and recrystallized from diethyl ether, 780 mg of the desired product being obtained, mp 138 to 139 ° C.
Elementaranalyse für C2oH28°5: C H Elemental analysis for C 2o H 28 ° 5 : CH
ber.: 68,97 %; 8,05 %. gef.: 68,99 %; 8,01 %.calc .: 68.97%; 8.05%. found: 68.99%; 8.01%.
-Spektrum (CDCl-) 6 ppm: 1,98 (3H, s); 5,10 (1H, m)-Spectrum (CDCl-) 6 ppm: 1.98 (3H, s); 5.10 (1H, m)
NMRp (l) ppm:NMRp (l) ppm:
IR-Spektrum (Nujol) υ cm : 3400, 1740.IR spectrum (Nujol) υ cm: 3400, 1740.
maxMax
Beispiel 3
ML-236A-3-butyrat Example 3
ML-236A-3-butyrate
Zu einer Lösung von 918 mg ML-236A in 5 ml Pyridin wird 1 ml Butyranhydrid getropft. Nachdem das Gemisch über Nacht bo.i. Raumtemperatur stehengelassen wurde, versetzt man mit Wasser und extrahiert mit Diethylether. Die Etherschicht wird mit einer gesättigten wäßrigen Natriumbicarbonatlosung, einer 1 N HCl und Wasser gewaschen und hierauf über Natriumsulfat getrocknet. Der durch Abdampfen des Diethylethers erhaltene Rückstand wird durch Chromatographieren an Silikagel getrennt und ergibt hierbei 930 mg des gewünschten Produkts.1 ml of butyranhydride is added dropwise to a solution of 918 mg of ML-236A in 5 ml of pyridine. After the mixture bo.i. Was left to stand at room temperature, water is added and the mixture is extracted with diethyl ether. The ether layer is with a saturated aqueous sodium bicarbonate solution, 1 N HCl and water and then washed over sodium sulfate dried. The residue obtained by evaporating the diethyl ether is separated by chromatography on silica gel and thereby gives 930 mg of the desired product.
Elementaranalyse für C22H32°5: C H Elemental analysis for C 22 H 32 ° 5 : CH
ber.: 70,21 %; 8,51 % gef.: 69,96 %; 8,69 %.calc .: 70.21%; 8.51% found: 69.96%; 8.69%.
NMR-Spektrum (CDCl3) öppm: 0,95 (3H, t) ; 4,27 (1H, m); 5,32 (1H, m).Nuclear Magnetic Resonance Spectrum (CDCl 3 ) rpm: 0.95 (3H, t); 4.27 (1H, m); 5.32 (1H, m).
IR-Spektrum (Film) vmnv cm"1: 3480, 1740.IR spectrum (film) v mnv cm " 1 : 3480, 1740.
Iu el λIu el λ
Beispiel 4 ML-236A-3-butyrat Example 4 ML-236A-3-butyrate
Gemäß Beispiel 2 werden 853 mg des gewünschten Produkts, das dieselben Eigenschaften wie das Produkt von Beispiel 3 hat, aus 918 mg ML-236A und 0,32 ml Butyrylchlorid hergestellt. According to Example 2, 853 mg of the desired product, which has the same properties as the product of Example 3 made from 918 mg of ML-236A and 0.32 ml of butyryl chloride.
Beispiel 5 ML-236A-3-isobutyrat Example 5 ML- 236A-3-isobutyrate
Gemäß Beispiel 2 werden 841 mg des gewünschten Produkts aus 918 mg ML-236A und 0,32 ml Isobutyrylchlorid hergestellt.According to Example 2, 841 mg of the desired product are prepared from 918 mg of ML-236A and 0.32 ml of isobutyryl chloride.
Elementaranalyse für C 22H32°5: C H Elemental analysis for C 2 2 H 32 ° 5 : CH
ber.: . 70,21 %; 8,51 %.ber .:. 70.21%; 8.51%.
gef.: 69,84 %; 8,32 %.found: 69.84%; 8.32%.
NMR-Spektrum (CDCl3) δ ppm: 1,17 (6H, d); 4,27 (1H, m);Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 1.17 (6H, d); 4.27 (1H, m);
5,25 (1H, m) .5.25 (1H, m).
IR-Spektrum (Film) ν cm"1: 3440, 1730, 1720.IR spectrum (film) ν cm " 1 : 3440, 1730, 1720.
maxMax
Gemäß Beispiel 2 werden 834 mg des gewünschten Produkts aus 918 mg ML-236A und 0,39 ml 4-Pentenoylchiorid hergestellt.According to Example 2, 834 mg of the desired product are prepared from 918 mg of ML-236A and 0.39 ml of 4-pentenoyl chloride.
Elementaranalyse für C73H32O-: C HElemental analysis for C 73 H 32 O-: CH
ber.: 71,13 %; 8,25 % gef.: 71,43 %; 8,00 %.calc .: 71.13 %; 8.25% found: 71.43%; 8.00%.
NMR-Spektrum (CDCl3) 5 ppm: 4,27 (1H, m); 4,8 - 6,2 (7H, m).Nuclear Magnetic Resonance Spectrum (CDCl 3 ) 5 ppm: 4.27 (1H, m); 4.8 - 6.2 (7H, m).
IR-Spektrum (Film) vmax cm"1: 3400, 1730, 1640.IR spectrum (film) v max cm " 1 : 3400, 1730, 1640.
ML-236A-3-isovalerat ML-236A-3-isova lerat
Gemäß Beispiel 2 werden 894 mg des gewünschten Produkts aus 918 mg ML-236A und 0,40 ml Isovalerylchlorid hergestellt.According to Example 2, 894 mg of the desired product are prepared from 918 mg of ML-236A and 0.40 ml of isovaleryl chloride.
Elementaranalyse für C73H34O1-: C HElemental analysis for C 73 H 34 O 1 -: CH
ber.: 70,77 %; 8,72 %.calc .: 70.77%; 8.72%.
gef.: 70,61 %; 8,80 %.found: 70.61%; 8.80%.
NMR-Spektrum (CDCl3) δ ppm: 0,95 (6H, d) ; 4,23 (1H, m) ;Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ pp m : 0.95 (6H, d); 4.23 (1H, m);
5,27 (1H, m).5.27 (1H, m).
IR-Spektrum (Film) υ cm" : 3460, 1740.IR spectrum (film) υ cm ": 3460, 1740.
ML-236A-3-hexanoatML-236A-3-hexanoate
(F. 70 bis 72°C) aus 2,70 g ML-236A und 1,36 ml Hexanoyl-(M.p. 70 to 72 ° C) from 2.70 g ML-236A and 1.36 ml hexanoyl
Gemäß Beispiel 2 werden 2,-90 g des gewünschten Produkts
(F. 70 bis 72°C) aus
Chlorid hergestellt.According to Example 2, 2.90 g of the desired product (melting point 70 to 72 ° C.) are obtained
Chloride produced.
Elementaranalyse fürElemental analysis for
Beispiel 9 ML-236A-3-octanoat Example 9 ML-236A-3-octanoate
Gemäß Beispiel 2 werden 690 mg des gewünschten Produkts aus 612 mg ML-236A und 0,54 ml Octanoylchlorid hergestellt.According to Example 2, 690 mg of the desired product are prepared from 612 mg of ML-236A and 0.54 ml of octanoyl chloride.
Elementaranalyse für c 2gH4o°5 : C H Elemental analysis for c 2 g H 40 ° 5 : CH
ber.: 7 2,22 %; 9,26 %: gef.: 72,45 %; 9,12 %.calc .: 7 2.22%; 9.26%: found: 72.45%; 9.12%.
