JPH048432B2 - - Google Patents
Info
- Publication number
- JPH048432B2 JPH048432B2 JP403084A JP403084A JPH048432B2 JP H048432 B2 JPH048432 B2 JP H048432B2 JP 403084 A JP403084 A JP 403084A JP 403084 A JP403084 A JP 403084A JP H048432 B2 JPH048432 B2 JP H048432B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- octadecyloxy
- group
- concentrated
- phosphate
- 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
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000005462 imide group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- -1 icosanyl Chemical group 0.000 description 33
- 150000001875 compounds Chemical class 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 17
- 108010003541 Platelet Activating Factor Proteins 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- 238000002347 injection Methods 0.000 description 14
- 239000007924 injection Substances 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 210000004623 platelet-rich plasma Anatomy 0.000 description 9
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- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 229960001866 silicon dioxide Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 5
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- 239000007787 solid Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000007815 allergy Effects 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
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- 239000002552 dosage form Substances 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- YTHYJLWEZRYZSR-UHFFFAOYSA-N 1-(1-hydroxy-3-octadecoxypropan-2-yl)pyrrolidine-2,5-dione Chemical compound CCCCCCCCCCCCCCCCCCOCC(CO)N1C(=O)CCC1=O YTHYJLWEZRYZSR-UHFFFAOYSA-N 0.000 description 3
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound 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 XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 3
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
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- 239000008194 pharmaceutical composition Substances 0.000 description 3
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- 230000002265 prevention Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 206010040560 shock Diseases 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 208000010444 Acidosis Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 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 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 206010040070 Septic Shock Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- NWJQLKMTZQMVBM-UHFFFAOYSA-N [2-(1,3-dioxoisoindol-2-yl)-3-octadecoxypropyl] 2-pyridin-1-ium-1-ylethyl phosphate Chemical compound O=C1C2=CC=CC=C2C(=O)N1C(COCCCCCCCCCCCCCCCCCC)COP([O-])(=O)OCC[N+]1=CC=CC=C1 NWJQLKMTZQMVBM-UHFFFAOYSA-N 0.000 description 2
- AVIKXXVBLCSYIY-UHFFFAOYSA-N [diphenyl(propoxy)methyl]benzene Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCCC)C1=CC=CC=C1 AVIKXXVBLCSYIY-UHFFFAOYSA-N 0.000 description 2
- 230000001780 adrenocortical effect Effects 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940127218 antiplatelet drug Drugs 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 2
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- 230000003247 decreasing effect Effects 0.000 description 2
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- 239000012153 distilled water Substances 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
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- 210000002381 plasma Anatomy 0.000 description 2
