JPH0123445B2 - - Google Patents
Info
- Publication number
- JPH0123445B2 JPH0123445B2 JP55183727A JP18372780A JPH0123445B2 JP H0123445 B2 JPH0123445 B2 JP H0123445B2 JP 55183727 A JP55183727 A JP 55183727A JP 18372780 A JP18372780 A JP 18372780A JP H0123445 B2 JPH0123445 B2 JP H0123445B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- thiaprostaglandin
- platelet aggregation
- solution
- hydrogen atom
- 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 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- FGOJCPKOOGIRPA-UHFFFAOYSA-N 1-o-tert-butyl 4-o-ethyl 5-oxoazepane-1,4-dicarboxylate Chemical compound CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O FGOJCPKOOGIRPA-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 229940127218 antiplatelet drug Drugs 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000000106 platelet aggregation inhibitor Substances 0.000 claims description 8
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 claims description 7
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 150000001768 cations Chemical class 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 2
- 229910001415 sodium ion Inorganic materials 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 28
- 239000000203 mixture Substances 0.000 description 21
- -1 1-methylpentyl group Chemical group 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 11
- 239000007788 liquid Substances 0.000 description 10
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 8
- 238000000862 absorption spectrum Methods 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 150000002642 lithium compounds Chemical class 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 210000004623 platelet-rich plasma Anatomy 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000004220 aggregation Methods 0.000 description 7
- 230000002776 aggregation Effects 0.000 description 7
- 150000001336 alkenes Chemical group 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003708 ampul Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 4
- 150000003180 prostaglandins Chemical class 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 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 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000003701 inert diluent Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical compound O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 2
- 241000238557 Decapoda Species 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000004931 aggregating effect Effects 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- PNNJYDODNCALKD-UHFFFAOYSA-M benzenethiolate;copper(1+) Chemical compound [Cu+].[S-]C1=CC=CC=C1 PNNJYDODNCALKD-UHFFFAOYSA-M 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000012457 nonaqueous media Substances 0.000 description 2
- 125000000962 organic group Chemical group 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- YEYKMVJDLWJFOA-UHFFFAOYSA-N 2-propoxyethanol Chemical compound CCCOCCO YEYKMVJDLWJFOA-UHFFFAOYSA-N 0.000 description 1
- KFTKJPWFFSOXRV-UHFFFAOYSA-N 4-[tert-butyl(dimethyl)silyl]oxy-6-oxabicyclo[3.1.0]hexan-2-one Chemical compound CC(C)(C)[Si](C)(C)OC1CC(=O)C2OC12 KFTKJPWFFSOXRV-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
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- ORKSTPSQHZNDSC-IDIVVRGQSA-L disodium;[[(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphate Chemical class [Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP(O)([O-])=O)[C@@H](O)[C@H]1O ORKSTPSQHZNDSC-IDIVVRGQSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000012155 injection solvent Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- SJWMQRJTNFZGFV-UHFFFAOYSA-N methyl 6-sulfanylhexanoate Chemical compound COC(=O)CCCCCS SJWMQRJTNFZGFV-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 150000002900 organolithium compounds Chemical class 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003018 phosphorus compounds Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229940057847 polyethylene glycol 600 Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002997 prostaglandinlike Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 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
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- XTTGYFREQJCEML-UHFFFAOYSA-N tributyl phosphite Chemical compound CCCCOP(OCCCC)OCCCC XTTGYFREQJCEML-UHFFFAOYSA-N 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- SJHCUXCOGGKFAI-UHFFFAOYSA-N tripropan-2-yl phosphite Chemical compound CC(C)OP(OC(C)C)OC(C)C SJHCUXCOGGKFAI-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は新規な７−チアプロスタグランジン
E1誘導体、その製造法およびそれを有効成分と
する血小板凝集阻止剤に関する。
天然プロスタグランジン類は生物学的および薬
理学的に高度な活性を持つ局所ホルモンとして知
られており、それ故にそれらの誘導体に関する研
究も数多く行なわれている。天然型プロスタグラ
ンジン類の中でもプロスタグランジンE1は強い
血小板凝集抑制作用、血管拡張作用等を有し、臨
床への応用が期待されている。
従来、特開昭53−68753号公報において下記式
〔〕、
〔式中、Ａ，Ｂは同一若しくは異なり、二価の有
機基、R1，R2，R3は同一若しくは異なり、水素
原子又は一価の有機基、R4，R5は水素原子又は
保護されていてもよい水酸基を表わす。〕
で表わされるチアプロスタン酸誘導体およびその
製造方法が報告されている。その報告によると上
記チアプロスタン酸誘導体は胃酸分秘抑制作用お
よび抗炎症剤によつて誘起される潰瘍に対しての
阻止作用を有し、抗潰瘍剤として有用性のある化
合物であることが明記されている。しかし上記チ
アプロスタン酸誘導体の血小板凝集阻止作用につ
いては何ら記載されていない。また上記一般式
〔〕で表わされるチアプロスタン酸誘導体のう
ちでR5が保護されていてもよい水酸基である場
合に相当する実験的な裏付けが実施例として具体
的に記載されていない。
本発明者らは、上記一般式〔〕においてR5
が保護されていてもよい水酸基の場合に相当する
新規チアプロスタン酸誘導体に関して鋭意研究し
た結果、その合成に成功した。しかも得られた化
合物は、驚くべきことに強い血小板凝集阻止作用
を示すことを見出し、本発明に到達したものであ
る。
しかるに本発明は、下記式〔〕
〔式中、R1は水素原子、低級アルキル基、ま
たは薬理学的に許容しうる陽イオンを表わし、
R2は水素原子またはメチル基を表わし、R3は炭
素数５〜７のアルキル基もしくはシクロアルキル
基を表わし、R4およびR5は水素原子または水酸
基の保護基を表わす。記号＊は不斉炭素原子を表
わし、その立体配置はαは配置またはβ配置ある
いは両者の任意の割合の混合物である。〕
で表わされる７−チアプロスタグランジンE1誘
導体およびその鏡像体あるいはそれら任意の割合
の混合物およびその製造法並びにそれを有効成分
とする血小板凝集阻止剤である。
上記式〔〕中、R1は水素原子、低級アルキ
ル基、または薬理学的に許容しうる陽イオンを表
わす。低級アルキル基としてはメチル基、エチル
基、プロピル基、ブチル基などの炭素数１〜４の
アルキル基をあげることができるが、水素原子、
メチル基が特に好ましい。薬理学的に許容しうる
陽イオンとしてはナトリウム、カリウムなどのア
ルカリ金属イオンやカルシウム、アンモニウム、
エタノールアミン、ジエタノールアミン、モルホ
リンなどがあげられるが、ナトリウムイオンが特
に好ましい。
R2は水素原子またはメチル基を表わし、R3は
炭素数５〜７のアルキル基もしくはシクロアルキ
ル基を表わす。炭素数５〜７のアルキル基もしく
はシクロアルキル基としては、ペンチル基、ヘキ
シル基、ヘプチル基、１−メチルペンチル基、１
−メチルヘキシル基、１，１−ジメチルペンチル
基、２−メチルペンチル基、２−メチルヘキシル
基、シクロペンチル基、シクロヘキシル基、シク
ロヘプチル基を表わすが、なかでもペンチル基、
ヘキシル基、２−メチルヘキシル基、シクロヘキ
シル基が好ましく、特にシクロヘキシル基は好ま
しい。
R4，R5は水素原子または水酸基の保護基を表
わし、同一であつても異なつていてもよい。水酸
基の保護基としてはｔ−ブチルジメチルシリル
基、ジフエニルメチルシリル基等のシリルエーテ
ル類、メトキシメチル基、１−エトキシエチル
基、１−エトキシ−２−プロピル基、メトキシエ
トキシメチル基、メチルチオメチル基、ベンジル
オキシメチル基、テトラヒドロピラン−２−イル
基等のアセタール類などが用いられるが、特に好
ましく用いられるのはｔ−ブチルジメチルシリル
基またはテトラヒドロピラン−２−イル基などで
ある。
