JPS6344159B2 - - Google Patents
Info
- Publication number
- JPS6344159B2 JPS6344159B2 JP54136038A JP13603879A JPS6344159B2 JP S6344159 B2 JPS6344159 B2 JP S6344159B2 JP 54136038 A JP54136038 A JP 54136038A JP 13603879 A JP13603879 A JP 13603879A JP S6344159 B2 JPS6344159 B2 JP S6344159B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- alkyl
- compound
- hydrogen
- bromine
- 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.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000010933 acylation Effects 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- 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 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 235000012000 cholesterol Nutrition 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000001840 cholesterol esters Chemical class 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- XQXPVVBIMDBYFF-UHFFFAOYSA-N 4-hydroxyphenylacetic acid Chemical compound OC(=O)CC1=CC=C(O)C=C1 XQXPVVBIMDBYFF-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 229910000085 borane Inorganic materials 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- 108010089254 Cholesterol oxidase Proteins 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- -1 alkyl hydroperoxide Chemical compound 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000012064 sodium phosphate buffer Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- ZICDZTXDTPZBKH-UHFFFAOYSA-N 2-(4-methylphenyl)-1-phenylethanamine Chemical compound C1=CC(C)=CC=C1CC(N)C1=CC=CC=C1 ZICDZTXDTPZBKH-UHFFFAOYSA-N 0.000 description 1
- QATUXQFZMCMCAF-UHFFFAOYSA-N 3-[decyl(dimethyl)silyl]propan-1-ol Chemical compound CCCCCCCCCC[Si](C)(C)CCCO QATUXQFZMCMCAF-UHFFFAOYSA-N 0.000 description 1
- UKERIRUZUWGBPW-UHFFFAOYSA-N 3-[decyl(dimethyl)silyl]propanoic acid Chemical compound CCCCCCCCCC[Si](C)(C)CCC(O)=O UKERIRUZUWGBPW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- AMKGKYQBASDDJB-UHFFFAOYSA-N 9$l^{2}-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1[B]2 AMKGKYQBASDDJB-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 108010059712 Pronase Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 102000000019 Sterol Esterase Human genes 0.000 description 1
- 108010055297 Sterol Esterase Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- LIKFHECYJZWXFJ-UHFFFAOYSA-N dimethyldichlorosilane Chemical compound C[Si](C)(Cl)Cl LIKFHECYJZWXFJ-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 230000003516 hyperlipidaemic effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- ISRXMEYARGEVIU-UHFFFAOYSA-N n-methyl-n-propan-2-ylpropan-2-amine Chemical compound CC(C)N(C)C(C)C ISRXMEYARGEVIU-UHFFFAOYSA-N 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、式
[式中、R1は(C1〜22)アルキルであり、
Rは
(a) 式
のアラルキル基であり、
Raは水素、弗素、塩素、臭素もしくは沃素、
(C1〜4)アルキルもしくはアルコキシ又はトル
フルオロメチルであり、
Rcは水素、(C1〜4)アルキル又は
The present invention is based on the formula [In the formula, R 1 is (C 1-22 ) alkyl, R is the formula (a) is an aralkyl group, and Ra is hydrogen, fluorine, chlorine, bromine or iodine,
(C 1-4 ) alkyl or alkoxy or trifluoromethyl, Rc is hydrogen, (C 1-4 ) alkyl or
【式】であり、
Y′は水素、弗素、塩素、臭素もしくは沃素、
又は(C1〜4)アルキルであり、或いは
Rは
(b) 式
のインドリル基であり、そして
R4は(C1〜8)アルキルである]
の化合物に関する。
式の好適な化合物は、式a
〔式中、R1′はα−炭素原子以外で分岐していて
もよいC1〜22アルキルであり、
Raは上述と同義であり、及び
Rc1は[Formula], Y′ is hydrogen, fluorine, chlorine, bromine or iodine,
or (C 1-4 )alkyl, or R is the formula (b) is an indolyl group, and R 4 is (C 1-8 )alkyl. Preferred compounds of formula a [In the formula, R 1 ' is C 1-22 alkyl which may be branched at a point other than the α-carbon atom, Ra is as defined above, and Rc 1 is
の化合物を式
[式中、R1は上述と同義である]
の化合物又はその反応性誘導体でアシル化するこ
とを特徴とする式の化合物の製造法も与える。
この種のアシル化反応の反応条件は公知であ
る。適当な化合物の誘導体は酸クロライド、活
性エステル、カルボジイミド付加物又は混合酸無
水物を含む。
アシル化剤は、好ましくは式
〔式中、R6は(C1〜4)アルキルであり、R1は上
述と同義であり、そしてR2とR3はいずれもメチ
ルである〕のものである。
本発明の方法は、無溶媒で或いは不活性な有機
溶媒例えばエーテル、ハロゲン化炭化水素、例え
ば塩化メチレン、クロロホルム、又は式の化合
物の過剰量の存在下に行なうことができる。塩化
メチレンは溶媒として好適である。反応温度は厳
密でないが、好ましくは約−50℃〜+30℃、特に
約−10℃〜+20℃である。反応は適当には約1〜
72時間、好ましくは約4〜16時間に亘つて行なわ
れる。得られる化合物は通常の技法で単離及び
精製することができる。
式の化合物は次の反応式に従つて製造でき
る:
上式において、R1、R2、R3及びR6は上述と同
義であり、Bはホウ素であり、R8及びR9はそれ
ぞれ互いに無関係に
The compound with the formula There is also provided a process for the preparation of a compound of the formula, characterized in that it is acylated with a compound of the formula: [wherein R 1 has the same meaning as defined above] or a reactive derivative thereof. Reaction conditions for this type of acylation reaction are known. Suitable compound derivatives include acid chlorides, active esters, carbodiimide adducts or mixed acid anhydrides. The acylating agent preferably has the formula [wherein R 6 is (C 1-4 )alkyl, R 1 is as defined above, and R 2 and R 3 are both methyl]. The process of the invention can be carried out neat or in the presence of an inert organic solvent such as an ether, a halogenated hydrocarbon such as methylene chloride, chloroform, or an excess of a compound of formula. Methylene chloride is suitable as solvent. The reaction temperature is not critical, but is preferably about -50°C to +30°C, especially about -10°C to +20°C. The reaction is suitably about 1~
This is carried out over a period of 72 hours, preferably about 4 to 16 hours. The resulting compounds can be isolated and purified using conventional techniques. Compounds of formula can be prepared according to the following reaction scheme: In the above formula, R 1 , R 2 , R 3 and R 6 have the same meanings as above, B is boron, and R 8 and R 9 are each independent of each other.