NMR-Spektrum (CDCl3) δ ppm: 0,88 (3H, br t) ; 4,28 (1H, πι); 5,33 (1H, m).Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.88 (3H, br t); 4.28 (1H, πι); 5.33 (1H, m).
IR-Spektrum (Film) ν cm" : 3450, 1735.IR spectrum (film) ν cm ": 3450, 1735.
ItIcLJCItIcLJC
Beispiel 10 ML-236A-3- palmitat Example 10 ML-236A-3 palmitate
Gemäß Beispiel 2 werden 749 mg des gewünschten Produkts aus 827 mg ML-236A und 0,82 g Palmitoylchlorid hergestellt.According to Example 2, 749 mg of the desired product are prepared from 827 mg of ML-236A and 0.82 g of palmitoyl chloride.
Elementaranalyse für C34H56O : C HElemental analysis for C 34 H 56 O: CH
ber.: 75,00 %; 10,29 %.calc .: 75.00%; 10.29%.
gef.: 74,89 %; 10,35 %.found: 74.89%; 10.35%.
NMR-Spektrum (CDCl3) δρρπι: 0,90 (3H, br t) ; 1,27 (24H, br s) ;Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δρρπι: 0.90 (3H, br t); 1.27 (24H, br s);
4,27 (1H, m) ; 5,32 (1H, m) .4.27 (1H, m); 5.32 (1H, m).
IR-Spektrum (Film) υ cm"1: 3460, 1735.IR spectrum (film) ½ cm " 1 : 3460, 1735.
maxMax
Beispiel 11 ML-236A-3-linoleat Example 11 ML-236A-3 linoleate
Gemäß Beispiel 2 werden 897 mg des gewünschten Produkts aus 918 mg ML-236A und 1,03 g Linoleylchlorid hergestellt.According to Example 2, 897 mg of the desired product are prepared from 918 mg of ML-236A and 1.03 g of linoleyl chloride.
Eleraentaranalyse für C3gH5g°5: c H Elemental analysis for C 3g H 5g ° 5 : c H
ber.: 76,06 %; 9,86 %: gef.: 76,24 %; 9,96 %.calc .: 76.06%; 9.86%: found: 76.24%; 9.96%.
NMR-Spektrum (CDCl3) 6 ppm: 0,90 (3H, br. t); 1,32 (18H, br s);Nuclear Magnetic Resonance Spectrum (CDCl 3 ) 6 ppm: 0.90 (3H, br. T); 1.32 (18H, br s);
4,27 (1H7 m). ·4.27 (1H 7 m). ·
IR-Spektrum (Film) ν cm"1: 3460, 1740.IR spectrum (film) ν cm " 1 : 3460, 1740.
ΠΙ 3.xΠΙ 3.x
Beispiel 12 MB-5 3 OA-3-butyrat Example 12 MB-5 3 OA-3-butyrate
Gemäß Beispiel 2 werden 250 mg des gewünschten Produkts aus 300 mg MB-53OA und 0,47 ml Butyrylchlorid hergestellt.According to Example 2, 250 mg of the desired product are prepared from 300 mg of MB-53OA and 0.47 ml of butyryl chloride.
Elementaranalyse für C23H O5: C HElemental analysis for C 23 HO 5 : CH
ber. : 70,77 %; . 8,72 %." gef.: 70,60 %; 8,89 %.calc .: 70.77%; . 8.72%. "Found: 70.60%; 8.89%.
NMR-Spektrum (CDCl3) δ ppm: 0,90 (3H, t); 4,17 (1H, m); 5,22 (1H, m).Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.90 (3H, t); 4.17 (1H, m); 5.22 (1H, m).
IR-Spektrum (Film) V^ cm" : 3450, 1730.IR spectrum (film) V ^ cm ": 3450, 1730.
Beispiel 13 MB-530A-3-isovalerat Example 13 MB-530A-3 isovalerate
Gemäß Beispiel 2 werden 235 mg des gewünschten Produkts aus 320 mg MB-53OA und 0,47 ml Isovalerylchlorid hergestellt. According to Example 2, 235 mg of the desired product are prepared from 320 mg of MB-53OA and 0.47 ml of isovaleryl chloride.
Elementaranalyse für C24H3fi°5: Elemental analysis for C 24 H 3fi ° 5 :
ber.: 71,29 %; 8,91 %.calc .: 71.29%; 8.91%.
gef.: 71,20 %; 8,87 %.found: 71.20%; 8.87%.
NMR-Spektrum (CDCl3) δ ppm: 0,89 (6H, d); 4,16 (1H, m) ;
5,22 (1H, m).
IR-Spektrum (Nujol) ν cm"1: 3510, 1730, 1710.Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.89 (6H, d); 4.16 (1H, m); 5.22 (1H, m).
IR spectrum (Nujol) ν cm " 1 : 3510, 1730, 1710.
Beispiel 14
MB-5 3 OA-3-hexanoat Example 14
MB-5 3 OA-3-hexanoate
Gemäß Beispiel 2 werden 410 mg des gewünschten Produkts aus 420 mg MB-53OA und 0,21 ml Hexanoylchlorid hergestellt.According to Example 2, 410 mg of the desired product are prepared from 420 mg of MB-53OA and 0.21 ml of hexanoyl chloride.
Elementaranalyse für C35H „0-: C HElemental analysis for C 35 H "0-: CH
ber.: 71,77 %; 9,09 %calc .: 71.77%; 9.09%
gef.: 71,55 %; 9,19 %.found: 71.55%; 9.19%.
NMR-Spektrum (CDCl3) δρρπι: 0,88 (3H, br t) ; 4,19 {1H, m) ;Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δρρπι: 0.88 (3H, br t); 4.19 (1H, m);
5,25 (1H, m).5.25 (1H, m).
IR-Spektrum (Film) υ cm" : 3400, 1730. ^ maxIR spectrum (film) υ cm ": 3400, 1730. ^ max
Beispiel 15
MB-5 30A-3-octanoat Example 15
MB-5 30A-3-octanoate
Gemäß Beispiel 2 werden 340 mg des gewünschten Produkts aus 322 mg MB-53OA und 0,28 ml Octanoylchlorid hergestellt:According to Example 2, 340 mg of the desired product are obtained 322 mg MB-53OA and 0.28 ml octanoyl chloride prepared:
Elementaranalyse für C27H4^O1-: C HElemental analysis for C 27 H 4 ^ O 1 -: CH
ber.: 72,65 %; 9,42 %.calc .: 72.65%; 9.42%.
gef.: 72,44 %; 9,34 %.found: 72.44%; 9.34%.
NMR-Spektrum (CDCl3) δ ppm: 0,84 (3H, br t); 1,21 (12H, br s);Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.84 (3H, br t); 1.21 (12H, br s);
4,18 (1H, m); 5,23 (1H, m).4.18 (1H, m); 5.23 (1H, m).
IR-Spektrum (Film) v^,, cm"1: 3400, 1730.IR spectrum (film) v ^ "cm" 1 : 3400, 1730.