記号＊は不斉炭素原子を表わし、その立体配置
はα配置またはβ配置あるいは両者の任意の混合
物である。立体配置がα配置とは下記式〔−
１〕
〔式中、R1，R2，R3，R4，R5は前記定義に同
じ。〕で表わされる立体異性体を表わし、β配置
はその逆の立体構造の下記式〔−２〕、
〔式中、R1，R2，R3，R4，R5は前記定義に同
じ。〕で表わされる立体異性体を表わす。天然の
プロスタグランジン類の立体構造は上記式〔−
１〕で表わされるようなα配置を有しており、そ
の意味で本発明の７−チアプロスタグランジン
E1誘導体の立体配置はα配置の方が好ましい。
また上記式〔〕で表わされる化合物の鏡像体
とは下記式〔−３〕
〔式中、R1，R2，R3，R4，R5は前記定義に同
じ。〕で表わされる立体異性体を表わす。後述す
るように本発明の７−チアプロスタグランジン
E1誘導体の製造法の特徴に起因して、上記式
〔〕と〔−３〕とが同時に生成し、両者とも
有用であるが、天然のプロスタグランジン類の立
体構造と同じ立体構造をもつ上記式〔〕で表わ
される７−チアプロスタグランジンE1誘導体が
好ましい。
本発明により提供される７−チアプロスタグラ
ンジンE1誘導体の具体例を示すと以下の通りで
ある。
１ ７−チアプロスタグランジンE1
２ 20−メチル−７−チアプロスタグランジン
E1
３ 17，20−ジメチル−７−チアプロスタグラン
ジンE1
４ 16，17，18，19，20−ペンタノル−15−シク
ロヘキシル−７−チアプロスタグランジンE1
５ 15−メチル−７−チアプロスタグランジン
E1
６ １）〜５）の化合物の15−エピマー
７ １）〜６）の化合物のメチルエステル
８ １）〜６）の化合物のナトリウム塩、カリウ
ム塩、アンモニウム塩、カルシウム塩、エタノ
ールアミン塩、ジエタノールアミン塩、あるい
はモルホリン塩
９ １）〜７）の化合物の水酸基がｔ−ブチルジ
メチルシリル基またはテトラヒドロピラン−２
−イル基で保護された化合物
10 １）〜９）の化合物の８位、11位、および12
位トリエビ体
等が挙げられるが、これらに限定されるものでは
ない。
本発明の７−チアプロスタグランジンE1誘導
体は下記式〔〕
〔式中、R11は低級アルキル基を表わし、R41
は水酸基の保護基を表わす。〕
で表わされる化合物あるいはその鏡像体あるいは
それらの任意の割合の混合物であるチアシクロペ
ンテノン誘導体と下記式〔〕
〔式中、R2，R3、記号＊は前記定義に同じで
あり、R51は水酸基の保護基を表わす。〕
で表わされる有機銅リチウム化合物とを非プロト
ン性不活性有機媒体の存在下に反応にせしめ、次
いで必要に応じて脱保護及び／又は加水分解及
び／又は塩生成反応に付することによつて製造さ
れる。
本発明の７−チアプロスタグランジンE1誘導
体の合成経路を、その原料化合物の合成経路も含
めて図示すると次のようになる。
〔上記図中、R2，R3、記号＊は前記定義に同
じ。R41，R51は水酸基の保護基を表わし、R11は
低級アルキル基を表わす。〕
なお、出発原料としてdl体を用いると、途中の
中間体は図示した化合物とその鏡像体との混合物
として合成経路を進んで行き、適当な段階におい
てクロマトグラフイー等の手段を用いて単離する
ことにより各々の立体異性体を純品として単離す
ることができる。
本発明方法において、原料化合物の一つである
上記式〔〕で表わされる有機銅リチウム化合物
は、例えば有機リチウム化合物と第１銅塩とを反
応させることにより製造することができる〔例え
ばG.H.Rosner，Organic Reaction，vol.19，１
（1972）などを参照〕。また本発明方法では有機銅
リチウム化合物として、前記式〔〕で表わされ
る化合物を、三価のリン化合物、例えば、トリア
ルキルホスフイン（例えば、トリエチルホスフイ
ン、トリーｎ−ブチルホスフインなど）、トリア
ルキルホスフアイト（例えば、トリメチルホスフ
アイト、トリエチルホスフアイト、トリイソプロ
ピルホスフアイト、トリ−ｎ−ブチルホスフアイ
トなど）、ヘキサメチルホスホラストリアミド、
あるいはトリフエニルホスフインなどとの錯体と
して用いてもよい。
本発明方法は前記式〔〕で示されるチアシク
ロペンテノン誘導体を前記式〔〕で示される有
機銅リチウム化合物と非プロトン性不活性有機媒
体の存在下に反応せしめることにより行なわれ
る。
該チアシクロペンテノン誘導体と該有機銅リチ
ウム化合物とは化学量論的には等モル反応を行な
うが、通常、チアシクロペンテノン誘導体１モル
に対し0.5〜5.0モル倍、特に好ましくは0.8〜2.0
モル倍の有機銅リチウム化合物を用いて行なわれ
る。
反応温度は−100℃〜50℃、特に好ましくは−
78℃〜０℃程度の温度範囲が採用される。反応時
間は反応温度により異なるが通常−78℃〜−20℃
にて約１時間反応せしめれば充分である。
反応は有機媒体の存在下に行なわれる。反応温
度下において液状であつて、反応試剤とは反応し
ない不活性の非プロトン性の有機媒体が用いられ
る。
かかる非プロトン性不活性有機媒体としては、
例えば、ペンタン、ヘキサン、ヘプタン、シクロ
ヘキサンの如き飽和炭化水素類、ベンゼン、トル
エン、キシレンの如き芳香族炭化水素類、ジエチ
ルエーテル、テトラヒドロフラン、ジオキサン、
ジメトキシエタン、ジエチレングリコールジメチ
ルエーテルの如きエーテル系溶媒、その他ヘキサ
メチルホスホリツクトリアミド（HMP）、Ｎ，
Ｎ−ジメチルホルムアミド（DMF）、Ｎ，Ｎ−ジ
メチルアセトアミド（DMAC）、ジメチルスルホ
キシド、スラホラン、Ｎ−メチルピロリドンの如
きいわゆる非プロトン性極性溶媒等があげられ、
二種以上の溶媒の混合溶媒として用いることも可
能である。また、かかる非プロトン性不活性有機
媒体としては、有機銅リチウム化合物を製造する
に用いられた不活性媒体を、そのまま用いること
もできる。すなわち、この場合有機銅リチウム化
合物を製造した反応系内に該チアシクロペンテノ
ン誘導体を添加せしめて反応を行なえばよい。有
機媒体の使用量は反応を円滑に進行させるに十分
な量があれば良く、通常は原料の１〜100倍容量、
好ましくは２〜20倍容量が用いられる。
かくして、上記式〔〕で表わされる化合物の
ち、その水酸基が保護され、かつその１位のカル
ボン酸のエステル体が得られる。次いで必要に応
じその水酸基の保護基を通常の方法によつて遊離
の水酸基とし、及び／又は、そのエステル体を通
常に用いられる方法により加水分解及び／又は塩
生成することによつて、本発明の７−チアプロス
タグランジン誘導体が製造される。
反応後、得られる生成物は通常の手段により反
応液から分離、精製される。例えば抽出、洗浄、
クロマトグラフイーあるいはこれらの組み合わせ
により行なわれる。
以上のような方法により製造される上記式
〔〕（〔−１〕、〔−２〕、および〔−３〕を
含む）で表わされる７−チアプロスタグランジン
E1誘導体は血小板凝集抑制作用、血管拡張作用
等のプロスタグランジン様作用を有し、これらの
生理作用により期待される医薬品、例えば血栓症
治療薬または予防薬、血小板凝集阻止剤、降圧剤
などとして有用である。
これらの化合物は、上記目的のために、経口的
にあるいは直腸内、皮下、筋肉内、静脈内等の非
経口的に投与されうるが、好適には経口投与また
は静脈投与によるのがよい。
経口投与のためには、固形製剤あるいは液体製
剤とされる。固定製剤としては、錠剤、丸剤、散
剤、あるいは顆粒剤がある。このような固定製剤
においては１つまたはそれ以上の活性物質が少な
くとも１つの不活性な希釈剤、例えばよく用いら
れる重炭酸ナトリウム、炭酸カルシウム、バレイ
シヨデンプン、シヨ糖、マンニト−ル、カルボキ
シメチルセルロースなどと混合される。製剤は常
法に従つて行なわれるが、希釈剤以外の添加剤、
例えばステアリン酸カルシウム、ステアリン酸マ
グネシウム、グリセリンのような潤滑剤を含有し
ていてもよい。
経口投与のための液体製剤は、薬剤的に受容さ
れる乳濁剤、溶液剤、顕濁剤、シロツプ剤あるい
はキシル剤を含み、一般的に用いられる不活性な
希釈剤、例えば水あるいは流動パラフインを含
む。
この製剤は、不活性な希釈剤以外に補助剤、例
えば湿潤剤、懸濁補助剤、甘味剤、風味剤、芳香
剤、安定剤、あるいは防腐剤を含む。
また、この液体製剤はゼラチンのような吸収さ
れる物質でつくられたカプセルに入れて投与して
もよい。
直腸内投与のための固形製剤としては、１つま
たはそれ以上の活性物質を含み、それ自体公知の
方法により製造される坐薬が含まれる。
非経口投与の製剤は、無菌の水性あるいは非水
性溶液剤、懸濁剤、または乳濁剤である。非水性
の溶液または懸濁剤としては、例えばプロピルグ
リコール、ポリエチレングリコールまたはオリー
ブ油のような植物油、オレイン酸エチルのような
注射しうる有機エステルがある。このような製剤
はまた、防腐剤、顕潤剤、乳化剤、分散剤、安定
剤のような補助剤を含むことができる。これら
は、例えばバクテリア保留フイルターをとおす
過、殺菌剤の配合、あるいは照射によつて無菌化
できる。また無菌の固形製剤を製造し、使用直前
に無菌水または無菌の注射用溶媒に溶解して使用
することができる。
本発明の活性化合物である７−チアプロスタグ
ランジンE1誘導体の投与量は、１日、体重Kgあ
たり0.001〜200mgであり、0.01〜50mgが好まし
い。これらの投与量は、患者の病状、体重、年令
あるいは投与経路により左右される。
以上のとおり、本発明で提供する新規な７−チ
アプロスタグランジンE1誘導体は、従来の11−
デオキシ−７−チアプロスタン酸誘導体（特開昭
53−68753）が抗潰瘍作用に優れているのに比較
して、優れた血小板凝集阻止作用を有するという
特徴ある生理作用を示すものである。
以下、実施例をあげ、本発明を更に具体的に説
明する。
参考例 １
dl−４−ｔ−ブチルジメチルシロキシ−２−シ
クロペンテノン（2.12ｇ，10mmol）をメタノー
ル（25ml）に溶解し、０℃に冷却し、30％過酸化
水素水（５ml，45mmol）を加えた。その中に
2Nカセイソーダ水溶液を数滴加えて30分間撹拌
した。メタノールを減圧留去し、残渣に水を加え
エーテル抽出後、乾燥（MgSO4）し、減圧濃縮
して、dl−４−ｔ−ブチルジメチルシロキシ−
２，３−エポキシシクロペンタノンを粗生成物と
して得た。このものをメタノール（20ml）に溶か
し、その中にメチル６−メルカプトヘキサノエー
ト（1.62ｇ，10mmol）のメタノール（10ml）溶
液を加え、さらにトリエチルアミン（１ml）を加
え、窒素雰囲気下室温で18時間撹拌した。反応後
減圧留去し、残渣をそのままカラムクロマトグラ
フイー（シリカゲル、ヘキサン：酢酸エチル＝
６：１）にかけて生成物を分離しdl−４−ｔ−ブ
チルジメチルシロキシ−２−（６−メトキシカル
ボニルヘキシルチオ）−２−シクロペンテノン
（2.24ｇ，6.02mmol，60.2％）を得た。
核磁気共鳴吸収（CDCl3，δ（ppm））：
0.15（6H，ｓ，SiMl2），
0.89（9H，ｓ，tBu），
1.4〜1.8（6H，ｍ），
2.0〜3.0（6H，ｍ），
3.61（3H，ｓ，COOCH3），
4.90（1H，ｍ，C4HOSi），
6.73（1H，ｄ，Ｊ＝３Hz，C3−Ｈ）。
赤外吸収スペクトル（KBr，cm-1）：
1740，1715。
質量スピクトル（12eV；ｍ／ｅ，％）：
372（M+，２），322（16），
315（27），120（60），
97（68），69（100）。
参考例 ２
３（Ｓ）−ｔ−ブチルジメチルシロキシ−１−ヨ
ード−トランス−１−オクテン（305mg，
0.828mmol）のエーテル溶液（３ml）に1.5Mの
ｔ−ブチルリチウムのペンタン溶液（1.1ml，
1.66mmol）を−78℃で加え、２時間撹拌した。
この溶液に、フエニルチオ銅（）（86mg，
0.5mmol）のエーテル（２ml）懸濁液にヘキサメ
チルホスホラストリアミド（163mg，1.0mmol）
を加え、室温で均一溶液になるまで撹拌して得ら
れた溶液を加え、−78℃で１時間撹拌した。この
溶液に実施例１で得られたシクロペンテノン
（154mg，0.414mmol）のエーテル（３ml）、テト
ラヒドロフラン（１ml）、ヘキサメチルホスホリ
ツクトリアミド（0.3ml）の溶液を加え、−78℃で
15分、−40℃で１時間、−20℃で１時間反応させ
た。反応終了後、アンモニアを含んだ塩化アンモ
ニウム溶液を加え、水層をエーテル（２×100ml）
で抽出し、塩化アンモニウム水溶液で洗浄後、乾
燥（MgSO4）、濃縮して449mgの粗生成物を得た。
これを調整用薄層クロマトグラフイー（ヘキサ
ン：酢酸エチル＝６：１）に付して11，15（Ｓ）−
ビス（ｔ−ブチルジメチルシリル）−７−チアプ
ロスタグランジンE1メチルエステルとその15−
エビ鏡像体の混合物（156mg，0.254mmol，61.4
％）を得た。
核磁気共鳴吸収（CDCl3，δ（ppm））：
0.07（12H，ｓ，SiMe2），
0.87（21H，ｓ，tBuと末端CH3），
1.1〜1.8（14H，ｍ），
2.1〜3.0（7H，ｍ），
3.37（1H，ｍ，C8−Ｈ），
3.61（3H，ｓ，COOCH3），
〜4.1（2H，ｍ，C11−ＨとC15−Ｈ），
5.43〜5.65（2H，ｍ，オレフインプロトン）。
赤外吸収スペクトル（液膜，cm-1）：
1740，1260，1120，965，
835，775。
参考例 ３
参考例２で得られたビスシリルエーテル156mg
（0.25mmol）を酢酸（３ml）、水（１ml）、テトラ
ヒドロフラン（１ml）に溶かし室温で48時間撹拌
した。トルエン（100ml）を加え減圧で濃縮し、
２回くり返して粗生成物112mgを得た。このもの
を調整用薄層クロマトグラフイー（ヘキサン：酢
酸エチル＝１：３）にかけて分離し７−チアプロ
スタグランジンE1メチルエステル（14mg，
0.036mmol，14.3％）とその15−エビ鏡像体（15
mg，0.039mmol，15.3％）と未完脱保護体（60
mg）とを得た。
７−チアプロスタグランジンE1メチルエステル
（No.１）
薄層クロマトグラフイー（ヘキサン：酢酸エチル
＝１：４）：
Rf＝0.35
核磁気共鳴吸収（CDCl3，δ（ppm））：
0.89（3H，ｍ，末端CH3），
1.1〜1.8（14H，ｍ），
2.1〜3.1（10H，ｍ），
3.61（3H，ｓ，COOCH3），
3.90〜4.25（2H，ｍ，C11
−ＨとC15−Ｈ），
5.5〜5.75（2H，ｍ，オレフインプロトン）。