【式】
水素又は(C1〜8)アルキルを表わし、或いはR8
及びR9は一緒になつて[Formula] Represents hydrogen or (C 1-8 ) alkyl, or R 8
and R 9 together
【式】又は[Formula] or
【式】であり、nは1〜3であり、及
び(R7)3−nは〔(C1〜8)アルキル〕3−nである
か或いはnが1のとき他に[Formula], n is 1-3, and (R 7 ) 3 -n is [(C 1-8 )alkyl] 3 -n, or when n is 1,
【式】又は[Formula] or
【式】である。
反応工程(d)において、好適な酸結合剤はピリジ
ン、トリエチルアミン及びジイソプロピルアミ
ン、好ましくはトリエチルアミンを含む。好適な
溶媒は、非プロトン性溶媒例えばハロゲン化炭化
水素、例えば塩化メチレン、クロロホルム又は芳
香族炭化水素、例えばベンゼン、トルエン及びア
セトニトリルである。好適な溶媒は塩化メチレン
である。反応温度は例えば約−50℃〜+30℃、特
に−20℃〜+20℃である。反応は例えば約10分間
〜18時間、好ましくは約30分間〜3時間に亘つて
行なわれる。生成物は通常の技法で回収すること
ができる。しかしながら、式の化合物は適当に
は単離せずにそのまま最終化合物の製造に使用さ
れる。
工程(c)においては、式の化合物を、酸化剤、
例えば過マンガン酸カリウム又は好ましくは三酸
化クロムと、好ましくは酸性条件下に反応させ
る。好適な酸は、鉱酸例えば燐酸、酢酸、又は特
に硫酸を含む。適当な溶媒は、アセトン、特にア
セトンと小量の水との組合せ物であるが、水と他
の不活性な溶媒、例えばジエチルエーテルとの組
合せ物を使用できる。反応温度は好ましくは約−
40゜〜+30℃、特に−10℃〜+5℃である。反応
は例えば約10分間〜6時間、好ましくは2〜3時
間に亘つて行なわれる。
工程(b)においては、式の化合物を水と、第1
段階で有機又は無機塩基と、及び第2段階で不活
性な有機溶媒中ハイドロパーオキサイド、例えば
tert−低級アルキルハイドロパーオキサイド又は
過酸化水素、好ましくはt−ブチルハイドロパー
オキサイドと反応させる。適当な塩基は有機塩基
例えばメチルジイソプロピルアミン、ピリジン、
又は好ましくはトリエチルアミンを含む。無機塩
基、例えばアルカリ金属水酸化物はそれよりも好
適でない。好適な溶媒はジオキサン、ジエチルエ
ーテル又は好ましくはテトラヒドロフランを含
む。反応温度は好ましくは約−20゜〜+40℃、特
に0〜25℃である。反応は例えば約3〜24時間、
好ましくは約12〜16時間に亘つて行なわれる。
反応工程(a)は、適当には不活性な雰囲気、例え
ば窒素下に及び非プロトン性溶媒の存在下に行な
うことができる。ホウ素試薬は少くとも1つの
活性水素を含有し、例えばBH3又はアルキル水
素化ホウ素、或いはハイドロボレーシヨンに通常
用いられる他の水素化ホウ素、例えば式[Formula]. In reaction step (d), suitable acid binders include pyridine, triethylamine and diisopropylamine, preferably triethylamine. Suitable solvents are aprotic solvents such as halogenated hydrocarbons such as methylene chloride, chloroform or aromatic hydrocarbons such as benzene, toluene and acetonitrile. A preferred solvent is methylene chloride. The reaction temperature is, for example, about -50°C to +30°C, in particular -20°C to +20°C. The reaction is carried out, for example, for about 10 minutes to 18 hours, preferably for about 30 minutes to 3 hours. The product can be recovered using conventional techniques. However, the compound of the formula is used as is in the preparation of the final compound without proper isolation. In step (c), a compound of formula is treated with an oxidizing agent,
For example, it is reacted with potassium permanganate or preferably with chromium trioxide, preferably under acidic conditions. Suitable acids include mineral acids such as phosphoric acid, acetic acid or especially sulfuric acid. A suitable solvent is acetone, especially acetone in combination with a small amount of water, but combinations of water with other inert solvents such as diethyl ether can also be used. The reaction temperature is preferably about -
40° to +30°C, especially -10°C to +5°C. The reaction is carried out, for example, for about 10 minutes to 6 hours, preferably 2 to 3 hours. In step (b), a compound of formula is mixed with water and a first
in one step with an organic or inorganic base and in a second step with a hydroperoxide in an inert organic solvent, e.g.
Reaction with tert-lower alkyl hydroperoxide or hydrogen peroxide, preferably t-butyl hydroperoxide. Suitable bases include organic bases such as methyldiisopropylamine, pyridine,
or preferably triethylamine. Less preferred are inorganic bases, such as alkali metal hydroxides. Suitable solvents include dioxane, diethyl ether or preferably tetrahydrofuran. The reaction temperature is preferably about -20° to +40°C, especially 0 to 25°C. The reaction takes about 3 to 24 hours, for example.
Preferably it is carried out over a period of about 12 to 16 hours. Reaction step (a) can suitably be carried out under an inert atmosphere, for example nitrogen, and in the presence of an aprotic solvent. The boron reagent contains at least one active hydrogen, e.g. BH3 or an alkyl borohydride, or other borohydrides commonly used in hydroboration, e.g.