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229960002317 succinimide Drugs 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000002834 transmittance Methods 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- VBJKCCNOCQEFBW-UHFFFAOYSA-N (1-octadecoxy-3-trityloxypropan-2-yl) 4-methylbenzenesulfonate Chemical compound C=1C=C(C)C=CC=1S(=O)(=O)OC(COCCCCCCCCCCCCCCCCCC)COC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 VBJKCCNOCQEFBW-UHFFFAOYSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- CBFTUJRVFRKISV-UHFFFAOYSA-N 1-(1-hydroxy-3-octadecoxypropan-2-yl)pyrrole-2,5-dione Chemical compound CCCCCCCCCCCCCCCCCCOCC(CO)N1C(=O)C=CC1=O CBFTUJRVFRKISV-UHFFFAOYSA-N 0.000 description 1
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- NYKRTKYIPKOPLK-UHFFFAOYSA-N 1-bromo-2-dichlorophosphoryloxyethane Chemical compound ClP(Cl)(=O)OCCBr NYKRTKYIPKOPLK-UHFFFAOYSA-N 0.000 description 1
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- RNDDJPOBYNIKQC-UHFFFAOYSA-N 1-trityloxypropan-1-ol Chemical compound CCC(O)OC(c1ccccc1)(c1ccccc1)c1ccccc1 RNDDJPOBYNIKQC-UHFFFAOYSA-N 0.000 description 1
- PYHRFLSEATWRSE-UHFFFAOYSA-N 2-(1-hydroxy-3-octadecoxypropan-2-yl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(C(CO)COCCCCCCCCCCCCCCCCCC)C(=O)C2=C1 PYHRFLSEATWRSE-UHFFFAOYSA-N 0.000 description 1
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- PPFSCHITNDOGHI-UHFFFAOYSA-N 2-amino-3-octadecoxypropan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCOCC(N)CO PPFSCHITNDOGHI-UHFFFAOYSA-N 0.000 description 1
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- IRAKOVQPPWUWLC-UHFFFAOYSA-N 2-bromoethyl [2-(2,5-dioxopyrrolidin-1-yl)-3-octadecoxypropyl] hydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCCCOCC(COP(O)(=O)OCCBr)N1C(=O)CCC1=O IRAKOVQPPWUWLC-UHFFFAOYSA-N 0.000 description 1
- GKKOKRSMESTHEC-UHFFFAOYSA-N 4-[(1-octadecoxy-3-trityloxypropan-2-yl)amino]-4-oxobutanoic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(COCCCCCCCCCCCCCCCCCC)NC(=O)CCC(O)=O)C1=CC=CC=C1 GKKOKRSMESTHEC-UHFFFAOYSA-N 0.000 description 1
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- 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
- 208000025865 Ulcer Diseases 0.000 description 1
- RTFXIYGZNVZEKR-UHFFFAOYSA-N [2-(1,3-dioxoisoindol-2-yl)-3-octadecoxypropyl] 2-(1,3-thiazol-3-ium-2-yl)ethyl phosphate Chemical compound O=C1C2=CC=CC=C2C(=O)N1C(COCCCCCCCCCCCCCCCCCC)COP([O-])(=O)OCCC1=[NH+]C=CS1 RTFXIYGZNVZEKR-UHFFFAOYSA-N 0.000 description 1
- PYBYRSKLFIEERW-UHFFFAOYSA-N [2-(2,5-dioxopyrrol-1-yl)-3-octadecoxypropyl] 2-(1,3-thiazol-3-ium-2-yl)ethyl phosphate Chemical compound O=C1C=CC(=O)N1C(COCCCCCCCCCCCCCCCCCC)COP([O-])(=O)OCCC1=[NH+]C=CS1 PYBYRSKLFIEERW-UHFFFAOYSA-N 0.000 description 1
- PJARLMBSZBSQDQ-UHFFFAOYSA-N [2-(2,5-dioxopyrrolidin-1-yl)-3-octadecoxypropyl] 2-(1,3-thiazol-3-ium-2-yl)ethyl phosphate Chemical compound O=C1CCC(=O)N1C(COCCCCCCCCCCCCCCCCCC)COP([O-])(=O)OCCC1=[NH+]C=CS1 PJARLMBSZBSQDQ-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical class CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000003130 blood coagulation factor inhibitor Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000001269 cardiogenic effect Effects 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- AGSFIZDITVHDFK-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.OC.ClC(Cl)Cl AGSFIZDITVHDFK-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- URZKCMPZWPHMAF-UHFFFAOYSA-N ethyl 1,3-dioxoisoindole-4-carboxylate Chemical compound CCOC(=O)C1=CC=CC2=C1C(=O)NC2=O URZKCMPZWPHMAF-UHFFFAOYSA-N 0.000 description 1