赤外吸収スペクトル（液膜，cm-1）：
3400，1735，1255，
1200，1165，1125，
1075，1010，960。
質量スペクトル（20eV；ｍ／ｅ，％）：
386（M+，２），368（27），
350（16），337（７），
269（28），237（74），
207（59），190（78），
119（91），99（100）。
７−チアプロスタグランジンE1メチルエステ
ルの15−エビ鏡像体（No.２）
薄層クロマトグラフイー（ヘキサン：酢酸エチル
＝１：４）：
Rf＝0.40
核磁気共鳴吸収（CDCl3，δ（ppm））：
0.88（3H，ｍ，末端CH3），
1.1〜1.8（14H，ｍ），
2.1〜2.8（10H，ｍ），
3.64（3H，ｓ，COOCH3），
3.85〜4.25（2H，ｍ，C11−ＨとC15−Ｈ），
5.6〜5.8（2H，ｍ、オリフインプロトン）。
赤外吸収スペクトル（液膜、cm-1）：
3420，1740，1260，
1205，1175，1130，
1080，1010，970。
質量スペクトル（20eV；ｍ／ｅ，％）：
386（M+，３），368（25），
350（12），298（17），
237（29），225（40），
207（72），190（40），
129（48），119（50），
118（50），99（100）。
参考例 ４
３（Ｓ）−ｔ−ブチルジメチルシロキシ−３−シ
クロヘキシル−１−ヨード−トランス−１−プロ
ペン（1.46ｇ，3.84mmol）のエーテル溶液（10
ml）に1.4Mのｔ−ブチルリチウムのペンタン溶
液（5.5ml，7.68mmol）を−78℃で加え、２時間
撹拌した。この溶液に、フエニルチオ銅（）
（795mg，4.61mmol）のエーテル（５ml）懸濁液
にヘキサメチルホスホラストリアミド（1.50ｇ，
9.22mmol）を加え、室温で均一溶液になるまで
撹拌して得られた溶液を加え、−78℃で１時間撹
拌した。この溶液に参考例２と同様にして参考例
１で得られたシクロペンテノン（930mg，
2.5mmol）と反応させ、同様に後処理して3.7ｇ
の粗生成物を得た。このものをシリカゲルカラム
クロマトグラフイー（ヘキサン：酢酸エチル＝
９：１）にかけて単離し11，15（Ｓ）−ビス（ｔ−
ブチルジメチルシリル）−16，17，18，19，20−
ペンタノル−15−シクロヘキシル−７−チアプロ
スタグランジンE1メチルエステルとその15−エ
ビ鏡像体の混合物（900mg，1.44mmol，57.5％）
を得た。
核磁気共鳴吸収（CDCl3，δ（ppm））：
0.06（12H，ｓ，SiCH3），
0.84（18H，ｓ，tBu），
1.0〜1.9（17H，ｍ）
2.1〜3.0（3H，ｍ），
3.56（3H，ｓ，COOCH3），
3.75（3H，ｍ，C11−ＨとC15−Ｈ），
5.3〜5.6（2H，ｍ，オレフインプロトン）。
赤外吸収スペクトル（液膜、cm-1）：
1740，1255，1110，
1070，1050，885，
840，780。
参考例 ５
参考例４で得られたビスシリルエーテル（900
mg，1.44mmol）を参考例３と同様にして酢酸
（30ml）、水（10ml）、THF（10ml）に溶かし、室
温で３日間反応させて脱シリルさせた。同様の後
処理により粗生成物を得、これをシリカゲルカラ
ムクロマトグラフイー（ヘキサン：酢酸エチル＝
１：３）に付して分離し、16，17，18，19，20−
ペンタノル−15−シクロヘキシル−７−チアプロ
スタグランジンE1メチルエステル（100mg，
0.25mmol，17％）とその15−エピ鏡像体（64mg，
0.16mmol，11％）とを得た。
16，17，18，19，20−ペンタノル−15−シクロヘ
キシル−７−チアプロスタグランジンE1メチル
エステル（No.３）
薄層クロマトグラフイー（ヘキサン：酢酸エチル
＝１：４）：
Rf＝0.25
核磁気共鳴吸収（CDCL3，８（ppm））：
0.9〜1.9（17H，ｍ），
2.1〜3.4（10H，ｍ），
3.61（3H，ｓ，COOCH3），
3.7〜4.5（2H，ｍ，C11−Ｈと
C15−Ｈ），
5.47〜5.73（2H，ｍ、オレフインプロトン）。
赤外吸収スペクトル（液膜、cm-1）：
3410，1735，1260，
1200，1170，1080，
1000，970，890，730。
質量スペクトル（20eV；ｍ／ｅ，％）：
398（M+，２），380（28），
367（３），362（18），
269（38），265（42），
237（100），220（39），
219（42），202（93），
83（97）。
16，17，18，19，20−ペンタノル−15−シクロ
ヘキシル−７−チアプロスタグランジンE1メチ
ルエステルの15−エビ鏡像体
薄層クロマトグラフイー（ヘキサン：酢酸エチル
＝１：４）：
Rf＝0.40
核磁気共鳴吸収（CDCl3，δ（ppm））：
0.9〜2.0（17H，ｍ），
2.1〜3.35（10H，ｍ），
3.61（3H，ｓ，COOCH3），
3.83（2H，ｍ，C11−ＨとC15−Ｈ），
5.57〜5.73（2H，ｍ，オレフインプロトン）。
赤外吸収スペクトル（液膜、cm-1）：
3430，1735，1260，
1200，1170，1080，
1000，970，915，730。
質量スペクトル（20eV；ｍ／ｅ，％）：
398（M+，１），380（23），
367（１），362（16），
269（40），265（32），
237（96），219（32），
202（88），119（56），
101（60），83（100）。
参考例 ６
子ぶたのすい臓のリパーゼ（シグマ社製）５ｇ
を0.1M塩化ナトリウム、0.05Mの塩化カルシウ
ム水溶液50mlに乳濁させ０℃で1.5時間激しく撹
拌した。これを高速冷却遠心機（9000rpm）にか
け、２℃で30分間遠心分離した。上澄液を分取し
0.1N NaOHでPH７に中和して粗酵素溶液を得
た。これに参考例５で得られた16，17，18，19，
20−ペンタノル−15−シクロヘキシル−７−チア
プロスタグランジンE1メチルエステル（50mg、
0.126mmol）の0.8mlアセトン溶液を加え４℃で
20分間超音波反応装置にて加水分解反応を行なつ
た。反応液を300mlのアセトン中に注ぎ、不溶物
をセライトで口別した後、得られたアセトン溶液
を減圧濃縮した。残つた水層（約50ml）に飽和硫
酸アンモニウム水溶液と酢酸エチル（200ml）を
加えて抽出し、飽和食塩水で洗浄、乾燥
（MgSO4）し、濃縮して、60mgの粗生成物を得
た。これを薄層クロマトグラフイー（ヘキサン：
酢酸エチル：酢酸＝30：70：１）に付し16，17，
18，19，20−ペンタノル−15−シクロヘキシル−
７−チアプロスタグランジンE1（No.４）（17mg，
0.044mmol，35％）を得た。
核磁気共鳴吸収（CDCl3，δ（ppm））：
0.8〜1.9（17H，ｍ），
1.9〜3.1（8H，ｍ），
3.7〜4.3（2H，ｍ，C11−ＨとC15−Ｈ），
5.53（3H，bs，OHとCOOH），
5.61（2H，ｍ、オレフインプロトン）。
参考例 ７
参考例６と同様の加水分解方法により16，17，
18，19，20−ペンタノル−15−シクロヘキシル−
７−チアプロスタグランジンE1メチルエステル
の15−−エピ鏡像体（（32mg、0.080mmol）から
対応するカルボン酸（No.５）（13mg，0.034mmol、
42％）を得た。
核磁気共鳴吸収スペクトル（CDCl3，δ
（ppm））：
0.8〜1.9（17H，ｍ），
2.1〜3.1（8H，ｍ），
3.7〜4.2（2H，ｍ，C11−ＨとC15−Ｈ），
4.93（3H，bs，OHとCOOH），
5.55〜5.77（2H，ｍ、オレフインプロトン）。
実施例１ （in vitro血小板凝集阻止作用）
本発明の７−チアプロスタグランジンE1誘導
体のin vitroにおける血小板凝集阻止作用を家兎
PRPを用いて測定した。
結果は血小板凝集の50％阻止濃度（IC50）で示
した。凝集剤はADP2ナトリウム塩を用いた。
〔PRP、薬物、凝集剤の調製〕
(1) PRP（富血小板血漿）の調整
体重2.0〜3.0Kgの雄性在来白色雄性家兎より心
臓穿刺法によつてクエン酸血（3.8％クエン酸ソ
ーダ１容と血液９容の割合）を採取した。
得られたクエン酸血を1.000rpmで10分間室温
で遠心し、上澄（PRP）を分離した。
得られたPRPは室温に保存し、なるべく早く
使用するようにし、調製後４時間を経過したもの
は使用しなかつた。
(2) 薬物の調整
被検薬物は一般的には10mg／mlとなるようにエ
チルアルコールに溶解し、生理含塩水で稀釈して
1.0μg／ml、0.3μg／ml、0.1μg／ml、0.03μg／ml、
0.01μg／ml、0.003μg／mlの溶液を各１mlづつ調
整した。
血小板凝集阻止試験の結果、0.003μg／ml（終
濃度に換算して0.0003μg／ml）でも薬物が血小板
の凝集を完全に抑制している場合には、さらにそ
の薬物溶液を生理食塩水にて稀釈して行きそれぞ
れの稀釈液についてさらに血小板阻止試験を行つ
た。
(3) 凝集剤の調整
協和醗酵社製ADP2ナトリウムを0.1Mトリス
−塩酸緩衝液（PH7.8）にて溶解して100μMADP
ナトリウム塩溶液を調整した。
〔血小板凝集阻止試験〕
(1) ブランクの血小板凝集度
アグリゴメーターの37℃のキユベツト中であら
かじめ温ためておいて200μlのPRPに25μlの生理
食塩水と25μlの凝集剤溶液を加えて血小板を凝集
させ、その凝集曲線を理化電機社製アブリコメー
ターにて３分間記録した。この血小板凝集におけ
る最大凝集度をブランクの最大凝集度とした。
(2) 血小板凝集阻止試験
200μlのPRPに25μlの被検薬物溶液を加え、上
記(2)と同様にして37℃２分間プレインキユベーシ
ヨンした後、ADP2ナトリウム溶液25μlを加えて
凝集曲線を３分間記録し、その時間内における血
小板の最大凝集度を潤定して阻害率を下記式にて
算出した。阻害率が50％を越す薬物の最低濃度を
IC50値として示した。
阻害率＝100−
（被検薬物添加糸の最大凝集度／ブランクの最大凝
集度×100）
結果は表に示した通りである。
The present invention is a novel 7-thiaprostaglandin
The present invention relates to an E 1 derivative, a method for producing the same, and a platelet aggregation inhibitor containing the same as an active ingredient. Natural prostaglandins are known as local hormones with high biological and pharmacological activity, and therefore many studies have been conducted on their derivatives. Among natural prostaglandins, prostaglandin E 1 has strong platelet aggregation inhibitory and vasodilatory effects, and is expected to have clinical application. Conventionally, in Japanese Patent Application Laid-Open No. 53-68753, the following formula [], [In the formula, A and B are the same or different and are divalent organic groups; R 1 , R 2 and R 3 are the same or different and are hydrogen atoms or monovalent organic groups; R 4 and R 5 are hydrogen atoms or protected Represents a hydroxyl group that may be ] A thiaprostanoic acid derivative represented by the following and a method for producing the same have been reported. According to the report, the above-mentioned thiaprostanic acid derivatives have an effect of suppressing gastric acid secretion and an effect of inhibiting ulcers induced by anti-inflammatory drugs, and are clearly stated to be useful compounds as anti-ulcer agents. ing. However, nothing is described about the platelet aggregation inhibiting effect of the above-mentioned thiaprostanic acid derivatives. Moreover, no experimental evidence is specifically described in the examples for the case where R 5 is an optionally protected hydroxyl group in the thiaprostanoic acid derivative represented by the above general formula []. The present inventors have discovered that in the above general formula [], R 5