【式】
の9−ボラビシクロ〔3,3,1〕ノナン、又は
構造式9-borabicyclo[3,3,1]nonane of [formula] or structural formula
【式】
のカテコール−ボランである。この試剤は好まし
くはテトラヒドフラン/ボラン試剤(1:1)、
例えばBH3・THFの形で使用される。好適な非
プロトン性溶媒はエーテル例えばジエチルエーテ
ル又はテトラヒドロフランであり、後者のものが
特に好適である。反応温度は好ましくは約−78゜
〜+100℃、特に約−10゜〜+30℃である。反応は
例えば約5分間〜12時間、好ましく約15分間〜1
時間に亘つて行なわれる。生成物は通常の技法で
回収することができるが、化合物は単離せずに
そのまま化合物の製造に使用することが好適で
ある。
化合物の多くは公知であり、或いは通常の技
法により、例えば珪素のハロゲンを金属有機物で
置換することによつて製造できる。
式、及びの化合物は公知であり、また通
常の方法により入手しうる物質から製造すること
ができる。R1が(C5〜22)アルキル、特に
(C8〜18)アルキルを表わす式、及びの化合
物は新規である。該新規化合物のうち更に特に興
味のある化合物は、R1がアルフア炭素原子以外
で分岐しているものであり、また同様にR1が直
鎖(C5〜22)アルキル、特に(C8〜18)アルキルで
あるものが好ましく、特にR2およびR3が共にメ
チルであるものが好ましい。
式の化合物は光学的に活性な異性体、例えば
対掌体の形で存在していてよい。これは光学的に
活性な化合物から製造できるし、また通常の技
法、即ち分割によつて分離・回収できることは理
解されよう。そのような異性体形も本発明の範囲
に包含される。
本発明の式の化合物は、薬理学的に活性であ
る。特に式の化合物は哺乳動物の動脈壁のコレ
ステロールエステル含量を制御するのに使用され
及びそれ故に特に抗アテローム性動脈硬化剤
(anti−atherosclerotic agents)として、即ちア
テローム性動脈硬化症(atherosclerosis)の予防
処置における及び動脈壁のコレステロールエステ
ルの蓄積によるアテローム性動脈硬化状態の制御
における薬剤として使用されうる。式の化合物
のそのような能力は、培養した細胞の全コレステ
ロールエステル含量が未処置の細胞に比べて試験
化合物により減せられることを示す公知の試験法
によつて例示できる。この試験法は、例えば次の
方法で行なわれる:
(A) 細胞の培養
K.フイツシヤー(Fischer)−ドゾガ
(Dzoga)らの方法〔Experimental and Mo−
lecular Patholagy、18、162〜176(1973)〕に
よつて得られるリーサス猿の平滑筋細胞(動
脈、例えば大動脈の壁から)を、10%の胎児牛
の漿液を補充した最底必須媒体(Mi−nimum
Essential Medium)〔イーグル(Ee−gle)〕
を用いる75cm2の組織培養フラスコ中で日常的に
生長させた。試験に対しては、近似融合性の細
胞生長を含む75cm2フラスコを選択した。細胞を
プロナーゼで穏やかに酵素処理することによつ
てフラスコ表面から取り除いた。酵素溶液を遠
心分離し及び傾斜した後、望ましい数の60mmの
組織培養皿に接種するために細胞ペレツトを適
当な容量の媒体中に再懸濁させた。接種後、皿
に細胞種、日付け及び起源のフラスコ番号のラ
ベルを貼り、高湿度の培養器中において約5%
のCO2雰囲気下に37℃で培養した。培養物が融
合したとき、実際の薬剤の試験を開始した。試
験化合物も100%エタノール中に溶解した。同
一量のエタノールを同様に対照群に添加した。
組織培養皿を任意に群に分けた。一つの群に
は、脂肪過多の(hyper−lipemic)ラビツト
の漿液(HRS)を5容量%で添加した(対照
群)。残りの群には、5%HRS及び試験化合物
0.1〜1mg/媒体100mlを添加した。次いで皿を
更に24時間培養器に戻した。最終的な培養に至
るすべての操作は層流フード内における殺菌法
を用いて行なつた。培養期間の後、皿を相対比
光学系を有するザイス・アキオマト(Zeiss
Axiomat)で顕微鏡的に観察し、培養の状態、
特に細胞質内包物の大きさ、数及び形体、及び
細胞の形態を記録した。媒体を培養物から除去
し、0.9%塩化ナトリウム溶液を添加した。細
胞をゴムポリスマンによりフラスコから取り出
し、円錐形の凹凸のある遠心離管に移した。細
胞を等張塩溶液に懸濁させ、800xgで10分間
遠心分離し及び上澄液を吸引することによつて
3回洗浄した。
(B) 細胞抽出法
次いで細胞のペレツトに適当量のイソプロピ
ルアルコール(約1ml/蛋白物mg)を添加し、
ブロンウエル・ビオソニク(Bronwell
Biosonik)型の“LO”セツト50下に10秒間
ミクロ試験管(140×3mm)内で試料を超音波
処理した。15分間800xgで遠心分離した後、
透明な上澄液を傾斜し、その一部をコレステロ
ールの分析に採取した。残渣を0.1N水酸化ナ
トリウム中に溶解し、その一部をロウリーら
(J.Biol.Chem.193、265;1951)の方法による
蛋白質の定量のために採取した。
(C) 分析
遊離のコレステロール:基準、試料及びブラ
ンク(イソプロピルアルコールのみ)のイソプ
ロピルアルコール性溶媒を同様の方法で処理し
た。イソプロピルアルコール性溶液20μを添
加し及び混合した10×75mmの使い拾てガラス製
試験管に、遊離の試剤(下表1の試剤A)の
0.4ml部分を添加した。室温で約5分間放置し
た後、0.5N水酸化ナトリウム(下表1の試剤
C)の0.8mlを添加し、混合した。次いでアミ
ンコーボウマン(Aminco−Bowman)螢光分
光計により、325nmの吸光波長及び415nmの
発光波長に関し螢光を測定した。この場合キセ
ノンランプ、IP28光電管及び2mmスリツト下
に光路1cmのキユーベト(cuvette)を使用し
た。
全コレステロール:試験Aの代りに全試剤
(下表1の試剤B)を用いる以外、遊離のコレ
ステロールに対して上述したものと同一の方法
に従つて全コレステロールを測定した。試料は
0.5N水酸化ナトリウム溶液(下表1の試剤C)
の添加前に37℃で20分間培養した。
他にコレステロールに対する分析、即ち工程
(A)及び(B)から得られる上述の工程(C))はイシカ
ワら(J.Lipid Res.15、286;1974)の方法に
よつても行なうこともできる。
コレステロールエステルの量は、分析で定量
した細胞の遊離のコレステロールの量を全コレ
ステロール含量かる差引くことによつて得られ
る。試験化合物を添加した細胞群におけるコレ