Beispiel 16
ML-2 3 6 A-8'-butyrat Example 16
ML-2 3 6 A-8'-butyrate
918 mg ML-236A und 0,36 ml Pyridin werden in 10 ml Methylen chlorid gelöst. Zu der auf 00C gekühlten Lösung wird Butyrylchlorid getropft. Nach beendeter Umsetzung versetzt man das Reaktionsgemisch mit Wasser, trennt die Methylenchlorid schicht ab, wäscht sie mit Wasser und trocknet sie über918 mg of ML-236A and 0.36 ml of pyridine are dissolved in 10 ml of methylene chloride. Butyryl chloride is added dropwise to the solution, which has been cooled to 0 ° C. After the reaction has ended, water is added to the reaction mixture, the methylene chloride layer is separated off, washed with water and dried over
■Natriumsulfat. Der durch. Abdampfen des Methylenchlorids erhaltene Rückstand wird durch Säulenchromatographie an Silicagel (10 g) getrennt. Durch Umkristallisieren aus Diethyläther erhält man 395 mg des gewünschten Produkts, P. 124 bis 125°C.■ sodium sulfate. The through. Evaporation of the methylene chloride obtained The residue is separated by column chromatography on silica gel (10 g). By recrystallization from diethyl ether 395 mg of the desired product are obtained, P. 124 to 125 ° C.
Elementaranalyse für ^22Η32°Γ: C IIElemental analysis for ^ 22 Η 32 ° Γ : C II
ber.: 70,21 %; 8,51 %. gef.: 70,25 %; 8,50 %.calc .: 70.21%; 8.51%. found: 70.25%; 8.50%.
NMR-Spektrum (CDCl ) δ ppm: 0,95 (3H, t); 4,42 (1H, m), 5,43 (1H, m).Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 0.95 (3H, t); 4.42 (1H, m), 5.43 (1H, m).
IR-Spektrum (Nujol) ν cm"1: 3400, 1730, 1710.IR spectrum (Nujol) ν cm " 1 : 3400, 1730, 1710.
JUdLXJUdLX
Gemäß Beispiel 16 werden 100 mg des gewünschten Produkts aus 285 mg ML-236A und 0,11 ml Isobutyrylchlorid hergestellt.According to Example 16, 100 mg of the desired product made from 285 mg of ML-236A and 0.11 ml of isobutyryl chloride.
Elementaranalyse für C22H32°5: C H Elemental analysis for C 22 H 32 ° 5 : CH
ber.: 70,21 %; 8,51 %. gef.: 70,05 %; 8,67 %.calc .: 70.21%; 8.51%. found: 70.05%; 8.67%.
NMR-Spektrum (CDCl3) δ ppm: 1,14 (6H, d); 4,35 (1H, m); 5,32 (1H, m) .Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 1.14 (6H, d); 4.35 (1H, m); 5.32 (1H, m).
IR-Spektrum (Film) ν cm"1: 3400, 1730, 1700.IR spectrum (film) ν cm " 1 : 3400, 1730, 1700.
ΓΩ.3.ΧΓΩ.3.Χ
Beispiel 18 ML-236A-8'-(4-pentenoat) Example 18 ML-236A-8 '- (4-pentenoate)
Gemäß Beispiel 16 werden 370 mg des gewünschten Produkts aus 918 mg ML-236A und 0,39 ml 4-Pentenoylchlorid hergestellt. According to Example 16, 370 mg of the desired product are prepared from 918 mg of ML-236A and 0.39 ml of 4-pentenoyl chloride.
Elementaranalyse für C.-H^-Oj-: C HElemental analysis for C.-H ^ -Oj-: C H
ber.: 71,13 %; 8,25 S. gef.: 70,82 %; 8,33 %.calc .: 71.13%; 8.25 S. found: 70.82%; 8.33%.
NMR-Spektrum (CDCl3) δ ppm: 4,14 (1H,'m); 4,8 - 6,2 (8H, m).Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 4.14 (1H, 'm); 4.8 - 6.2 (8H, m).
IR-Spektrum (Film) vm=v cm"1: 3400, 1730.IR spectrum (film) v m = v cm " 1 : 3400, 1730.
maxMax
Beispiel 19 ML-236A-8'-isovalerat Example 19 ML-236A-8'-isovalerate
Gemäß Beispiel 16 werden 365 mg des gewünschten Produkts aus 918 mg ML-236A und 0,47 ml Isovalerylchlorid hergestellt.According to Example 16, 365 mg of the desired product are prepared from 918 mg of ML-236A and 0.47 ml of isovaleryl chloride.
Elementaranalyse für C33H34O5: C HElemental analysis for C 33 H 34 O 5 : CH
ber.: 70,77 %; 8,72 %. gef.: 70,59 %; 8,90 %.calc .: 70.77%; 8.72%. found: 70.59%; 8.90%.
NMR-Spektrum (CDCl3) δ ppm: 0,93 (6H, d) ,- 4,35 (1H, m) ,-5,35 (1H, m).Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.93 (6H, d), -4.35 (1H, m), -5.35 (1H, m).
IR-Spektrum (Film) ν . cm"1: 3430, 1730, 1710.IR spectrum (film) ν. cm " 1 : 3430, 1730, 1710.
ill 3, Xill 3, X
Beispiel 20 ML-236A-8'-hexanoat Example 20 ML-236A-8'-hexanoate
Gemäß Beispiel 16 werden 408 mg des gewünschten Produkts aus 918 mg ML.-236A und 0,46 ml Hexanoylchlorid hergestellt.According to Example 16, 408 mg of the desired product are prepared from 918 mg of ML.-236A and 0.46 ml of hexanoyl chloride.
Elementaranalyse für C24H36°5: "C HElemental analysis for C 24 H 36 ° 5 : "CH
ber.: 71,29 %; 8,91 %. gef.: 71,07 %; 9,01 %.calc .: 71.29%; 8.91%. found: 71.07%; 9.01%.
NMR-Spektrum (CDCl3) δ ppm: 0,87 (3H, t); 4,32 (1H, m); 5,32 (1H, m).Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.87 (3H, t); 4.32 (1H, m); 5.32 (1H, m).
IR-Spektrum (Film) ν cm"1: 3400, 1720, 1710.IR spectrum (film) ν cm " 1 : 3400, 1720, 1710.
maxMax
Beispiel 21 ML-236Ä-8'-octanoab Example 21 ML-236A-8'-octanoab
Gemäß Beispiel 16 werden 462 mg des gewünschten Produkts aus 918 mg ML-236A und 0,54 ml Octanoylchlorid hergestellt.According to Example 16, 462 mg of the desired product are prepared from 918 mg of ML-236A and 0.54 ml of octanoyl chloride.
Elementaranalyse für C26H4O°5: C H Elemental analysis for C 26 H 4O ° 5 : CH
ber.: 72,22 %; 9,26 %.calc .: 72.22%; 9.26%.
gef.: 72,04 %; 9,10 %.found: 72.04%; 9.10%.
NMR-Spektrum (CDCl3) δ ppm: 0,88 (3H, br t) ; 1,28 (12ίΙ, br s) ;Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.88 (3H, br t); 1.28 (12ίΙ, br s);
4,42 (1H, m); 5,42 (1H, m).4.42 (1H, m); 5.42 (1H, m).
IR-Spektrum (Film) ν cm"1: 3470, 1735.IR spectrum (film) ν cm " 1 : 3470, 1735.
ITlclXITlclX
Beispiel 22 ML-236A-8'-palmitat Example 22 ML-236A-8'-palmitate
Gemäß Beispiel 16 werden 490 mg des gewünschten Produkts aus 918 mg ML-236A und 640 mg Palmitoylchlorid hergestellt.According to Example 16, 490 mg of the desired product are prepared from 918 mg of ML-236A and 640 mg of palmitoyl chloride.
Elementaranalyse für C34H5OO5: C HElemental analysis for C 34 H 5 OO 5 : CH
ber.: 74,73 %; 10,62 %.calc .: 74.73%; 10.62%.
gef.: 74,56 %; 10,78 %.found: 74.56%; 10.78%.
NMR-Spektrum (CDCl3) δ ppm: 0,88 (3H, br t); 1,28 (24H, br s);Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.88 (3H, br t); 1.28 (24H, br s);
4,38 (1H, m); 5,40 (1H, m).4.38 (1H, m); 5.40 (1H, m).