As a result of intensive research on new thiaprostanoic acid derivatives corresponding to the case where the hydroxyl group is optionally protected, we succeeded in synthesizing them. Moreover, it was discovered that the obtained compound surprisingly exhibits a strong platelet aggregation inhibiting effect, and the present invention was achieved based on this finding. However, the present invention is based on the following formula [] [In the formula, R 1 represents a hydrogen atom, a lower alkyl group, or a pharmacologically acceptable cation,
R 2 represents a hydrogen atom or a methyl group, R 3 represents an alkyl group or cycloalkyl group having 5 to 7 carbon atoms, and R 4 and R 5 represent a hydrogen atom or a hydroxyl group protecting group. The symbol * represents an asymmetric carbon atom, and its configuration is α configuration or β configuration, or a mixture of both in any proportion. The present invention provides a 7-thiaprostaglandin E 1 derivative represented by the following formula, its enantiomer, or a mixture thereof in any proportion, a method for producing the same, and a platelet aggregation inhibitor containing the same as an active ingredient. In the above formula [], R 1 represents a hydrogen atom, a lower alkyl group, or a pharmacologically acceptable cation. Examples of lower alkyl groups include alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, and butyl groups, but hydrogen atoms,
A methyl group is particularly preferred. Pharmacologically acceptable cations include alkali metal ions such as sodium and potassium, calcium, ammonium,
Examples include ethanolamine, diethanolamine, and morpholine, but sodium ion is particularly preferred. R 2 represents a hydrogen atom or a methyl group, and R 3 represents an alkyl group or cycloalkyl group having 5 to 7 carbon atoms. Examples of the alkyl group or cycloalkyl group having 5 to 7 carbon atoms include pentyl group, hexyl group, heptyl group, 1-methylpentyl group, 1
-Methylhexyl group, 1,1-dimethylpentyl group, 2-methylpentyl group, 2-methylhexyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, but especially pentyl group,
Hexyl group, 2-methylhexyl group, and cyclohexyl group are preferred, and cyclohexyl group is particularly preferred. R 4 and R 5 represent a hydrogen atom or a hydroxyl group protecting group, and may be the same or different. Protecting groups for hydroxyl groups include silyl ethers such as t-butyldimethylsilyl group and diphenylmethylsilyl group, methoxymethyl group, 1-ethoxyethyl group, 1-ethoxy-2-propyl group, methoxyethoxymethyl group, and methylthiomethyl group. Although acetals such as a benzyloxymethyl group, a tetrahydropyran-2-yl group, and the like are used, particularly preferably used are a t-butyldimethylsilyl group and a tetrahydropyran-2-yl group. The symbol * represents an asymmetric carbon atom whose configuration is α configuration or β configuration or any mixture of both. The α configuration means that the configuration is the following formula [−
1] [In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 are the same as defined above. ] represents the stereoisomer represented by the following formula [-2] whose β configuration is the opposite steric structure, [In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 are the same as defined above. ] represents a stereoisomer. The three-dimensional structure of natural prostaglandins is the above formula [-
1], and in that sense, the 7-thiaprostaglandin of the present invention
The configuration of the E 1 derivative is preferably α configuration. The enantiomer of the compound represented by the above formula [] is the following formula [-3] [In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 are the same as defined above. ] represents a stereoisomer. 7-thiaprostaglandin of the present invention as described below
Due to the characteristics of the manufacturing method of E1 derivatives, the above formulas [] and [-3] are produced simultaneously, and both are useful, but they have the same three-dimensional structure as that of natural prostaglandins. A 7-thiaprostaglandin E 1 derivative represented by the above formula [] is preferred. Specific examples of the 7-thiaprostaglandin E 1 derivative provided by the present invention are as follows. 1 7-thiaprostaglandin E 1 2 20-methyl-7-thiaprostaglandin
E 1 3 17,20-dimethyl-7-thiaprostaglandin E 1 4 16,17,18,19,20-pentanol-15-cyclohexyl-7-thiaprostaglandin E 1 5 15-methyl-7-thia prostaglandin
E 1 6 15-epimer of compounds 1) to 5) 7 Methyl esters of compounds 1) to 6) 8 Sodium salts, potassium salts, ammonium salts, calcium salts, ethanolamine salts of compounds 1) to 6), Diethanolamine salt or morpholine salt 9 The hydroxyl group of the compounds 1) to 7) is a t-butyldimethylsilyl group or tetrahydropyran-2
Compound 10 protected with -yl group 8-position, 11-position, and 12-position of compounds 1) to 9)
Examples thereof include, but are not limited to, avian shrimp bodies and the like. The 7-thiaprostaglandin E 1 derivative of the present invention has the following formula [] [In the formula, R 11 represents a lower alkyl group, R 41
represents a hydroxyl protecting group. ] A thiacyclopentenone derivative which is a compound represented by the following formula, its enantiomer, or a mixture of any proportion thereof, and the following formula [] [In the formula, R 2 , R 3 and the symbol * are the same as defined above, and R 51 represents a hydroxyl group-protecting group. ] by reacting with an organocopper lithium compound represented by in the presence of an aprotic inert organic medium, and then subjecting it to deprotection and/or hydrolysis and/or salt formation reaction as necessary. Manufactured. The synthetic route for the 7-thiaprostaglandin E 1 derivative of the present invention, including the synthetic route for its raw material compounds, is as follows. [In the above figure, R 2 , R 3 and the symbol * are the same as the above definitions. R 41 and R 51 represent a hydroxyl protecting group, and R 11 represents a lower alkyl group. ] Note that when the dl form is used as a starting material, the intermediate intermediate will proceed through the synthetic route as a mixture of the compound shown and its enantiomer, and be isolated at an appropriate stage using means such as chromatography. By doing so, each stereoisomer can be isolated as a pure product. In the method of the present invention, the organocopper lithium compound represented by the above formula [], which is one of the raw material compounds, can be produced, for example, by reacting an organolithium compound and a cuprous salt [for example, GHRosner, Organic Reaction, vol. 19 , 1