ステロールエステルが対照群(未処置)に比べ
て低値である場合には、試験化合物が細胞中の
コレステロールエステルを減少させるのに活性
であることを示す。
第 1 表
コレステロールの測定に対する試剤の組成
A 遊離のコレステロールの試剤
燐酸ナトリウム緩衝液PH7.0 0.05M
コレステロール・オキシダーゼ 0.08U/ml
ホルセラデイシユ・ペルオキシダーゼ
(Horseradish pero−xidase) 30.00U/ml
p−ヒドロキシフエニル酢酸 0.10mg/ml
B 全コレステロールの試剤
燐酸ナトリウム緩衝液PH7.0 0.05M
コレステロールエステル・ヒドロラーゼ
0.08U/ml
コレステロール・オキシダーゼ 0.08U/ml
ホルセラデイシユ・ペルオキシダーゼ
30.00U/ml
ナトリウムタウロコレート 5.00mM
カーボワツクス−6000 0.17mM
p−ヒドロキシフエニル酢酸 0.15mg/ml
C 水酸化ナトリウム溶液 0.5N
上述の用途のために適当な一日の投薬量は10mg
〜約5000mgであり、適当には1日当り2〜4回に
亘る2.5〜2500mgの分割投薬量で又は遅効形で投
与される。
式aの化合物を用いるのに適当な一日の投薬
量は約10〜約1000mgであり、適当には1日当り2
〜4に亘る2.5〜500mgの分割投薬量で又は遅効形
で投与される。
式bの化合物に対して適当な一日の投薬量は
約100〜約5000mg、好ましくは約100〜2000mgであ
り、適当には1日当り2〜4回に亘る25〜2500mg
の分割投薬量で又は遅効形で投与される。
本化合物は、通常の製薬学的に許容しうる稀釈
剤及び担体及び随時他の賦形剤と混合でき、及び
錠剤又はカプセルのような形で投与しうる。
次の調製例及び実施例は本発明を説明する。
調製例 1
4,4−ジメチル−4−シラ−テトラデセン−
1。化合物
窒素下において、マグネシウムリボン73g
(3.04モル)、無水テトラヒドロフラン570ml及び
ジメチルジクロルシラン183g(172ml、1.42モ
ル)の撹拌された混合物に、反応開始後外部から
冷却して反応温度が40℃を越えないように保てる
速度で1−ブロムデカン205g(0.928モル)を添
加した。この添加及び発熱反応の完結後、混合物
を40℃で1時間撹拌した。試料をギルマン試験
(Gilman test)に供すると、すべてのグリニヤ
試薬が消費されていた。得られた混合物を厳密に
無水の条件及び真空下に濃縮した。次いで得られ
た半固体の物体を、アリルブロマイド218g(1.8
モル)及び無水テトラヒドロフラン400mlを添加
しながら約45〜65℃で撹拌した。この発熱反応を
冷却によつて制御した。撹拌を60℃で16時間継続
した。次いで混合物を冷却し、ヘキサン2を添
加し、この内容物を氷水中に溶解した塩化アルミ
ニウム318g中に注いだ。リグロインをいくらか
添加した後有機相を分離した。次いで生成物を3
回水洗し、無水硫酸ナトリウムで乾燥し、過
し、真空下に濃縮した。粗生成物を充填塔で精留
し、4,4−ジメチル−4−シラーテトラデセン
−1の画分を得た:沸点69〜81゜/0.015〜0.030mm
Hg。
調製例 2
4,4−ジメチル−4−シラーテトラデカノー
ル。化合物
窒素下において温度を25℃以下に保ちながら、
無水テトラヒドロフラン550ml中4,4−ジメチ
ル−4−シラーテトラデセン−1 166.4g
(0.69モル)に、テトラヒドロフラン中1Mボラン
270ml(0.81当量)を添加した。この反応混合物
を20℃で1/2時間放置し、次いで水10mlを注意深
く添加して過剰のヒドリドを分解させた(H2発
生)。ガスの発生が終つたとき、トリエチルアミ
ン140g(0.39モル)を添加し、続いて(発熱の
ために)5〜10℃に冷却しながらtert−ブチルハ
イドロパーオキサイド93g(1.03モル)を添加し
た。この反応混合物を20℃で16時間放置し、真空
下及び40℃以下で濃縮した。この濃縮物をトルエ
ン及び稀水性水酸化ナトリウム間に分配させ、有
機相を更なる水酸化ナトリウムで、水で2回、僅
かに酸性(HCl)の硫酸第一鉄溶液(残存するパ
ーオキサイドを除去するため)で2回、稀塩酸で
2回及び炭酸水素ナトリウム溶液で1回洗浄し、
硫酸ナトリウムで乾燥し、過し、及び真空下に
濃縮して無色の油を得た。次いでこの油を、ステ
ンレス鋼製の突出充填物を含む塔を通して真空下
に精留することにより、表題の生成物を得た;沸
点110〜114℃/0.035mm。
調製例 3
4,4−ジメチル−4−シラートラデカン酸。
化合物
アセトン0.2中4,4−ジメチル−4−シラ
ーテトラデカノール143.4g(0.554モル)の溶液
を−10℃まで冷却した。−10゜〜0℃まで冷却し且
つ撹拌しながら、ジヨーンズ試薬(Jones
reagent)(水性硫酸中クロム酸の8N酸化当量)
302ml(4.36×0.554電子当量)を30分間に亘つて
添加した。次いで撹拌を−10゜〜0℃で45分間及
び0゜〜5℃で1時間継続した。この混合物を撹拌
しながら1/2時間10℃まで暖め、次いで氷及びヘ
プタン中に注いだ。得られた有機相を半飽和塩化
ナトリウム溶液で3回、水で2回洗浄し、硫酸ナ
トリウムで乾燥し、過し、真空下に濃縮して油
を得た。得られた物質のほとんどを、ステンレス
鋼製の突出充填物を充填した塔を通して精留し、
表題の生成物を得た;沸点138〜140℃/0.05mm。
調製例 4〜21
上述の方法に従い及び対応する出発物質を当量
で用いることにより、次の生成物(但しR2及び
R3はCH3である)を得た:[Formula] is catechol-borane. This reagent is preferably a tetrahydrofuran/borane reagent (1:1),
For example, it is used in the form of BH3.THF . Suitable aprotic solvents are ethers such as diethyl ether or tetrahydrofuran, the latter being particularly preferred. The reaction temperature is preferably about -78° to +100°C, especially about -10° to +30°C. The reaction is carried out for example for about 5 minutes to 12 hours, preferably for about 15 minutes to 1 hour.