IR-Spektrum (Film) ν cm"1 : 3450, 1735.IR spectrum (film) ν cm " 1 : 3450, 1735.
Beispiel 23 ML-236A-8'-linoleat Example 23 ML-236A-8'-linoleate
Gemäß Beispiel 16 werden 415 mg des gewünschten Produkts aus 918 ml ML-236A und 1,0 g Linoleylchlorid hergestellt.According to Example 16 there are 415 mg of the desired product made from 918 ml ML-236A and 1.0 g linoleyl chloride.
Elementaranalyse für C36H56O5: C HElemental analysis for C 36 H 56 O 5 : CH
ber.: 76,06 %; 9,86 %.calc .: 76.06%; 9.86%.
gef.: 76,23 %; 10,03 %.found: 76.23%; 10.03%.
NMR-Spektrum (CDCl3) δ ppm: 0,90 (3H, br t); 1,32 (18H, br s);Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.90 (3H, br t); 1.32 (18H, br s);
4,40 (1H, m); 5,2 - 5,5 (5H, m).4.40 (1H, m); 5.2 - 5.5 (5H, m).
IR-Spektrum (Film) ν cm"1: 3440, 1735.IR spectrum (film) ν cm " 1 : 3440, 1735.
ITl clXITl clX
Beispiel 24 MB-5 3OA-8'-butyrat Example 24 MB-5 3OA-8'-butyrate
Gemäß Beispiel 16 werden 154 mg des gewünschten Produkts aus 309 mg MB-53OA und 0,16 ml Butyrylchlorid hergestellt.According to Example 16, 154 mg of the desired product are prepared from 309 mg of MB-53OA and 0.16 ml of butyryl chloride.
Elementaranalyse für C33H .O5: C HElemental analysis for C 33 H .O 5 : CH
ber.: 70,77 %; 8,72 %.calc .: 70.77%; 8.72%.
gef.: 70,58 %; 8,61 %.found: 70.58%; 8.61%.
NMR-Spektrum (CDCl3) öppm: 0,90 (3H, t); 4,17 (1H, m) ;Nuclear Magnetic Resonance Spectrum (CDCl 3 ) rpm: 0.90 (3H, t); 4.17 (1H, m);
5,22 (1H, m).5.22 (1H, m).
IR-Spektrum (Film) ν cm"1: 3450, 1730.IR spectrum (film) ν cm " 1 : 3450, 1730.
maxMax
Beispiel 25 MB-53OA-8'-isovalerat Example 25 MB-53OA-8'-isovalerate
Gemäß Beispiel 16 werden 109 mg des gewünschten Produkts aus 308 mg MB-53OA und 0,12 ml Isovalerylchlorid hergestellt. According to Example 16, 109 mg of the desired product are prepared from 308 mg of MB-53OA and 0.12 ml of isovaleryl chloride.
Elementaranalyse für C24H36°5: C H Elemental analysis for C 24 H 36 ° 5 : CH
ber.: 71,29 %; 8,91 %.calc .: 71.29%; 8.91%.
gef.: 71 ,17 %; 8,69 %.found: 71.17%; 8.69%.
NMR-Spektrum (CDCl3) δ ppm: 0,88 (6H, d); 4,15 (1H, m);Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.88 (6H, d); 4.15 (1H, m);
5,22 (1H, m).5.22 (1H, m).
IR-Spektrum (Film) ν cm"1: 3420, 1730.IR spectrum (film) ν cm " 1 : 3420, 1730.
maxMax
Beispiel 26 MB-53OA-8'-hexanoat Example 26 MB-53OA-8'-hexanoate
Gemäß Beispiel 16 werden 87 mg des gewünschten Produkts aus 308 mg MB-53OA und 0,15 ml Hexanoylchlorid hergestellt.According to Example 16, 87 mg of the desired product are prepared from 308 mg of MB-53OA and 0.15 ml of hexanoyl chloride.
Elementaranalyse für. C-cH^O,.: C HElemental analysis for. C-cH ^ O,.: C H
ber.: 71,77 %; 9,09 %.calc .: 71.77%; 9.09%.
gef.: 71,95 %; 9,17 %.found: 71.95%; 9.17%.
NMR-Spektrum (CDCl3) δ ppm: 0,90 (3H, t); 4,33 (1H, m),Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.90 (3H, t); 4.33 (1H, m),
5,33 (1H, m).5.33 (1H, m).
IR-Spektrum (Film) ν cm"1: 3440, 1735.IR spectrum (film) ν cm " 1 : 3440, 1735.
maxMax
MB-53OA-8'-octanoab MB-53OA-8'-octanoa b
Gemäß Beispiel 16 werden 96 mg des gewünschten Produkts aus 304 mg MB-53OA und 0,11 ml Octanoylchlorid hergestellt. According to Example 16, 96 mg of the desired product are prepared from 304 mg of MB-53OA and 0.11 ml of octanoyl chloride.
Elementaranalyse für Cp7H^^Oc.'· ^- ^Elemental analysis for Cp 7 H ^ ^ Oc. '· ^ - ^
ber.: 72,65 %; 9,42 %.calc .: 72.65%; 9.42%.
gef.: 72,52 %; 9,50 %.found: 72.52%; 9.50%.
NMR-Spektrum (CDCl3) δ ppm: 0,85 (3H, br t) ; 1,22 (12H, br s) ;.Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.85 (3H, br t); 1.22 (12H, br s);
4,19 (1H, m); 5,23 (1H, m).4.19 (1H, m); 5.23 (1H, m).
IR-Spektrum (Film) ν cm"1: 3400, 1735. ^ ' maxIR spectrum (film) ν cm " 1 : 3400, 1735. ^ ' max
Beispiel 28 ML-236A-3,8'-diacetat Example 28 ML-236A-3,8'-diacetate
Gemäß Beispiel 3 werden 914 mg des gewünschten Produkts aus 918 mg ML-236A, 5 ml Pyridin und 1 ml Acetanhydrid hergestellt. According to Example 3, 914 mg of the desired product are obtained made from 918 mg ML-236A, 5 ml pyridine and 1 ml acetic anhydride.
Elementaranalyse für c 22H3O°6: C H Elemental analysis for c 2 2 H 3O ° 6 : CH
ber.: 67,69 %; 7,69 %.calc .: 67.69%; 7.69%.
gef.: 67,44 %; 7,79 %.found: 67.44%; 7.79%.
NMR-Spektrum (CDCl3) δ ppm: 1,89 (6H, s); 5,10 (2H, m).Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 1.89 (6H, s); 5.10 (2H, m).
IR-Spektrum (Film) ν cm"1: 1735, 1250, 11701IR spectrum (film) ν cm " 1 : 1735, 1250, 11701
ms χms χ
Beispiel 29
ML-236Ä-3,8'-dibutyrat Example 29
ML-236E-3,8'-dibutyrate
306 mg ML-236A und 0,5 ml Pyridin werden in 3 ml Methylenchlorid gelöst, worauf man die erhaltene Lösung unter Eiskühlung mit 0,5 ml Butyrylchlorid versetzt. Das Gemisch wird 1 Stunde bei Raumtemperatur gerührt und dann gemäß Beispiel 2 weiter verarbeitet. Der erhaltene Rückstand ergibt beim Chromatographieren 384 mg des gewünschten Produkts.306 mg of ML-236A and 0.5 ml of pyridine are dissolved in 3 ml of methylene chloride dissolved, whereupon the resulting solution is treated with 0.5 ml of butyryl chloride while cooling with ice. The mixture is stirred for 1 hour at room temperature and then processed according to Example 2 further. The residue obtained gives on chromatography, 384 mg of the desired product.