(1972)]. Further, in the method of the present invention, the compound represented by the above formula [] is used as the organocopper lithium compound, and trivalent phosphorus compounds such as trialkylphosphine (e.g., triethylphosphine, tri-n-butylphosphine, etc.), trivalent phosphine, etc. Alkyl phosphite (e.g. trimethyl phosphite, triethyl phosphite, triisopropyl phosphite, tri-n-butyl phosphite, etc.), hexamethyl phosphorus triamide,
Alternatively, it may be used as a complex with triphenylphosphine or the like. The method of the present invention is carried out by reacting a thiacyclopentenone derivative represented by the above formula [] with an organocopper lithium compound represented by the above formula [] in the presence of an aprotic inert organic medium. The thiacyclopentenone derivative and the organocopper lithium compound react in equimolar terms stoichiometrically, but usually 0.5 to 5.0 moles per mole of the thiacyclopentenone derivative, particularly preferably 0.8 to 2.0 moles.
It is carried out using twice the molar amount of organocopper lithium compound. The reaction temperature is -100°C to 50°C, particularly preferably -
A temperature range of about 78°C to 0°C is adopted. Reaction time varies depending on reaction temperature, but usually -78℃ to -20℃
It is sufficient to react for about 1 hour. The reaction is carried out in the presence of an organic medium. An inert aprotic organic medium is used that is liquid at the reaction temperature and does not react with the reaction reagents. Such aprotic inert organic medium includes:
For example, saturated hydrocarbons such as pentane, hexane, heptane, cyclohexane, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran, dioxane,
Ether solvents such as dimethoxyethane, diethylene glycol dimethyl ether, hexamethylphosphoric triamide (HMP), N,
Examples include so-called aprotic polar solvents such as N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), dimethyl sulfoxide, sulfolane, and N-methylpyrrolidone.
It is also possible to use a mixed solvent of two or more types of solvents. Further, as the aprotic inert organic medium, the inert medium used for producing the organocopper lithium compound can also be used as it is. That is, in this case, the reaction may be carried out by adding the thiacyclopentenone derivative into the reaction system in which the organocopper lithium compound was produced. The amount of organic medium used should be sufficient to allow the reaction to proceed smoothly, and is usually 1 to 100 times the volume of the raw materials.
Preferably 2 to 20 times the volume is used. In this way, the hydroxyl group of the compound represented by the above formula [] is protected, and an ester of the carboxylic acid at the 1-position is obtained. Then, if necessary, the protective group for the hydroxyl group is converted into a free hydroxyl group by a conventional method, and/or the ester is hydrolyzed and/or salt-formed by a conventional method, thereby producing the present invention. A 7-thiaprostaglandin derivative is produced. After the reaction, the resulting product is separated from the reaction solution and purified by conventional means. For example, extraction, washing,
It is carried out by chromatography or a combination of these methods. 7-Thiaprostaglandin represented by the above formula [] (including [-1], [-2], and [-3]) produced by the above method
E1 derivatives have prostaglandin-like effects such as platelet aggregation inhibition and vasodilation, and these physiological effects are expected to result in pharmaceuticals such as thrombosis therapeutics or prophylaxis, platelet aggregation inhibitors, antihypertensive agents, etc. It is useful as These compounds can be administered orally or parenterally, such as intrarectally, subcutaneously, intramuscularly, intravenously, etc., for the above purpose, but oral or intravenous administration is preferred. For oral administration, it is formulated into solid or liquid preparations. Fixed preparations include tablets, pills, powders, and granules. In such fixed formulations, one or more active substances are present in at least one inert diluent, such as the commonly used sodium bicarbonate, calcium carbonate, potato starch, sucrose, mannitol, carboxymethyl cellulose, etc. mixed with. The formulation is made according to conventional methods, but additives other than diluents,
For example, lubricants such as calcium stearate, magnesium stearate, and glycerin may be included. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, clouding agents, syrups or xyls, and commonly used inert diluents such as water or liquid paraffin. including. In addition to inert diluents, the formulations may also contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, stabilizers, or preservatives. The liquid preparation may also be administered in a capsule made of an absorbable material such as gelatin. Solid preparations for rectal administration include suppositories containing one or more active substances and prepared by methods known per se. Preparations for parenteral administration are sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Non-aqueous solutions or suspensions include, for example, propyl glycol, polyethylene glycol or vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Such formulations may also contain adjuvants such as preservatives, emulsifiers, emulsifiers, dispersants, stabilizers. These can be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of a disinfectant, or by irradiation. Alternatively, a sterile solid preparation can be prepared and used by dissolving it in sterile water or a sterile injection solvent immediately before use. The dosage of the 7-thiaprostaglandin E 1 derivative, which is the active compound of the present invention, is 0.001 to 200 mg per kg of body weight per day, preferably 0.01 to 50 mg. These dosages depend on the patient's medical condition, weight, age, or route of administration. As described above, the novel 7-thiaprostaglandin E 1 derivative provided by the present invention is different from the conventional 11-thiaprostaglandin E 1 derivative.