It takes place over a period of time. Although the product can be recovered by conventional techniques, it is preferable to use the compound as it is in the preparation of the compound without isolation. Many of the compounds are known or can be prepared by conventional techniques, for example by replacing halogens in silicon with metal organics. Compounds of formulas and are known and can be prepared from available materials by conventional methods. The formulas and compounds in which R 1 represents (C 5-22 )alkyl, especially (C 8-18 )alkyl, are new. Among the novel compounds, compounds of further particular interest are those in which R 1 is branched at a point other than an alpha carbon atom; 18 ) Those in which R 2 and R 3 are both methyl are preferred, and those in which R 2 and R 3 are both methyl are preferred. The compounds of formula may exist in the form of optically active isomers, eg enantiomers. It will be appreciated that this can be prepared from optically active compounds and separated and recovered by conventional techniques, ie resolution. Such isomeric forms are also included within the scope of this invention. Compounds of the formula of this invention are pharmacologically active. In particular, the compounds of the formula are used to control the cholesterol ester content of mammalian arterial walls and are therefore particularly used as anti-atherosclerotic agents, i.e. for the prevention of atherosclerosis. It can be used as a drug in the treatment and control of atherosclerotic conditions due to the accumulation of cholesterol esters in the walls of arteries. Such ability of compounds of formula can be illustrated by known test methods showing that the total cholesterol ester content of cultured cells is reduced by the test compound compared to untreated cells. This test method is carried out, for example, by the following method: (A) Cell culture K. Fischer-Dzoga et al. [Experimental and Mo-
lecular Pathology, 18 , 162-176 (1973)], rhesus monkey smooth muscle cells (from the walls of arteries, e.g. the aorta) were cultured in basal essential medium (Mi −nimum
Essential Medium)〔Ee−gle〕
were routinely grown in 75 cm 2 tissue culture flasks. A 75 cm 2 flask containing near confluent cell growth was selected for testing. Cells were removed from the flask surface by gentle enzymatic treatment with pronase. After centrifuging and decanting the enzyme solution, the cell pellet was resuspended in an appropriate volume of media for seeding the desired number of 60 mm tissue culture dishes. After inoculation, the dish is labeled with the cell type, date and flask number of origin, and placed in a high humidity incubator at approximately 5%
Cultured at 37 °C under a CO2 atmosphere. When the cultures were confluent, actual drug testing began. Test compounds were also dissolved in 100% ethanol. The same amount of ethanol was added to the control group as well.
Tissue culture dishes were randomly divided into groups. Hyper-lipemic rabbit serum (HRS) was added to one group at 5% by volume (control group). The remaining groups received 5% HRS and test compound.
0.1-1 mg/100ml of vehicle was added. The dishes were then returned to the incubator for an additional 24 hours. All operations leading up to the final culture were performed using sterilization methods in a laminar flow hood. After the incubation period, the dishes were placed in a Zeiss
Axiomat) was used to observe the state of the culture microscopically.
In particular, the size, number and shape of cytoplasmic inclusions and cell morphology were recorded. Media was removed from the culture and 0.9% sodium chloride solution was added. Cells were removed from the flask with a rubber policeman and transferred to a conically textured centrifuge tube. Cells were suspended in isotonic salt solution and washed three times by centrifuging at 800xg for 10 minutes and aspirating the supernatant. (B) Cell extraction method Next, add an appropriate amount of isopropyl alcohol (approximately 1 ml/mg of protein) to the cell pellet.
Bronwell Biosonique
The samples were sonicated in a microtube (140 x 3 mm) for 10 seconds under the "LO" set 50 of the Biosonik model. After centrifugation at 800xg for 15 minutes,
The clear supernatant was decanted and a portion was taken for cholesterol analysis. The residue was dissolved in 0.1N sodium hydroxide and a portion was taken for protein quantification by the method of Lowry et al. (J. Biol. Chem. 193 , 265; 1951). (C) Analysis Free cholesterol: Standard, sample and blank (isopropyl alcohol only) isopropyl alcoholic solvents were treated in a similar manner. Free reagent (Reagent A in Table 1 below) was added to a 10 x 75 mm disposable glass test tube to which 20μ of isopropyl alcoholic solution was added and mixed.
A 0.4 ml portion was added. After standing at room temperature for about 5 minutes, 0.8 ml of 0.5N sodium hydroxide (Reagent C in Table 1 below) was added and mixed. Fluorescence was then measured on an Aminco-Bowman fluorescence spectrometer with an absorption wavelength of 325 nm and an emission wavelength of 415 nm. In this case a xenon lamp, an IP28 phototube and a cuvette with a 1 cm light path under a 2 mm slit were used. Total Cholesterol: Total cholesterol was measured according to the same method as described above for free cholesterol, except that Test A was replaced by the total reagent (Reagent B in Table 1 below). The sample is
0.5N sodium hydroxide solution (Reagent C in Table 1 below)
The cells were incubated at 37°C for 20 minutes before addition of . Other analysis for cholesterol, i.e. process
The above step (C)) obtained from (A) and (B) can also be carried out by the method of Ishikawa et al. (J. Lipid Res. 15 , 286; 1974). The amount of cholesterol esters is obtained by subtracting the amount of free cholesterol of the cells determined in the assay by the total cholesterol content. A lower value of cholesterol esters in the cell group to which the test compound has been added compared to the control group (untreated) indicates that the test compound is active in reducing cholesterol esters in the cells. Table 1 Composition of reagents for the determination of cholesterol A Reagent for free cholesterol Sodium phosphate buffer PH 7.0 0.05M Cholesterol oxidase 0.08 U/ml Horseradish peroxidase 30.00 U/ml p-hydroxyphenyl Acetic acid 0.10mg/ml B Total cholesterol reagent Sodium phosphate buffer PH7.0 0.05M Cholesterol ester hydrolase
0.08U/ml Cholesterol Oxidase 0.08U/ml Forceradyl Peroxidase
30.00U/ml Sodium taurocholate 5.00mM Carbowax-6000 0.17mM p-Hydroxyphenylacetic acid 0.15mg/ml C Sodium hydroxide solution 0.5N A suitable daily dosage for the above application is 10mg
~5000 mg, suitably administered in divided doses of 2.5 to 2500 mg over 2 to 4 times per day or in slow-release form. A suitable daily dosage using a compound of formula a is from about 10 to about 1000 mg, suitably 2 mg per day.
Administered in ~4 divided doses of 2.5-500 mg or in slow-release form. A suitable daily dosage for a compound of formula b is from about 100 to about 5000 mg, preferably from about 100 to 2000 mg, suitably from 25 to 2500 mg two to four times per day.