Elementaranalyse für C„,H_„Ofi: C HElemental analysis for C ", H_" O fi : CH
ber.: 69,96 %; 8,52 %. gef.: 70,14 %; 8,31 %. calc .: 69.96%; 8.52%. found: 70.14%; 8.31 %.
NMR-Spektrum (CDCl3) δ ppm: 0,93 (6H, t); 5,2 - 5,5 (2H, m).Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.93 (6H, t); 5.2 - 5.5 (2H, m).
IR-Spektrum (Film) ν cm"1: 1735, 1250, 1175.IR spectrum (film) ν cm " 1 : 1735, 1250, 1175.
Beispiel 30
ML-236A-3,8'-bis(4-pentenoat) Example 30
ML-236A-3,8'-bis (4-pentenoate)
Gemäß Beispiel 29 werden 405 mg des gewünschten Produkts aus 306 mg ML-236A, 0,5 ml Pyridin und 0,4 ml 4-Pentenoylchlorid hergestellt.According to Example 29, 405 mg of the desired product are obtained from 306 mg of ML-236A, 0.5 ml of pyridine and 0.4 ml of 4-pentenoyl chloride manufactured.
Elementaranalyse für C28Ht8°6: C H Elemental analysis for C 28 H t8 ° 6 : CH
ber.: 71,48 %; 8,09 %. gef.: 71,25 %; 8,30 %.calc .: 71.48%; 8.09%. found: 71.25%; 8.30%.
NMR-Spektrum (CDCl3) δ ppm: 4,8 - 6,2 (11H, m). ' IR-Spektrum (Film) ν cm"1: 1735, 1640, 1460, 1240, 1170.Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 4.8-6.2 (11H, m). 'IR spectrum (film) ν cm " 1 : 1735, 1640, 1460, 1240, 1170.
Beispiel 31
ML-2 36A-3,8'-dioctanoat
Gemäß Beispiel 29 werden 1,7 g des gewünschten Produkts ausExample 31
ML-2 36A-3,8'-dioctanoate
According to Example 29, 1.7 g of the desired product are obtained
- 41 918 mg ML-236A und 1,4 ml Octanoylchlorid hergestellt.- Prepared 41,918 mg of ML-236A and 1.4 ml of octanoyl chloride.
Elementaranalvse für C_,HC.O : C HElemental analysis for C_, H C .O: CH
ber.: 73,12 %; 9,68 %. gef.: 72,95 %; 9,79 %.calc .: 73.12%; 9.68%. found: 72.95%; 9.79%.
NMR-Spektrum (CDCl3) δ ppm: 0,88 (6H, br t) ; 1,32 (24H, br s); 5,2 - 5,5 (2H, m).Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.88 (6H, br t); 1.32 (24H, br s); 5.2 - 5.5 (2H, m).
IR-Spektrum (Film) ν cm"1: 1735, 1460, 1250, 1165.IR spectrum (film) ν cm " 1 : 1735, 1460, 1250, 1165.
ItI 3. XItI 3. X
Beispiel 32 ML-236A-3,8'-dipalmitat Example 32 ML-236A-3,8'-dipalmitate
Gemäß Beispiel 29 werden 1,0 g des gewünschten Produkts aus 415 mg ML-236A und 0,71 ml Palmitoylchlorid hergestellt. According to Example 29, 1.0 g of the desired product is prepared from 415 mg of ML-236A and 0.71 ml of palmitoyl chloride.
Elementaranalyse für C50Ho6O1-: C HElemental analysis for C 50 Ho 6 O 1 -: CH
ber.: 76,73 %; 11,00 %. gef.: 76,99 %; 10,81 %.calc .: 76.73%; 11.00%. found: 76.99%; 10.81%.
NMR-Spektrum (CDCl3) ö ppm: 0,87 (6H, br t); 1,25 (52H, br s); 5,2 - 5,5 (2H, m).Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.87 (6H, br t); 1.25 (52H, br s); 5.2 - 5.5 (2H, m).
IR-Spektrum (Film) ν . cm" : 1735, 1460.IR spectrum (film) ν. cm ": 1735, 1460.
Gemäß Beispiel 29 werden 804 mg des gewünschten Produkts aus 306 mg ML-236A und 0,6 ml Linoleylchlorid hergestellt.According to Example 29, 804 mg of the desired product are prepared from 306 mg of ML-236A and 0.6 ml of linoleyl chloride.
Elementaranalyse für C54Hn^O6: C HElemental analysis for C 54 Hn ^ O 6 : CH
ber.: 78,07 %; 10,36 %. gef.: 78,30 %: 10,19 %calc .: 78.07%; 10.36%. found: 78.30%: 10.19%
NMR-Spektrum (CDCl3) δ ppm: 0,90 (6H, br t) 1,30 (36H, br s); 5,1 - 6,2 (13H, m).Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.90 (6H, br t) 1.30 (36H, br s); 5.1 - 6.2 (13H, m).
IR-Spektrum (Film) ν cm"1: 1740, 1460, 1240, 1170.IR spectrum (film) ν cm " 1 : 1740, 1460, 1240, 1170.
IQcL XIQcL X
Beispiel 34 MB-5 3OA-3,8'-dihexanoat Example 34 MB-5 30A-3,8'-dihexanoate
Gemäß Beispiel 29 werden 440 mg des gewünschten Produkts aus 330 mg MB-53OA und 0,5 ml Hexanoylchlorid hergestellt.According to Example 29, 440 mg of the desired product are prepared from 330 mg of MB-53OA and 0.5 ml of hexanoyl chloride.
Elementaranalyse für C3oH4R°6: C H Elemental analysis for C 3o H 4R ° 6 : CH
ber.: 71,43%; 9,52 %.calc .: 71.43%; 9.52%.
gef.: 71,58%; 9,30 %.found: 71.58%; 9.30%.
NMR-Spektrum (CDCl3) δ ppm: 0,86 (3H, br t); 0,91 (3H, br t);Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.86 (3H, br t); 0.91 (3H, br t);
5,0 - 6,1 (5H, m).5.0 - 6.1 (5H, m).
IR-Spektrum (Film) v cm" : 1730.IR spectrum (film) v cm ": 1730.
c max c max
Beispiel 35 MB-5 30A-3,8'-dioctanoat Example 35 MB-5 30A-3,8'-dioctanoate
Gemäß Beispiel 29 werden 498 mg des gewünschten Produkts, aus 330 mg MB-53OA, 0,5 ml Pyridin und 0,5 ml Octanoylchlorid hergestellt.According to Example 29, 498 mg of the desired product, made from 330 mg of MB-53OA, 0.5 ml of pyridine and 0.5 ml of octanoyl chloride.
Elementaranalyse für C34H56O6: C HElemental analysis for C 34 H 56 O 6 : CH
ber.: 72,85 %; 10,00 %.calc .: 72.85%; 10.00%.
gef.: 72,58 %; 10,18 %.found: 72.58%; 10.18%.
NMR-Spektrum (CDCl3) δ ppm: 0,82 (3H, br t) ,- 0,91 (3H, br m) ;Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 0.82 (3H, br t), -0.91 (3H, br m);
5,0 - 6,1 (5H, m).5.0 - 6.1 (5H, m).