Deoxy-7-thiaprostanoic acid derivative (JP-A-Sho
53-68753) which has an excellent anti-ulcer effect, it exhibits a unique physiological effect in that it has an excellent platelet aggregation inhibiting effect. EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples. Reference example 1 Dissolve dl-4-t-butyldimethylsiloxy-2-cyclopentenone (2.12 g, 10 mmol) in methanol (25 ml), cool it to 0°C, and add 30% hydrogen peroxide solution (5 ml, 45 mmol). added. in it
A few drops of 2N caustic soda aqueous solution was added and stirred for 30 minutes. Methanol was distilled off under reduced pressure, water was added to the residue, extracted with ether, dried (MgSO 4 ), and concentrated under reduced pressure to give dl-4-t-butyldimethylsiloxy-
2,3-epoxycyclopentanone was obtained as a crude product. This product was dissolved in methanol (20 ml), a solution of methyl 6-mercaptohexanoate (1.62 g, 10 mmol) in methanol (10 ml) was added, and triethylamine (1 ml) was added thereto for 18 hours at room temperature under a nitrogen atmosphere. Stirred. After the reaction, the reaction was evaporated under reduced pressure, and the residue was directly subjected to column chromatography (silica gel, hexane: ethyl acetate =
6:1) to separate the product to give dl-4-t-butyldimethylsiloxy-2-(6-methoxycarbonylhexylthio)-2-cyclopentenone (2.24 g, 6.02 mmol, 60.2%). Nuclear magnetic resonance absorption ( CDCl3 , δ (ppm)): 0.15 (6H, s, SiMl2 ), 0.89 (9H, s, tBu), 1.4-1.8 (6H, m), 2.0-3.0 (6H, m) , 3.61 (3H, s, COOCH3 ), 4.90 (1H, m, C4HOSi ), 6.73 (1H, d, J=3Hz, C3- H). Infrared absorption spectrum (KBr, cm -1 ): 1740, 1715. Mass spectra (12eV; m/e, %): 372 (M + , 2), 322 (16), 315 (27), 120 (60), 97 (68), 69 (100). Reference example 2 3(S)-t-butyldimethylsiloxy-1-iodo-trans-1-octene (305 mg,
A solution of 1.5 M t-butyllithium in pentane (1.1 ml,
1.66 mmol) was added at -78°C and stirred for 2 hours.
To this solution, add phenylthiocopper () (86mg,
Hexamethylphosphorus triamide (163 mg, 1.0 mmol) in ether (2 ml) suspension of 0.5 mmol)
was added and stirred at room temperature until a homogeneous solution was obtained, and the resulting solution was added and stirred at -78°C for 1 hour. A solution of cyclopentenone (154 mg, 0.414 mmol) obtained in Example 1 in ether (3 ml), tetrahydrofuran (1 ml), and hexamethylphosphoric triamide (0.3 ml) was added to this solution, and the mixture was heated at -78°C.
The reaction was carried out for 15 minutes, at -40°C for 1 hour, and at -20°C for 1 hour. After the reaction is complete, ammonium chloride solution containing ammonia is added, and the aqueous layer is diluted with ether (2 x 100 ml).
After washing with an aqueous ammonium chloride solution, drying (MgSO 4 ) and concentration, 449 mg of a crude product was obtained.
This was subjected to preparative thin layer chromatography (hexane: ethyl acetate = 6:1) to obtain 11,15(S)-
Bis(t-butyldimethylsilyl)-7-thiaprostaglandin E 1 methyl ester and its 15-
Mixture of shrimp enantiomers (156 mg, 0.254 mmol, 61.4
%) was obtained. Nuclear magnetic resonance absorption ( CDCl3 , δ (ppm)): 0.07 (12H, s, SiMe2 ), 0.87 (21H, s, tBu and terminal CH3 ), 1.1-1.8 (14H, m), 2.1-3.0 ( 7H, m), 3.37 (1H, m, C 8 -H), 3.61 (3H, s, COOCH 3 ), ~4.1 (2H, m, C 11 -H and C 15 -H), 5.43 - 5.65 (2H , m, olefin proton). Infrared absorption spectrum (liquid film, cm -1 ): 1740, 1260, 1120, 965, 835, 775. Reference example 3 156 mg of bissilyl ether obtained in reference example 2
(0.25 mmol) was dissolved in acetic acid (3 ml), water (1 ml) and tetrahydrofuran (1 ml) and stirred at room temperature for 48 hours. Add toluene (100ml) and concentrate under reduced pressure.
The process was repeated twice to obtain 112 mg of crude product. This was subjected to preparative thin layer chromatography (hexane: ethyl acetate = 1:3) to separate 7-thiaprostaglandin E 1 methyl ester (14 mg,
0.036mmol, 14.3%) and its 15-shrimp enantiomer (15
mg, 0.039 mmol, 15.3%) and incompletely deprotected form (60
mg) was obtained. 7-thiaprostaglandin E 1 methyl ester (No. 1) Thin layer chromatography (hexane: ethyl acetate = 1:4): Rf = 0.35 Nuclear magnetic resonance absorption (CDCl 3 , δ (ppm)): 0.89 ( 3H, m, terminal CH 3 ), 1.1-1.8 (14H, m), 2.1-3.1 (10H, m), 3.61 (3H, s, COOCH 3 ), 3.90-4.25 (2H, m, C 11 -H and C15 -H), 5.5-5.75 (2H, m, olefin proton). Infrared absorption spectrum (liquid film, cm -1 ): 3400, 1735, 1255, 1200, 1165, 1125, 1075, 1010, 960. Mass spectrum (20eV; m/e, %): 386 (M + , 2), 368 (27), 350 (16), 337 (7), 269 (28), 237 (74), 207 (59), 190 (78), 119 (91), 99 (100). 15-Shrimp enantiomer of 7-thiaprostaglandin E 1 methyl ester (No. 2) Thin layer chromatography (hexane: ethyl acetate = 1:4): Rf = 0.40 Nuclear magnetic resonance absorption (CDCl 3 , δ ( ppm)): 0.88 (3H, m, terminal CH3 ), 1.1-1.8 (14H, m), 2.1-2.8 (10H, m), 3.64 (3H, s, COOCH3 ), 3.85-4.25 (2H, m , C11 -H and C15 -H), 5.6-5.8 (2H, m, orifin proton). Infrared absorption spectrum (liquid film, cm -1 ): 3420, 1740, 1260, 1205, 1175, 1130, 1080, 1010, 970. Mass spectrum (20eV; m/e, %): 386 (M + , 3), 368 (25), 350 (12), 298 (17), 237 (29), 225 (40), 207 (72), 190 (40), 129 (48), 119 (50), 118 (50), 99 (100). Reference Example 4 Ether solution (10
A 1.4 M solution of t-butyllithium in pentane (5.5 ml, 7.68 mmol) was added to the solution (5.5 ml, 7.68 mmol) at -78°C, and the mixture was stirred for 2 hours. In this solution, phenylthiocopper ()
Hexamethylphosphorus triamide (1.50 g,
9.22 mmol) and stirred at room temperature until a homogeneous solution was obtained.The resulting solution was added and stirred at -78°C for 1 hour. Add cyclopentenone (930 mg,
2.5 mmol) and post-treated in the same way to give 3.7 g
A crude product was obtained. This product was subjected to silica gel column chromatography (hexane: ethyl acetate =
9:1) and isolated 11,15(S)-bis(t-
butyldimethylsilyl)-16,17,18,19,20-
Mixture of pentanol-15-cyclohexyl-7-thiaprostaglandin E 1 methyl ester and its 15-shrimp enantiomer (900 mg, 1.44 mmol, 57.5%)
I got it. Nuclear magnetic resonance absorption ( CDCl3 , δ (ppm)): 0.06 (12H, s, SiCH3 ), 0.84 (18H, tBu), 1.0-1.9 (17H, m) 2.1-3.0 (3H, m), 3.56 (3H, s, COOCH3 ), 3.75 (3H, m, C11 -H and C15 -H), 5.3-5.6 (2H, m, olefin proton). Infrared absorption spectrum (liquid film, cm -1 ): 1740, 1255, 1110, 1070, 1050, 885, 840, 780. Reference Example 5 Bissilyl ether obtained in Reference Example 4 (900
mg, 1.44 mmol) was dissolved in acetic acid (30 ml), water (10 ml), and THF (10 ml) in the same manner as in Reference Example 3, and the mixture was reacted at room temperature for 3 days to desilylate. A crude product was obtained by the same post-treatment, and this was subjected to silica gel column chromatography (hexane: ethyl acetate =
1:3) and separated, 16, 17, 18, 19, 20−
Pentanol-15-cyclohexyl-7-thiaprostaglandin E 1 methyl ester (100mg,
0.25 mmol, 17%) and its 15-epi enantiomer (64 mg,
0.16 mmol, 11%) was obtained. 16,17,18,19,20-pentanol-15-cyclohexyl-7-thiaprostaglandin E 1 methyl ester (No. 3) Thin layer chromatography (hexane: ethyl acetate = 1:4): Rf = 0.25 Nuclear magnetic resonance absorption (CDCL 3 , 8 (ppm)): 0.9-1.9 (17H, m), 2.1-3.4 (10H, m), 3.61 (3H, s, COOCH 3 ), 3.7-4.5 (2H, m, C11 -H and C15 -H), 5.47-5.73 (2H, m, olefin proton). Infrared absorption spectrum (liquid film, cm -1 ): 3410, 1735, 1260, 1200, 1170, 1080, 1000, 970, 890, 730. Mass spectrum (20eV; m/e, %): 398 (M + , 2), 380 (28), 367 (3), 362 (18), 269 (38), 265 (42), 237 (100), 220 (39), 219 (42), 202 (93), 83 (97). Thin layer chromatography of 15-shrimp enantiomer of 16,17,18,19,20-pentanol-15-cyclohexyl-7-thiaprostaglandin E 1 methyl ester (hexane: ethyl acetate = 1:4): Rf = 0.40 Nuclear magnetic resonance absorption (CDCl 3 , δ (ppm)): 0.9-2.0 (17H, m), 2.1-3.35 (10H, m), 3.61 (3H, s, COOCH 3 ), 3.83 (2H, m, C 11 -H and C15 -H), 5.57-5.73 (2H, m, olefin proton). Infrared absorption spectrum (liquid film, cm -1 ): 3430, 1735, 1260, 1200, 1170, 1080, 1000, 970, 915, 730. Mass spectrum (20eV; m/e, %): 398 (M + , 1), 380 (23), 367 (1), 362 (16), 269 (40), 265 (32), 237 (96), 219 (32), 202 (88), 119 (56), 101 (60), 83 (100). Reference example 6 Little pig pancreas lipase (manufactured by Sigma) 5g
was emulsified in 50 ml of 0.1M sodium chloride and 0.05M calcium chloride aqueous solution, and the mixture was vigorously stirred at 0°C for 1.5 hours. This was placed in a high-speed refrigerated centrifuge (9000 rpm) and centrifuged at 2°C for 30 minutes. Separate the supernatant
A crude enzyme solution was obtained by neutralizing to pH 7 with 0.1N NaOH. In addition to this, 16, 17, 18, 19, obtained in Reference Example 5,
20-pentanol-15-cyclohexyl-7-thiaprostaglandin E 1 methyl ester (50mg,
Add 0.8ml acetone solution of 0.126mmol) and heat at 4℃.