Administered in divided doses or in slow-release form. The compounds can be mixed with conventional pharmaceutically acceptable diluents and carriers and optionally other excipients, and can be administered in the form of tablets or capsules. The following Preparations and Examples illustrate the invention. Preparation example 1 4,4-dimethyl-4-sila-tetradecene-
1. Compound Magnesium ribbon 73g under nitrogen
(3.04 mol), 570 ml of anhydrous tetrahydrofuran, and 183 g (172 ml, 1.42 mol) of dimethyldichlorosilane were added with 1- 205 g (0.928 mol) of bromdecane was added. After the addition and completion of the exothermic reaction, the mixture was stirred at 40° C. for 1 hour. When the sample was subjected to the Gilman test, all of the Grignard reagent had been consumed. The resulting mixture was concentrated under strictly anhydrous conditions and vacuum. The resulting semi-solid material was then mixed with 218 g (1.8 g) of allyl bromide.
mol) and 400 ml of anhydrous tetrahydrofuran while stirring at about 45-65°C. This exothermic reaction was controlled by cooling. Stirring was continued at 60°C for 16 hours. The mixture was then cooled, 2 portions of hexane were added, and the contents were poured into 318 g of aluminum chloride dissolved in ice water. The organic phase was separated after adding some ligroin. Then the product is 3
Washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was rectified using a packed column to obtain a fraction of 4,4-dimethyl-4-silatetetradecene-1: boiling point 69-81°/0.015-0.030 mm.
Hg. Preparation Example 2 4,4-dimethyl-4-silatetetradecanol. Compound Under nitrogen, keeping the temperature below 25℃,
166.4 g of 4,4-dimethyl-4-silatetetradecene-1 in 550 ml of anhydrous tetrahydrofuran
(0.69 mol) of 1M borane in tetrahydrofuran
270ml (0.81 equivalents) was added. The reaction mixture was left at 20° C. for 1/2 hour, then 10 ml of water was carefully added to decompose the excess hydride (H 2 evolution). When gas evolution had ceased, 140 g (0.39 mol) of triethylamine were added followed by 93 g (1.03 mol) of tert-butyl hydroperoxide while cooling to 5-10°C (due to exotherm). The reaction mixture was left at 20°C for 16 hours and concentrated under vacuum and below 40°C. This concentrate was partitioned between toluene and dilute aqueous sodium hydroxide, the organic phase was washed twice with water and slightly acidic (HCl) ferrous sulfate solution (to remove any remaining peroxide). 2 times with dilute hydrochloric acid and once with sodium bicarbonate solution,
Dry over sodium sulfate, filter, and concentrate under vacuum to give a colorless oil. This oil was then rectified under vacuum through a column containing stainless steel overhanging packings to give the title product; boiling point 110-114°C/0.035mm. Preparation Example 3 4,4-dimethyl-4-silatotradecanoic acid.
Compound A solution of 143.4 g (0.554 mol) of 4,4-dimethyl-4-silatetradecanol in 0.2 acetone was cooled to -10<0>C. Cool to -10° to 0°C and add Jones reagent (Jones) while stirring.
reagent) (8N oxidation equivalent of chromic acid in aqueous sulfuric acid)
302 ml (4.36 x 0.554 electron equivalents) was added over 30 minutes. Stirring was then continued for 45 minutes at -10° to 0°C and for 1 hour at 0° to 5°C. The mixture was warmed to 10° C. with stirring for 1/2 hour, then poured into ice and heptane. The resulting organic phase was washed three times with half-saturated sodium chloride solution and twice with water, dried over sodium sulfate, filtered and concentrated under vacuum to give an oil. Most of the resulting material is rectified through a column filled with stainless steel protruding packings,
The title product was obtained; boiling point 138-140°C/0.05mm. Preparation Examples 4-21 By following the method described above and using equivalent amounts of the corresponding starting materials, the following products (with the exception of R 2 and
R3 is CH3 ) obtained:
【表】
実施例 1
(+)−4,4−ジメチル−4−シラ−テトラ
デカノイル−1′−フエニルアミド。化合物
温度を20゜〜30℃に保ちながら、塩化メチレン
200ml中4,4−ジメチル−4−シラ−テトラデ
カン酸35g(128.5ミリモル)にトリエチルアミ
ン14.3g(128.5ミリモル)を添加した(発熱)。
得られた透明な溶液を、塩化メチレン100ml中ク
ロルギ酸エチル15.4g(128.5ミリモル)を添加
しながら0゜〜−20℃に維持し、式の混合無水物
を得た。次いで得られた混合物を3/4時間に亘つ
て15℃の温度にもつていき、次いで温度を20℃以
下に保ち且つ連続的に撹拌ながら(+)−α−メ
チルベンジルアミン34.4g(2×1.1×128.5ミリ
モル)を添加した。この混合物を20℃で3時間撹
拌し、氷上に注いだ。有機相を1N塩酸で2回及
び炭酸水素ナトリウム及び炭酸ナトリウム溶液の
混合物で1回洗浄し、硫酸ナトリウムで乾燥し、
過し及び真空下に濃縮して油47.2gを得た。
“クゲルロール(Kugelrohr)”装置を用いる精留
により、分析級の純度の表題の生成物を170〜177
℃/0.06mmHgの最後の画分として得た;融点32
〜34℃。
実施例 2
(±)−4,4−ジメチル−4−シラ−テトラ
デカノイル−1′−フエニル−2′−p−トリル−
エチルアミド(化合物)
乾燥したフラスコに、4,4−ジメチル−4−
シラーテトラデカン酸3.17g(11.6ミリモル)、
トリエチルアミン2.53g(23.2ミリモル)及び塩
化メチレン5mlを添加した。得られた溶液を氷浴
中で冷却した。撹拌し且つ温度を0℃に保ちなが
ら、塩化メチレン3ml中クロルギ酸エチル1.385
g(12.8ミリモル)の溶液を約1分間で添加し、
次いで得られた溶液を塩化メチレン2mlで処理し
た。得られた白色のスラリーを1時間0℃で撹拌
した。次いで氷溶中で撹拌しながら塩化メチレン
3ml中(±)1−フエニル−2−p−トリルエチ
ルアミン2.45g(11.6ミリモル)の溶液を添加
し、次いで塩化メチレン2mlで洗い込んだ。得ら
れた混合物を撹拌しながら室温まで暖めた。更に
48時間穏やかに撹拌し続けた。次いで反応混合物
を水約25mlで洗浄し、続いて水性抽出物が酸性に
なるまで有機相を稀塩酸で抽出した。次いで有機
相を炭酸水素ナトリウム溶液(PH=8)で洗浄
し、無水ナトリウムで乾燥し、過し、40℃で真
空下に濃縮して無色の油を得た。この油をシリカ
ゲルのクロマトグラフイーにかけ、1:1ヘキサ
ン:クロロホルムで流出させ、表題の化合物を得
た;融点39〜42゜。
実施例1及び2の方法に従い、及び対応する出
発物質を凡そ当量で用いることにより、次の式
の化合物(但しR2及びR3はメチルである)を得
た:[Table] Example 1 (+)-4,4-dimethyl-4-sila-tetradecanoyl-1'-phenylamide. Compound Methylene chloride while keeping the temperature between 20° and 30°C
14.3 g (128.5 mmol) of triethylamine were added to 35 g (128.5 mmol) of 4,4-dimethyl-4-sila-tetradecanoic acid in 200 ml (exothermic).