IR-Spektrum (Film) v cm"1: 1730. ^ maxIR spectrum (film) v cm " 1 : 1730. ^ max
Beispiel 36 ML-236B-acetat Example 36 ML-236B acetate
7,8 g ML-236B werden in 10 ml trockenem Pyridin gelöst und mit 4,5 ml destilliertem Acetanhydrid versetzt. Das Reaktionsgemisch wird 1 Stunde unter Rühren auf 40 bis 45°C erhitzt. 7.8 g of ML-236B are dissolved in 10 ml of dry pyridine, and 4.5 ml of distilled acetic anhydride are added. The reaction mixture is heated to 40 to 45 ° C. for 1 hour while stirring.
Hierauf gießt man das Reaktionsgemisch in mit Salzsäure angesäuertes Eiswasser und extrahiert mit Benzol. Die Benzolschicht wird mit Wasser gewaschen und über Natriumsulfat getrocknet. Das durch Abdampfen des Lösungsmittels erhaltene ölige Produkt wird durch Chromatographieren an Silikagel mit Benzol/Ethylacetat als Eluiermittel getrennt und ergibt hierbei 7,3 g ML-236B-acetat als öliges Produkt. Dieses wird aus wäßrigem Ethanol umkristallisiert und ergibt hierbei 6,6 g ML-236B-acetat in Form weißer Kristalle, F. 48 bis 51°C.The reaction mixture is then poured into ice water acidified with hydrochloric acid and extracted with benzene. The benzene layer is washed with water and dried over sodium sulfate. That obtained by evaporation of the solvent Oily product is separated by chromatography on silica gel with benzene / ethyl acetate as the eluent and this gives 7.3 g of ML-236B acetate as an oily product. This is recrystallized from aqueous ethanol and gives 6.6 g of ML-236B acetate in the form of white crystals, mp 48 to 51 ° C.
Elementaranalyse für C35H^6O,: C HElemental analysis for C 35 H ^ 6 O ,: CH
ber.: 69,44 %; 8,33 %.calc .: 69.44%; 8.33%.
gef.: 69,35 %; 8,50 %.found: 69.35%; 8.50%.
NMR-Spektrum (CDCl3) δ ppm: 6,05 (1H, d); 5,80 (1H, dd);Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 6.05 (1H, d); 5.80 (1H, dd);
2,8 (2H, d); 2,1 (3H, s).2.8 (2H, d); 2.1 (3H, s).
IR-Spektrum (KBr) ν cm"1: 1740, 1710.IR spectrum (KBr) ν cm " 1 : 1740, 1710.
maxMax
Beispiel 37
ML-236B-benzoat Example 37
ML-236B benzoate
7,8 g ML-236B werden in 20 ml trockenem Pyridin gelöst und unter Eiskühlung mit 4,2 g Benzoylchlprid versetzt. Das Gemisch wird 15 Stunden bei Raumtemperatur gerührt, dann in mit Salzsäure angesäuertes Eiswasser gegossen und mit Benzol extrahiert. Die Benzolschicht wird mit Wasser gewaschen, über Natriumsulfat getrocknet und unter vermindertem Druck eingedampft. Das erhaltene ölige Konzentrat wird durch Chromatographieren an Silicagel mit Benzol/Ethylacetat als Eluiermittel getrennt und gereinigt. Durch Umkristallisieren aus Diethylether/Hexan erhält man 9,1 g ML-236B-benzoat in Form weißer Kristalle, F. 102 bis 104°C.7.8 g of ML-236B are dissolved in 20 ml of dry pyridine, and 4.2 g of benzoyl chloride are added while cooling with ice. The mixture is stirred for 15 hours at room temperature, then poured into ice water acidified with hydrochloric acid and with benzene extracted. The benzene layer is washed with water, dried over sodium sulfate and under reduced pressure evaporated. The oily concentrate obtained is purified by chromatography on silica gel with benzene / ethyl acetate Eluent separated and purified. Recrystallization from diethyl ether / hexane gives 9.1 g of ML-236B-benzoate in Form of white crystals, m.p. 102 to 104 ° C.
NMR-Spektrum (CDCl3) δ ppm: 7,2 (5H, m); 6,10 (1H, d);Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 7.2 (5H, m); 6.10 (1H, d);
5,82 (1H, d); 2,82 (2H, d).5.82 (1H, d); 2.82 (2H, d).
IR-Spektrum (Paraffinöl) vra=>v cm"1: 1745, 1708IR spectrum (paraffin oil) v ra => v cm " 1 : 1745, 1708
Beispiel 38
ML-236B-pivaloat Example 38
ML-236B pivaloate
7,8 g ML-236B werden in 20 ml trockenem Pyridin gelöst und unter Eiskühlung mit 3,6 g Pivaloylchlorid versetzt. Das Gemisch wird 1 Stunde bei Raumtemperatur gerührt und dann in mit Salzsäure angesäuertes Eiswasser gegossen. Das Reaktionsprodukt wird mit Benzol extrahiert, worauf man den Benzolextrakt mit Wasser wäscht, über Natriumsulfat trocknet and unter vermindertem Druck einengt. Das ölige Konzentrat wird durch Chromatographieren an Silicagel gereinigt. Durch Umkristallisieren aus wäßrigem Ethanol erhält man 4,9 g ML-236B-pivaloat in Form weißer Kristalle, F. 104 bis 105°C.7.8 g of ML-236B are dissolved in 20 ml of dry pyridine and 3.6 g of pivaloyl chloride were added while cooling with ice. The mixture is stirred for 1 hour at room temperature and then in Poured ice water acidified with hydrochloric acid. The reaction product is extracted with benzene, whereupon the benzene extract is obtained Washed with water, dried over sodium sulfate and concentrated under reduced pressure. The oily concentrate will purified by chromatography on silica gel. Recrystallization from aqueous ethanol gives 4.9 g ML-236B pivaloate in the form of white crystals, m.p. 104 to 105 ° C.
Elementaranalyse fürElemental analysis for
NMR-Spektrum (CDCl3) 6 ppm: 6,00 (1H, d), 5,93 (1H, dd); 5,52 (1H, m); 5,22 (2H, m); 4,38 (1H, m); 2,63 (2H, d); 1,14 (9H, s).Nuclear Magnetic Resonance Spectrum (CDCl 3 ) 6 ppm: 6.00 (1H, d), 5.93 (1H, dd); 5.52 (1H, m); 5.22 (2H, m); 4.38 (1H, m); 2.63 (2H, d); 1.14 (9H, s).
IR-Spektrum (Paraffinöl) ν cm"1 :' 1735, 1720.IR spectrum (paraffin oil) ν cm " 1 : '1735, 1720.
maxMax
Beispiel 39
ML-236 B-phenoxyacetat Example 39
ML-236 B-phenoxyacetate
7,8 g ML-236B werden in 20 ml trockenem Pyridin gelöst und unter Eiskühlung mit 5,1 g Phenoxyacetylchlorid versetzt. Das Gemisch wird 1 Stunde bei Raumtemperatur gerührt und dann in mit Salzsäure angesäuertes Eiswasser gegossen. Das Reaktionsprodukt wird mit Ethylacetat extrahiert, worauf man den Extrakt mit Wasser wäscht, über Natriumsulfat trocknet und7.8 g of ML-236B are dissolved in 20 ml of dry pyridine and 5.1 g of phenoxyacetyl chloride were added while cooling with ice. The mixture is stirred at room temperature for 1 hour and then poured into ice water acidified with hydrochloric acid. The reaction product is extracted with ethyl acetate, whereupon the Wash the extract with water, dry over sodium sulfate and
unter vermindertem Druck einengt. Das ölige Konzentrat wird durch Chromatographieren an Silicagel mit einem Lösungsmittelsystem aus Hexan, Diethylether und Ethylacetat getrennt und gereinigt. Durch Umkristallisieren aus wäßrigem Ethanol erhält man 2,5 g ML-236B-phenoxyacetat in Form weißer Kristalle, P. 42 bis 44°C.constricts under reduced pressure. The oily concentrate is purified by chromatography on silica gel with a solvent system separated from hexane, diethyl ether and ethyl acetate and cleaned. Recrystallization from aqueous ethanol gives 2.5 g of ML-236B-phenoxyacetate in the form of white Crystals, P. 42 to 44 ° C.