Hydrolysis reaction was carried out in an ultrasonic reactor for 20 minutes. The reaction solution was poured into 300 ml of acetone, and insoluble matter was separated with Celite, and the resulting acetone solution was concentrated under reduced pressure. The remaining aqueous layer (approximately 50 ml) was extracted with a saturated aqueous ammonium sulfate solution and ethyl acetate (200 ml), washed with saturated brine, dried (MgSO 4 ), and concentrated to obtain 60 mg of a crude product. This was carried out using thin layer chromatography (hexane:
ethyl acetate:acetic acid=30:70:1)16,17,
18,19,20-pentanol-15-cyclohexyl-
7-thiaprostaglandin E 1 (No. 4) (17mg,
0.044 mmol, 35%) was obtained. Nuclear magnetic resonance absorption ( CDCl3 , δ (ppm)): 0.8-1.9 (17H, m), 1.9-3.1 (8H, m), 3.7-4.3 (2H, m, C11 -H and C15 -H) , 5.53 (3H, bs, OH and COOH), 5.61 (2H, m, olefin proton). Reference Example 7 By the same hydrolysis method as Reference Example 6, 16, 17,
18,19,20-pentanol-15-cyclohexyl-
From the 15--epi enantiomer of 7-thiaprostaglandin E 1 methyl ester (32 mg, 0.080 mmol) to the corresponding carboxylic acid (No. 5) (13 mg, 0.034 mmol,
42%). Nuclear magnetic resonance absorption spectrum (CDCl 3 , δ
(ppm)): 0.8-1.9 (17H, m), 2.1-3.1 (8H, m), 3.7-4.2 (2H, m, C11 -H and C15 -H), 4.93 (3H, bs, OH and COOH), 5.55-5.77 (2H, m, olefin proton). Example 1 (In vitro platelet aggregation inhibiting effect) The in vitro platelet aggregation inhibiting effect of the 7-thiaprostaglandin E 1 derivative of the present invention was tested in rabbits.
Measured using PRP. The results were expressed as 50% inhibitory concentration (IC 50 ) of platelet aggregation. ADP disodium salt was used as a flocculant. [Preparation of PRP, drugs, and aggregating agents] (1) Preparation of PRP (platelet-rich plasma) Citric blood (3.8% sodium citrate) was obtained from male domestic white male rabbits weighing 2.0 to 3.0 kg by cardiac puncture. 1 volume and 9 volumes of blood) were collected. The obtained citrate blood was centrifuged at 1.000 rpm for 10 minutes at room temperature, and the supernatant (PRP) was separated. The obtained PRP was stored at room temperature and used as soon as possible, and was not used more than 4 hours after preparation. (2) Preparation of drug The test drug is generally dissolved in ethyl alcohol to a concentration of 10 mg/ml and diluted with physiological saline.
1.0μg/ml, 0.3μg/ml, 0.1μg/ml, 0.03μg/ml,
1 ml each of 0.01 μg/ml and 0.003 μg/ml solutions were prepared. If the result of the platelet aggregation inhibition test shows that the drug completely inhibits platelet aggregation even at 0.003 μg/ml (converted to a final concentration of 0.0003 μg/ml), the drug solution should be further diluted with physiological saline. The mixture was diluted and each diluted solution was further subjected to a platelet inhibition test. (3) Adjustment of flocculant Dissolve ADP2 sodium manufactured by Kyowa Hakko Co., Ltd. in 0.1M Tris-HCl buffer (PH7.8) to make 100μMADP.
A sodium salt solution was prepared. [Platelet aggregation inhibition test] (1) Platelet aggregation rate of blank Platelets were pre-warmed in a 37°C cuvette of an aggregometer, and 25 μl of physiological saline and 25 μl of aggregating agent solution were added to 200 μl of PRP. The aggregation curve was recorded for 3 minutes using an ablicometer manufactured by Rika Denki. The maximum aggregation degree in this platelet aggregation was defined as the maximum aggregation degree of the blank. (2) Platelet aggregation inhibition test Add 25 μl of the test drug solution to 200 μl of PRP, preincubate at 37°C for 2 minutes in the same manner as in (2) above, and then add 25 μl of ADP2 sodium solution to determine the aggregation curve. The rate of inhibition was calculated by the following formula by recording for minutes and determining the maximum aggregation degree of platelets within that time. The lowest concentration of drug at which the inhibition rate exceeds 50%
Expressed as IC 50 value. Inhibition rate = 100 - (maximum aggregation degree of test drug-added thread/maximum aggregation degree of blank x 100) The results are shown in the table.
【表】
実施例２ （錠剤の製剤）
１錠が次の組成よりなる錠剤を製造した。
活性成分 200mg
乳糖 280mg
ジヤガイモデンプン 80mg
ポリビニルヒロリドン 11mg
ステアリン酸マグネシウム ５mg
576mg
活性成分、乳糖およびジヤガイモデンプンを混
合し、これをポリビニルヒロリドンの20％エタノ
ール溶液で均等に湿潤させ、20mmメツシユのフル
イを通し、45℃にて乾燥させ、かつ再び15mmのメ
ツシユのフルイを通した。こうして得た顆粒をス
テアリン酸マグネシウムと混和し、錠剤に圧縮し
た。
活性成分として、代表的に、参考例５および６
の化合物を用いた。
実施例３ （カプセル剤の製剤）
１カプセルが次の組成を含有する硬質ゼラチン
カプセルを製造した。
活性成分 200mg
微晶セルロース 195mg
無定形珪酸 ５mg
400mg
細かく粉末化した形の活性成分、微晶セルロー
ス及び未プレスの無定形珪酸を十分に混合し、硬
質ゼラチンカプセルに詰めた。
活性成分として、代表的に参考例５および６の
化合物を用いた。
実施例４ （アンプル剤の製剤）
１本のアンプル（５ml容量）に次の組成を含有
するアンプルを製造した。
活性成分 200mg
ポリエチレングリコール600 200mg
蒸留水 全量 50ml
ポリエチレングリコールおよび活性成分を窒素
下に水中に溶解させ、これを沸騰させ、窒素下に
冷却させ、かつ蒸留した。この溶液に前処理した
水を加えて与えられた容量にし、無菌状態下に
過した。本製造は散光中にて行われる。
充填は窒素気流中にて行なわれ、滅菌は121℃
にて20分間行なつた。
なお、上記活性成分としては、参考例５および
６の化合物を用いた。
実施例 ５
16，17，18，19，20−ペンタノル−15−シクロ
ヘキシル−７−チアプロスタグランジンE1（実施
例６）10mgをエタノール５mlに溶かし、バクテリ
ア保留フイルターをとおして殺菌し、１ml容量ア
ンプル当り0.1mlずついれ、アンプルを封管する。
アンプルの内容物は適当な容量に希釈する。例え
ばPH8.6のトリス塩酸緩衝液で１mlに希釈して注
射投与用とする。
実施例 ６
16，17，18，19，20−ペンタノル−15−シクロ
ヘキシル−７−チアプロスタグランジンE1メチ
ルエステルについて、SD系ラツト雄性６週令２
例づつを用い、経口投与で急性毒性のテストを行
つた。結果は下表の通りであつた。[Table] Example 2 (Preparation of tablets) Tablets each having the following composition were manufactured. Active Ingredients 200mg Lactose 280mg Gym Starch 80 mg Polyvinylhyrolidone 11mg Magnesium Stearate 5mg 576mg Mix the active ingredients, lactose and Gyote starch, evenly moisten with a 20% ethanol solution of polyvinylhyrolidone, and pass through a 20mm mesh sieve. , dried at 45°C, and passed through a 15 mm mesh sieve again. The granules thus obtained were mixed with magnesium stearate and compressed into tablets. As active ingredients, typically Reference Examples 5 and 6
The compound was used. Example 3 (Capsule formulation) Hard gelatin capsules were prepared, one capsule containing the following composition: Active Ingredients 200 mg Microcrystalline Cellulose 195 mg Amorphous Silicic Acid 5 mg 400 mg The active ingredient in finely powdered form, microcrystalline cellulose and unpressed amorphous silicic acid were thoroughly mixed and packed into hard gelatin capsules. The compounds of Reference Examples 5 and 6 were typically used as active ingredients. Example 4 (Formulation of ampoule) An ampoule containing the following composition in one ampoule (5 ml volume) was manufactured. Active ingredient 200 mg Polyethylene glycol 600 200 mg Distilled water Total volume 50 ml Polyethylene glycol and active ingredient were dissolved in water under nitrogen, which was boiled, cooled under nitrogen and distilled. The solution was made up to the given volume with pretreated water and filtered under sterile conditions. This production is carried out under diffused light. Filling is done in a nitrogen stream and sterilization is at 121℃
It lasted for 20 minutes. Note that the compounds of Reference Examples 5 and 6 were used as the above active ingredients. Example 5 16,17,18,19,20-pentanol-15-cyclohexyl-7-thiaprostaglandin E 1 (Example 6) Dissolve 10 mg in 5 ml of ethanol, sterilize it through a bacteria retention filter, and make a volume of 1 ml. Add 0.1ml per ampoule and seal the ampoule.