The resulting clear solution was maintained at 0 DEG to -20 DEG C. while adding 15.4 g (128.5 mmol) of ethyl chloroformate in 100 ml of methylene chloride to give a mixed anhydride of formula. The resulting mixture was then brought to a temperature of 15° C. for 3/4 hour and then 34.4 g (+)-α-methylbenzylamine (2× 1.1 x 128.5 mmol) was added. The mixture was stirred at 20°C for 3 hours and poured onto ice. The organic phase was washed twice with 1N hydrochloric acid and once with a mixture of sodium bicarbonate and sodium carbonate solution, dried over sodium sulfate,
Filtration and concentration under vacuum gave 47.2 g of oil.
Rectification using a “Kugelrohr” apparatus yields the title product of analytical purity from 170 to 177
Obtained as the last fraction at °C/0.06 mmHg; melting point 32
~34℃. Example 2 (±)-4,4-dimethyl-4-sila-tetradecanoyl-1'-phenyl-2'-p-tolyl-
Ethylamide (compound) In a dry flask, add 4,4-dimethyl-4-
3.17 g (11.6 mmol) of sylar tetradecanoic acid,
2.53 g (23.2 mmol) triethylamine and 5 ml methylene chloride were added. The resulting solution was cooled in an ice bath. 1.385 ethyl chloroformate in 3 ml of methylene chloride while stirring and keeping the temperature at 0°C.
g (12.8 mmol) of solution was added in about 1 minute,
The resulting solution was then treated with 2 ml of methylene chloride. The resulting white slurry was stirred for 1 hour at 0°C. A solution of 2.45 g (11.6 mmol) of (±) 1-phenyl-2-p-tolylethylamine in 3 ml of methylene chloride was then added with stirring in an ice solution, followed by washing with 2 ml of methylene chloride. The resulting mixture was allowed to warm to room temperature while stirring. Furthermore
Gentle stirring was continued for 48 hours. The reaction mixture was then washed with approximately 25 ml of water, followed by extraction of the organic phase with dilute hydrochloric acid until the aqueous extract became acidic. The organic phase was then washed with sodium bicarbonate solution (PH=8), dried over anhydrous sodium, filtered and concentrated under vacuum at 40° C. to give a colorless oil. Chromatography of this oil on silica gel, eluting with 1:1 hexane:chloroform, afforded the title compound; mp 39-42°. By following the methods of Examples 1 and 2 and using approximately equivalent amounts of the corresponding starting materials, compounds of the following formula, where R 2 and R 3 are methyl, were obtained:
【表】【table】
【表】【table】
【表】
下記表には、本発明の油状化合物のNMR値を
示す。値は0PPMにおける対照化合物であるテト
ラメチルシランを基準にしてPPMで示されてお
り、溶媒はCDCl3(D=重水素)である。表中で
は、次の記号が用いられている;S−一重線、D
−二重線、Q−四重線、M−多重線およびB−ブ
ロード(broad)。カツコ内の数はプロトンの数
である。[Table] The table below shows the NMR values of the oily compounds of the present invention. Values are expressed in PPM relative to the reference compound tetramethylsilane at 0 PPM, and the solvent is CDCl 3 (D=deuterium). In the table, the following symbols are used: S - singlet, D
- doublet, Q-quartet, M-multiplet and B-broad. The number in the box is the number of protons.
【表】【table】
Claims (1)
(C1〜4)アルキルもしくはアルコキシ又はトリ
フルオロメチルであり、 Rcは水素、(C1〜4)アルキル又は であり、 Y′は水素、弗素、塩素、臭素もしくは沃素、
又は(C1〜4)アルキルであり、或いは Rは (b) 式 のインドリル基であり、そして R4は(C1〜4)アルキルである] で表わされる化合物。 2 式a [式中、R′1はα−炭素原子以外で分岐していて
もよいC1〜22アルキルであり、 Raは特許請求の範囲第1項記載のと同義であ
り、及び Rc1は【式】であり、但しY″は弗 素、塩素、臭素もしくは沃素、又は(C1〜4)アル
キルである] で表わされる特許請求の範囲第1項に記載の化合
物。 3 式b [式中、R′1およびRaは特許請求の範囲第2項記
載のと同義であり、及び Rc2は(C1〜4)アルキルである] で表わされる特許請求の範囲第1記に記載の化合
物。 4 4,4−ジメチル−4−シラ−テトラデカノ
イル−1′−フエニル−2′−p−トリル−エチルア
ミドである特許請求の範囲第1項に記載の化合
物。 5 式 [式中、R1は(C1〜22)アルキルであり、 Rは (a) 式 のアラルキル基であり、 Raは水素、弗素、塩素、臭素もしくは沃素、
(C1〜4)アルキルもしくはアルコキシ又はトリ
フルオロメチルであり、 Rcは水素、(C1〜4)アルキル又は であり、 Y′は水素、弗素、塩素、臭素もしくは沃素、
又は(C1〜4)アルキルであり、或いは Rは (b) 式 のインドリル基であり、そして R4は(C1〜4)アルキルである] の化合物を製薬学的に許容しうる希釈剤又は担体
と共に含んでなる抗アテローム性動脈硬化剤。 6 式 [式中、R1は(C1〜22)アルキルであり、 Rは (a) 式 のアラルキル基であり、 Raは水素、弗素、塩素、臭素もしくは沃素、
(C1〜4)アルキルもしくはアルコキシ又はトリ
フルオロメチルであり、 Rcは水素、(C1〜4)アルキル又は 【式】であり、 Y′は水素、弗素、塩素、臭素もしくは沃素、
又は(C1〜4)アルキルであり、或いは Rは (b) 式 のインドリル基であり、そして R4は(C1〜4)アルキルである] の化合物を製造する方法であつて、式 H2N−R … [式中、Rは上述と同義である] の化合物を式 [式中、R1は上述と同義である] の化合物又はその反応性誘導体でアシル化するこ
とを特徴とする式の化合物の製造法。[Claims] 1 formula [In the formula, R 1 is (C 1-22 ) alkyl, R is the formula (a) is an aralkyl group, and Ra is hydrogen, fluorine, chlorine, bromine or iodine,
(C 1-4 ) alkyl or alkoxy or trifluoromethyl, Rc is hydrogen, (C 1-4 ) alkyl or and Y′ is hydrogen, fluorine, chlorine, bromine or iodine,