Elementaranalyse für C^1H40O7: C HElemental analysis for C ^ 1 H 40 O 7 : CH
ber.: 70,97 %; 7,69 %. gef.: 70,89 %; 7,68 %.calc .: 70.97%; 7.69%. found: 70.89%; 7.68%.
NMR-Spektrum (CDCl3) δ ppm: 6,6 - 7,4 (5H, m); 5,86 (1H, d); 5,65 (1H, dd); 4,51 (2H, s); 4,15 (1H, m).Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 6.6-7.4 (5H, m); 5.86 (1H, d); 5.65 (1H, dd); 4.51 (2H, s); 4.15 (1H, m).
IR-Spektrum (Paraffinöl) ν cm" : 174Ο (Schulter), 1725.IR spectrum (paraffin oil) ν cm ": 174Ο (shoulder), 1725.
ICl 3.XICl 3.X
Beispiel 40 MB-53OB-acetat Example 40 MB-53OB acetate
0,081 g MB-53OB werden in 0,2 ml trockenem Pyridin gelöst und mit 0,05 ml Acetanhydrid versetzt. Das Gemisch wird 2 Stunden bei Raumtemperatur gerührt, dann in mit Salzsäure angesäuertes Salzwasser gegossen und mit Benzol extrahiert. Die Benzolschicht wird mit Wasser gewaschen, über Natriumsulfat getrocknet und unter vermindertem Druck eingeengt. Das ölige Konzentrat wird an einer Silicagelsäule (Rover-Säule von der Merck Co., USA) getrennt und gereinigt. Durch Umkristallisieren aus Diethylether/Hexan erhält man 0,076 g MB-53OB-acetat in Form weißer Nadeln, F. 92 bis 93°C.0.081 g of MB-53OB are dissolved in 0.2 ml of dry pyridine and 0.05 ml of acetic anhydride are added. The mixture is stirred for 2 hours at room temperature, then in hydrochloric acid Poured acidified salt water and extracted with benzene. The benzene layer is washed with water over sodium sulfate dried and concentrated under reduced pressure. The oily concentrate is placed on a silica gel column (Rover column from Merck Co., USA) separated and cleaned. Recrystallization from diethyl ether / hexane gives 0.076 g MB-53OB acetate in the form of white needles, m.p. 92 to 93 ° C.
Elementaranalyse für C26H38°6: Elemental analysis for C 26 H 38 ° 6 :
ber.:ber .:
gef. :found :
NMR-Spektrum (CDCl3) δ ppm: 6,06 (1H, d); 5,88 (1H, dd) ;
2,73 (2H, d); 2,10 (3H, s).
IR-Spektrum (Paraffinöl) ν cm"1: 1736, 1720.Nuclear Magnetic Resonance Spectrum (CDCl 3 ) δ ppm: 6.06 (1H, d); 5.88 (1H, dd); 2.73 (2H, d); 2.10 (3H, s).
IR spectrum (paraffin oil) ν cm " 1 : 1736, 1720.
Iu 3 XIu 3 X
Beispiel 41 MB-5 30B-benzoat Example 41 MB-5 30B-benzoate
Gemäß Beispiel 40 werden aus 0,081 g MB-53OB und 0,044 g Benzoylchlorid 0,09 g MB-530B-benzoat hergestellt.According to Example 40, 0.081 g of MB-53OB and 0.044 g Benzoyl chloride 0.09 g of MB-530B benzoate prepared.
NMR-Spektrum (CDCl3) öppm: 8,1 (2H, m) ; 7,6 (3H, m) ; 6,01 (1H, d); 5,85 (1H, dd) ; 2,78 (2H, d) . IR-Spektrum (Film) ν cm"1: 1750 - 1720, 1600, 1580.Nuclear Magnetic Resonance Spectrum (CDCl 3 ) rpm: 8.1 (2H, m); 7.6 (3H, m); 6.01 (1H, d); 5.85 (1H, dd); 2.78 (2H, d). IR spectrum (film) ν cm " 1 : 1750-1720, 1600, 1580.
ΙΏ. 3.xΙΏ. 3.x
LeerseiteBlank page
Claims (26)
stoffatorae sind und R keine a-Methylb\ityrylgruppe dar-2
are stoffatorae and R does not represent an a-methylb \ ityryl group.
daß R eine geradkettige oder verzweigte C„-Cfi-Alkanoylgruppe oder eine geradkettige oder verzweigte C_.-Cfi-Alkenoy!gruppe ist.2
that R is a linear or branched C "-C fi alkanoyl group or a linear or branched C _.- C -Alkenoy fi! group.
daß R eine Butyryl-, Isobutyryl-, 4-Propenoyl- oder Isovalery!gruppe ist.2
that R is a butyryl, isobutyryl, 4-propenoyl or isovalery! group.
und R ein Wasserstoffatom oder eine a-Methylbutyrylgruppe2
and R is a hydrogen atom or an α-methylbutyryl group
R eine a-Methylbutyrylgruppe ist.2
R is α-methylbutyryl group.
daß R und R gleich oder unterschiedlich geradkettige oder verzweigte C„-C -Alkanoylgruppen, geradkettige oder verzweig-1 2
that R and R identically or differently straight-chain or branched C "-C -alkanoyl groups, straight-chain or branched
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP55041292A JPH0692381B2 (en) | 1980-03-31 | 1980-03-31 | MB-530A derivative |
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DE3112566A1 true DE3112566A1 (en) | 1982-03-11 |
DE3112566C2 DE3112566C2 (en) | 1990-04-05 |
Family
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DE3153666A Expired - Lifetime DE3153666C2 (en) | 1980-03-31 | 1981-03-30 | Monacoline derivatives, processes for their preparation and medicinal products containing them |
DE19813112566 Granted DE3112566A1 (en) | 1980-03-31 | 1981-03-30 | MONACOLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE DERIVATIVES |
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DE3153666A Expired - Lifetime DE3153666C2 (en) | 1980-03-31 | 1981-03-30 | Monacoline derivatives, processes for their preparation and medicinal products containing them |
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JP (1) | JPH0692381B2 (en) |
AT (1) | ATA150781A (en) |
AU (1) | AU6893281A (en) |
BE (1) | BE888214A (en) |
CH (1) | CH646966A5 (en) |
DE (2) | DE3153666C2 (en) |
DK (3) | DK151273C (en) |
FI (1) | FI810991L (en) |
FR (1) | FR2479222A1 (en) |
GB (1) | GB2073193A (en) |
IE (1) | IE52367B1 (en) |
IT (1) | IT1144325B (en) |
MX (1) | MX9203567A (en) |
NL (1) | NL8101592A (en) |
SE (1) | SE461590B (en) |
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US4472426A (en) * | 1982-12-22 | 1984-09-18 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
ATE69602T1 (en) * | 1985-09-13 | 1991-12-15 | Sankyo Co | HYDROXY-ML-236B DERIVATIVES, THEIR PREPARATION AND USE. |
US4997848A (en) * | 1987-10-27 | 1991-03-05 | Sankyo Company, Limited | Octahydronaphthalene oxime derivatives for cholesterol synthesis inhibition |
US5075327A (en) * | 1988-08-10 | 1991-12-24 | Hoffmann-La Roche Inc. | Antipsoriatic agents |
US5021451A (en) * | 1988-11-14 | 1991-06-04 | Hoffman-La Roche Inc. | Method for inhibiting hyperproliferative diseases |
US5200549A (en) * | 1988-11-14 | 1993-04-06 | Hoffman-La Roche Inc. | Antipsoriatic agents |
US5073568A (en) * | 1988-11-14 | 1991-12-17 | Hoffmann-La Roche Inc. | Antipsoriatic agents |
US5159104A (en) * | 1991-05-01 | 1992-10-27 | Merck & Co., Inc. | Process to simvastatin ester |