The contents of the ampoule are diluted to the appropriate volume. For example, dilute to 1 ml with Tris-HCl buffer of pH 8.6 for injection administration. Example 6 Regarding 16,17,18,19,20-pentanol-15-cyclohexyl-7-thiaprostaglandin E 1 methyl ester, SD male rats aged 6 weeks 2
Each example was tested for acute toxicity by oral administration. The results were as shown in the table below.
Claims (1)
たは薬理学的に許容しうる陽イオンを表わし、
R2は水素原子またはメチル基を表わし、R3は炭
素数５〜７のアルキル基もしくはシクロアルキル
基を表わし、R4およびR5は水素原子を表わす。〕 で表わされる化合物である７−チアプロスタグラ
ンジンE1誘導体の有効量および製剤学的に許容
される担体を含む血小板凝集阻止剤。 ２ 上記式［］において、R1が水素原子、メ
チル基、またはナトリウムイオンである特許請求
の範囲第１項記載の血小板凝集阻止剤。 ３ 上記式［］において、R2が水素原子であ
る特許請求の範囲第１項又は第２項記載の血小板
凝集阻止剤。 ４ 上記式［］において、R3がペンチル基、
ヘキシル基、２−メチルヘキシル基、又はシクロ
ヘキシル基である特許請求の範囲第１項から第３
項のいずれか１項記載の血小板凝集阻止剤。 ５ 上記式［］で表わされる化合物が16，17，
18，19，20−ペンタノル−15−シクロヘキシル−
７−チアプロスタグランジンE1メチルエステル
又は16，17，18，19，20−ペンタノル−15−シク
ロヘキシル−７−チアプロスタグランジンE1で
ある特許請求の範囲第１項記載の血小板凝集阻止
剤。[Claims] 1. The following formula [] [In the formula, R 1 represents a hydrogen atom, a lower alkyl group, or a pharmacologically acceptable cation,
R 2 represents a hydrogen atom or a methyl group, R 3 represents an alkyl group or cycloalkyl group having 5 to 7 carbon atoms, and R 4 and R 5 represent a hydrogen atom. ] A platelet aggregation inhibitor comprising an effective amount of a 7-thiaprostaglandin E 1 derivative, which is a compound represented by: and a pharmaceutically acceptable carrier. 2. The platelet aggregation inhibitor according to claim 1, wherein in the above formula [], R 1 is a hydrogen atom, a methyl group, or a sodium ion. 3. The platelet aggregation inhibitor according to claim 1 or 2, wherein in the above formula [], R 2 is a hydrogen atom. 4 In the above formula [], R 3 is a pentyl group,
Claims 1 to 3 are hexyl group, 2-methylhexyl group, or cyclohexyl group.
The platelet aggregation inhibitor according to any one of paragraphs. 5 The compound represented by the above formula [] is 16, 17,
18,19,20-pentanol-15-cyclohexyl-
The platelet aggregation inhibitor according to claim 1, which is 7-thiaprostaglandin E 1 methyl ester or 16,17,18,19,20-pentanol-15-cyclohexyl-7-thiaprostaglandin E 1 .
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP55183727A JPS57108065A (en) | 1980-12-26 | 1980-12-26 | 7-thiaprostaglandin e1 derivative, its preparation, and blood platelet coagulation inhibiting agent containing said derivative as active component |
| DE8181109250T DE3168199D1 (en) | 1980-10-31 | 1981-10-29 | Novel thiaprostaglandin e1 derivatives, process for production thereof, and pharmaceuticals containing these compounds |
| EP81109250A EP0051284B1 (en) | 1980-10-31 | 1981-10-29 | Novel thiaprostaglandin e1 derivatives, process for production thereof, and pharmaceuticals containing these compounds |
| US06/316,902 US4466980A (en) | 1980-10-31 | 1981-10-30 | Thiaprostaglandin E1 derivatives, process for production thereof, and pharmaceutical use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP55183727A JPS57108065A (en) | 1980-12-26 | 1980-12-26 | 7-thiaprostaglandin e1 derivative, its preparation, and blood platelet coagulation inhibiting agent containing said derivative as active component |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS57108065A JPS57108065A (en) | 1982-07-05 |
| JPH0123445B2 true JPH0123445B2 (en) | 1989-05-02 |
Family
ID=16140901
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP55183727A Granted JPS57108065A (en) | 1980-10-31 | 1980-12-26 | 7-thiaprostaglandin e1 derivative, its preparation, and blood platelet coagulation inhibiting agent containing said derivative as active component |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS57108065A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5929661A (en) * | 1982-08-12 | 1984-02-16 | Teijin Ltd | 7-thiaprostaglandin e1, its preparation and blood platelet coagulation inhibiting agent containing said compound as active component |
| JPS60185761A (en) * | 1984-03-05 | 1985-09-21 | Teijin Ltd | 7-thiaprostaglandin e1 compound and its preparation |
| WO1985003936A1 (en) * | 1984-03-05 | 1985-09-12 | Teijin Limited | 7-thiaprostaglandin e1's and process for their preparation |
| US5159102A (en) * | 1984-03-05 | 1992-10-27 | Teijin Limited | 7-thiaprostaglandins E, and process for producing same |
| JPH10265454A (en) * | 1997-01-27 | 1998-10-06 | Ono Pharmaceut Co Ltd | 3,7dithiaprostanoic acid derivative, its production and medicine containing the same derivative as active ingredient |
| US6043275A (en) * | 1998-04-16 | 2000-03-28 | Ono Pharmaceutical Co., Ltd. | 3,7-dithiaprostanoic acid derivative |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5368753A (en) * | 1976-12-01 | 1978-06-19 | Teijin Ltd | Thiaprostanoic acid derivatives and their preparation |
| JPS53127832A (en) * | 1977-04-11 | 1978-11-08 | Teijin Ltd | Antiphkogistics for oral administration containing thiaprostaglandins |
-
1980
- 1980-12-26 JP JP55183727A patent/JPS57108065A/en active Granted
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5368753A (en) * | 1976-12-01 | 1978-06-19 | Teijin Ltd | Thiaprostanoic acid derivatives and their preparation |
| JPS53127832A (en) * | 1977-04-11 | 1978-11-08 | Teijin Ltd | Antiphkogistics for oral administration containing thiaprostaglandins |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57108065A (en) | 1982-07-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4446147A (en) | Azaprostacyclins, their preparation and pharmaceutical use | |
| EP0055208B1 (en) | Carbacyclins, process for their preparation and their utilization as pharmaceutical preparations | |
| US4466980A (en) | Thiaprostaglandin E1 derivatives, process for production thereof, and pharmaceutical use thereof | |
| JPH0123445B2 (en) | ||
| EP0099538A1 (en) | Carbacyclines, process for their preparation and their use as medicines | |
| DE2423156A1 (en) | 5-OXA-PROSTAGLANDIN AND METHOD FOR MANUFACTURING THEREOF | |
| US4497830A (en) | Carbacyclins, their preparation and pharmacological use | |
| US4034003A (en) | 15-Cycloalkyl-prostaglandins | |
| HU191150B (en) | Process for producing new prostacycline derivatives | |
| JPH0446256B2 (en) | ||
| CA1215362A (en) | Carbacyclins, process for their preparation thereof, and use thereof as medicinal agents | |
| JPH037666B2 (en) | ||
| SU1272980A3 (en) | Method of producing optically active or racemic compounds or their pharmaceutically or veterinarily acceptable salts | |
| US4315032A (en) | Process for preparation of adjacently disubstituted ketones | |
| EP0051557B1 (en) | 5-cyano-prostacycline derivatives, their preparation and their use in medicaments | |
| JPS5929661A (en) | 7-thiaprostaglandin e1, its preparation and blood platelet coagulation inhibiting agent containing said compound as active component | |
| JPH01502750A (en) | 6-Oxoprostaglandin-E-derivative, its production method and its pharmaceutical use | |
| US4029698A (en) | Cycloalkylidenol analogues of prostaglandins E and F | |
| CA1202968A (en) | Process for the preparation of new cis-bi- cyclo[3.3.0]octane derivatives | |
| US4180675A (en) | 15-Cycloalkyl-prostaglandin derivatives | |
| JPS604154A (en) | 13-azathromboxane-mimic compound, its preparation and remedy for disease caused by thromboxane containing said compound as active component | |
| JPS5936657A (en) | 6-nitroprostaglandin e1 compound, its preparation and drug containing said compound as active component | |
| EP0038613B1 (en) | Novel prostaglandins e1 and anti-thrombotic compositions containing them | |
| KR800000315B1 (en) | Process for the preparation of prostaglandins | |
| US5190973A (en) | 20-alkyl-7-oxoprostacyclin derivatives useful as pharmaceuticals |