or (C 1-4 )alkyl, or R is the formula (b) is an indolyl group, and R 4 is (C 1-4 )alkyl]. 2 formula a [In the formula, R′ 1 is C 1-22 alkyl which may be branched at a point other than the α-carbon atom, Ra has the same meaning as described in claim 1, and Rc 1 is [Formula ], where Y″ is fluorine, chlorine, bromine or iodine, or (C 1-4 )alkyl]. 3 Formula b [In the formula, R' 1 and Ra have the same meanings as described in claim 2, and Rc 2 is (C 1-4 ) alkyl] compound. 4. The compound according to claim 1, which is 4,4-dimethyl-4-sila-tetradecanoyl-1'-phenyl-2'-p-tolyl-ethylamide. 5 formula [In the formula, R 1 is (C 1-22 ) alkyl, R is the formula (a) is an aralkyl group, and Ra is hydrogen, fluorine, chlorine, bromine or iodine,
(C 1-4 ) alkyl or alkoxy or trifluoromethyl, Rc is hydrogen, (C 1-4 ) alkyl or and Y′ is hydrogen, fluorine, chlorine, bromine or iodine,
or (C 1-4 )alkyl, or R is the formula (b) and R 4 is (C 1-4 )alkyl, together with a pharmaceutically acceptable diluent or carrier. 6 formula [In the formula, R 1 is (C 1-22 ) alkyl, R is the formula (a) is an aralkyl group, and Ra is hydrogen, fluorine, chlorine, bromine or iodine,
(C 1-4 ) alkyl or alkoxy or trifluoromethyl, Rc is hydrogen, (C 1-4 ) alkyl or [Formula], Y′ is hydrogen, fluorine, chlorine, bromine or iodine,
or (C 1-4 )alkyl, or R is the formula (b) is an indolyl group, and R 4 is (C 1-4 )alkyl] A method for producing a compound of the formula H 2 NR... [wherein R is as defined above] formula the compound [wherein R 1 has the same meaning as defined above] A method for producing a compound of the formula, characterized by acylation with the compound of the formula or a reactive derivative thereof.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US95441078A | 1978-10-25 | 1978-10-25 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5557594A JPS5557594A (en) | 1980-04-28 |
JPS6344159B2 true JPS6344159B2 (en) | 1988-09-02 |
Family
ID=25495394
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP13603879A Granted JPS5557594A (en) | 1978-10-25 | 1979-10-23 | 4*44dimethyll44silafatty acid amide*its manufacture and its pharmacological composition |
Country Status (2)
Country | Link |
---|---|
JP (1) | JPS5557594A (en) |
ZA (1) | ZA795705B (en) |
-
1979
- 1979-10-23 JP JP13603879A patent/JPS5557594A/en active Granted
- 1979-10-25 ZA ZA00795705A patent/ZA795705B/en unknown
Also Published As
Publication number | Publication date |
---|---|
ZA795705B (en) | 1981-05-27 |
JPS5557594A (en) | 1980-04-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2104306C1 (en) | Method of synthesis of optically active (2s)- or (2r)-endo-bicyclo-[2,2,1]-heptane-2-ol, method of synthesis of 5-(3-[(2r)-exo-bicyclo-[2,2,1]-hept-2-yloxy]-4-methoxyphenyl)- -3,4,5,6-tetrahydropyrimidine-2(1h)-one | |
CZ286579B6 (en) | 20-methyl substituted derivatives of vitamin D, process of their preparation, pharmaceutical preparations in which these substances are comprised and their use | |
Fodran et al. | Catalytic synthesis of enantiopure mixed diacylglycerols–synthesis of a major M. tuberculosis phospholipid and platelet activating factor | |
US4297349A (en) | Silicon-bearing carboxylic acids and amides | |
Rodríguez et al. | An efficient asymmetric synthesis of prostaglandin E1 | |
CA1066213A (en) | Process for the preparation of 4-hydroxycyclopent-2-en-1-one derivatives | |
JP4749336B2 (en) | Method for preparing 2,3,5-trimethylhydroquinone diacylate | |
EP0012183B1 (en) | 4,4 dialkyl-4-sila-fatty acid amides, intermediates and process for their preparation and pharmaceutical compositions containing them | |
US4415501A (en) | Alkenylzirconium reagents useful for prostaglandin analog synthesis | |
JPS6344159B2 (en) | ||
US4713380A (en) | Production of optically pure organoboranes | |
US4420475A (en) | Silicon-bearing amides | |
JPH072712A (en) | Structurally new acyclic tocotrienol analogue | |
US4201785A (en) | Cyclopropanyl-bearing hydrazides | |
JPS6323987B2 (en) | ||
US4098801A (en) | Synthesis of 1α-hydroxylated derivatives of cholesterol | |
US5055613A (en) | Metabolites of pentanedioic acid derivatives | |
US4456619A (en) | Amides of 2-alkynoic acids and use for inhibiting accumulation of cholesterol ester in arterial walls | |
EP0003221B1 (en) | Process for the manufacture of 3,4-dihydro-benzopyran derivatives and starting materials in this process | |
Varma et al. | Synthesis, configuration, and optical purity of asymmetric primary alcohols | |
US5233063A (en) | Metabolites of pentanedioic acid derivatives | |
US4296240A (en) | Silacycloalkane amides | |
US4611063A (en) | Silicon-bearing amides | |
Shuto et al. | Synthesis of two optical isomers of the insect anti-juvenile hormone agent fluoromevalonolactone (FMev) and their biological activities | |
US4808734A (en) | 16-cycloalkyl-7-fluoro-prostacyclins |