FR2937537A1 (en) * | 2008-10-29 | 2010-04-30 | Centre Nat Rech Scient | NANOPARTICLES OF STATIN |
KR101820099B1 (en) | 2013-01-18 | 2018-01-18 | 에스프린팅솔루션 주식회사 | resistive heat generating material, heating member and fusing device adopting the same |
CN111788196A (en) * | 2018-01-09 | 2020-10-16 | 配体药物公司 | Acetal compounds and their therapeutic use |
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US3983140A (en) * | 1974-06-07 | 1976-09-28 | Sankyo Company Limited | Physiologically active substances |
DE3006216A1 (en) * | 1979-02-20 | 1980-09-04 | Sankyo Co | NEW MONACOLIN K COMPOUND, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THIS COMPOUND |
US4231938A (en) * | 1979-06-15 | 1980-11-04 | Merck & Co., Inc. | Hypocholesteremic fermentation products and process of preparation |
EP0033536A2 (en) * | 1980-02-04 | 1981-08-12 | Merck & Co. Inc. | 6(R)-(2-(8'-etherified-hydroxy-2',6'-dimethylpolyhydro-naphthyl-1')-ethyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones, the hydroxy acid form of said pyranones, the salts of said acid form, process for preparing the same and an antihypercholesterolemic pharmaceutical composition containing the same |
EP0033537A2 (en) * | 1980-02-04 | 1981-08-12 | Merck & Co. Inc. | Hydrogenation products of mevinolin and dihydromevinolin, a process for preparing the same and an antihypercholesterolemic pharmaceutical composition containing the same |
EP0033538A2 (en) * | 1980-02-04 | 1981-08-12 | Merck & Co. Inc. | 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 |
EP0022478B1 (en) * | 1979-06-15 | 1983-02-23 | Merck & Co. Inc. | Polyhydro-3,7-dimethyl-8-(2-(tetrahydro-4-hydroxy-6-oxo-2h-pyran-2-yl)-ethyl)-1-naphthylenyl-2-methylbutanoates, corresponding hydroxy acids, process for preparing and pharmaceutical compositions containing the same |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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ZA81703B (en) * | 1980-02-04 | 1982-09-29 | Merck & Co Inc | New antihypercholesterolemic compounds,intermediates and processes |
-
1980
- 1980-03-31 JP JP55041292A patent/JPH0692381B2/en not_active Expired - Lifetime
-
1981
- 1981-03-27 IE IE698/81A patent/IE52367B1/en not_active IP Right Cessation
- 1981-03-30 CH CH215381A patent/CH646966A5/en not_active IP Right Cessation
- 1981-03-30 DE DE3153666A patent/DE3153666C2/en not_active Expired - Lifetime
- 1981-03-30 DE DE19813112566 patent/DE3112566A1/en active Granted
- 1981-03-30 IT IT67438/81A patent/IT1144325B/en active
- 1981-03-31 DK DK145481A patent/DK151273C/en not_active IP Right Cessation
- 1981-03-31 SE SE8102047A patent/SE461590B/en not_active Application Discontinuation
- 1981-03-31 NL NL8101592A patent/NL8101592A/en not_active Application Discontinuation
- 1981-03-31 FR FR8106403A patent/FR2479222A1/en active Granted
- 1981-03-31 BE BE0/204328A patent/BE888214A/en not_active IP Right Cessation
- 1981-03-31 FI FI810991A patent/FI810991L/en not_active Application Discontinuation
- 1981-03-31 AT AT0150781A patent/ATA150781A/en not_active IP Right Cessation
- 1981-03-31 GB GB8110075A patent/GB2073193A/en not_active Withdrawn
- 1981-03-31 AU AU68932/81A patent/AU6893281A/en not_active Abandoned
-
1990
- 1990-02-07 DK DK032290A patent/DK32290A/en not_active Application Discontinuation
- 1990-02-07 DK DK032190A patent/DK167805B1/en not_active IP Right Cessation
-
1992
- 1992-06-26 MX MX9203567A patent/MX9203567A/en unknown
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US3983140A (en) * | 1974-06-07 | 1976-09-28 | Sankyo Company Limited | Physiologically active substances |
DE3006216A1 (en) * | 1979-02-20 | 1980-09-04 | Sankyo Co | NEW MONACOLIN K COMPOUND, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THIS COMPOUND |
US4231938A (en) * | 1979-06-15 | 1980-11-04 | Merck & Co., Inc. | Hypocholesteremic fermentation products and process of preparation |
EP0022478B1 (en) * | 1979-06-15 | 1983-02-23 | Merck & Co. Inc. | Polyhydro-3,7-dimethyl-8-(2-(tetrahydro-4-hydroxy-6-oxo-2h-pyran-2-yl)-ethyl)-1-naphthylenyl-2-methylbutanoates, corresponding hydroxy acids, process for preparing and pharmaceutical compositions containing the same |
EP0033536A2 (en) * | 1980-02-04 | 1981-08-12 | Merck & Co. Inc. | 6(R)-(2-(8'-etherified-hydroxy-2',6'-dimethylpolyhydro-naphthyl-1')-ethyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones, the hydroxy acid form of said pyranones, the salts of said acid form, process for preparing the same and an antihypercholesterolemic pharmaceutical composition containing the same |
EP0033537A2 (en) * | 1980-02-04 | 1981-08-12 | Merck & Co. Inc. | Hydrogenation products of mevinolin and dihydromevinolin, a process for preparing the same and an antihypercholesterolemic pharmaceutical composition containing the same |
EP0033538A2 (en) * | 1980-02-04 | 1981-08-12 | Merck & Co. Inc. | 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 |
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Also Published As
Publication number | Publication date |
---|---|
IE810698L (en) | 1981-09-30 |
DK32190D0 (en) | 1990-02-07 |
SE461590B (en) | 1990-03-05 |
SE8102047L (en) | 1981-10-01 |
JPH0692381B2 (en) | 1994-11-16 |
JPS56138181A (en) | 1981-10-28 |
BE888214A (en) | 1981-09-30 |
DK151273B (en) | 1987-11-16 |
FR2479222B1 (en) | 1983-08-26 |
DE3112566C2 (en) | 1990-04-05 |
DK151273C (en) | 1988-07-04 |
AU6893281A (en) | 1981-10-08 |
DK32290D0 (en) | 1990-02-07 |
DK167805B1 (en) | 1993-12-20 |
IT1144325B (en) | 1986-10-29 |
MX9203567A (en) | 1992-09-01 |
IT8167438A0 (en) | 1981-03-30 |
FI810991L (en) | 1981-10-01 |
FR2479222A1 (en) | 1981-10-02 |
ATA150781A (en) | 1983-03-15 |
GB2073193A (en) | 1981-10-14 |
DK32290A (en) | 1990-02-07 |
CH646966A5 (en) | 1984-12-28 |
DE3153666C2 (en) | 1993-11-11 |
DK145481A (en) | 1981-10-01 |
IE52367B1 (en) | 1987-09-30 |
DK32190A (en) | 1990-02-07 |
NL8101592A (en) | 1981-10-16 |
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