- XUXSQROIUORWRI-UHFFFAOYSA-N ethyl 2,5-dioxopyrrole-1-carboxylate Chemical compound CCOC(=O)N1C(=O)C=CC1=O XUXSQROIUORWRI-UHFFFAOYSA-N 0.000 description 1
- HACODILRQLESNH-UHFFFAOYSA-N ethyl 2,5-dioxopyrrolidine-1-carboxylate Chemical compound CCOC(=O)N1C(=O)CCC1=O HACODILRQLESNH-UHFFFAOYSA-N 0.000 description 1
- STXJWMUXKCYVJA-UHFFFAOYSA-N ethyl 2,5-dioxopyrrolidine-3-carboxylate Chemical compound CCOC(=O)C1CC(=O)NC1=O STXJWMUXKCYVJA-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229950008696 farnesil Drugs 0.000 description 1
- 239000007941 film coated tablet Substances 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
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000006371 metabolic abnormality Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- KRLWOFRQXDUIKD-UHFFFAOYSA-N methyl 1,3-dioxoisoindole-2-carboxylate Chemical compound C1=CC=C2C(=O)N(C(=O)OC)C(=O)C2=C1 KRLWOFRQXDUIKD-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000001196 nonadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229950004354 phosphorylcholine Drugs 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical group O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000003848 thrombocyte activating factor antagonist Substances 0.000 description 1
- 201000005060 thrombophlebitis Diseases 0.000 description 1
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は新規血小板活性化因子抑制剤に関す
る。さらに詳しくは、本発明は式
〔式中、R1は炭素数10〜24のアルキル基を、
R2は置換されていてもよい環状イミド基を、A+
は環状アンモニオ基を示す）で表わされるリン脂
質およびその塩に関する。
血小板凝集は各種の循環器障害疾患の原因と考
えられており、血小板凝集抑制剤は医薬として重
要な地位を占めている。
従来、血小板凝集を起す物質としてアデノシン
二リン酸（ADP）とアラキドン酸代謝物、特に
トロンボキサンA2（TXA2）が代表的化合物とし
て知られてきた。従つて、従来の血小板凝集抑制
剤はこれら化合物の作用阻止を第１スクリーニン
グ法として検策がなされて来た。
しかるに、最近、ADP，TXA2とは異つた作
用機序でさらに強力な血小板凝集作用を起す物質
として、血小板活性化因子〔Platelet
ActivatingFactor（PAF）〕解明され、その構造
が１−Ｏ−アルキル−２−アセチル−sn−グリセ
リル−３−フオスホリルコリンであることがわか
つた〔ネイチヤー，285巻，193（1980）〕。PAFは
ADP，TXA2とは異なる作用機序と、より低濃
度で強い活性を有することが見出されている。ま
た、PAFはアレルギーの強力な化学伝達物質で
あり、たとえば気管支狭窄をメルクマールとする
測定では、既知の化合物の中で最強の活性を有す
ることが知られている〔European Journal of
Pharmacology，65，185−192（1980）〕。従つて、
PAFに対して阻止作用をもつ化合物を見出すこ
とができれば生物体の血小板凝集に対しより効果
的な抑制剤になりうるし、かつまた、その他の
PAFによつて惹起される疾病、たとえばアレル
ギー症などに対する有効な抑制剤になりうる。
またPAFは血小板凝集作用の他に強力な血圧
降下作用を有しており、シヨツク・インデユーサ
ーとして働くのではないかと考えられている
〔European Journal of Pharmacology，86，
403〜413（1983）〕。シヨツクは、外傷、出血、心
原性、細菌性など種々の原因によつて発生する。
しかし、原因は異つてもシヨツクの病態はほぼ同
じで、血圧下降、心拍出量低下等の循環異常およ
び代謝性アシドーシス、高カリウム血症、乳酸血
症等の代謝異常が観察される。細菌性シヨツクの
場合を例にとると、グラム陰性桿菌（大腸菌、緑
濃菌、クレブシエラなど）による感染で特に発生
しやすく、これらの菌の細胞壁成分であるエンド
トキシンがその原因と考えられている。実際に動
物にエンドキシンを注射することによりシヨツク
を起すことができる。抗生物質や輸液療法などの
進歩にもかかわらず、シヨツクによる致死率の改
善はみられていない。従つてシヨツクが予想され
る時は抗生物質と共にエンドトキシンシヨツクを
防ぐ薬物が併用される。このためハイドロコーチ
ゾン、デキサメサゾンなどの副腎皮質ホルモンが
繁用されているが、シヨツク時には大量用いられ
るため、副腎皮質ホルモンによる副作用の発現が
問題となる。またインドメサシンのような抗炎症
剤も使用されているが、潰瘍形成などの副作用が
あるばかりでなく、その効果もはつきりしない。
本発明者らは種々の循環障害疾患やシヨツクに
関与するPAFの作用を抑制する方法を鋭意検討
した結果、式（）で示される化合物が強い抗
PAF作用を有することを見出し、本発明を完成
した。
前記式（）に関し、R1で示されるC10-24アル
キル基は直鎖状もしくは分枝状のいずれでもよ
く、たとえばデシル、ドデシル、トリデシル、テ
トラデシル、ペンタデシル、ヘキサデシル、ヘプ
タデシル、オクタデシル、ノナデシル、アイコサ
ニル、ドコサニル、フアルネシール、ジヒドロフ
イチルなどがあげられ、なかでもC14-20アルキル
基が好ましい。
R2として示される環状イミド基としては、た
とえばフタルイミド基、サクシンイミド基、マレ
インイミド基などがあげられ、これらの基は、た
とえばメチル、エチル、プロピル、イソプロピ
ル、ブチル、イソブチルなどの低級アルキル基、
メトキシ、エトキシなどの低級アルコキシ基、ク
ロル、プロムなどのハロゲン基、ニトロ基、アセ
チル基などで置換されていてもよい。
A+として示される環状アンモニオ基としては、
たとえばピリジニオ基、オキサゾリオ基、チアゾ
リオ基、イソチアゾリオ基、ピリダジニオ基、キ
ノリニオ基、イソキノリニオ基、Ｎ−メチルモル
ホリニオ基、Ｎ−メチルピペリジニオ基、Ｎ−メ
チルピロリジニオ基などがあげられる。
また化合物（）は、たとえば（ａ），（
ｂ）で表わされるような薬理学的に許容されうる
塩の形で存在することもある。
〔式中、X-はCl-，Br-，I-，OH-，CO2- 3，
SO2- 4などのアニオンを、Ｍはアルカリ金属（例、
Na，Ｋ）またはアルカリ土類金属（例、Ca）を
示し、他の記号は前記と同意義〕。
化合物（）においては、２位の炭素に関し
て、Ｒ−配位、Ｓ−配位の２種の立体異性体が存
在するが、その各々あるいはその混合体およびラ
セミ体のいずれも本発明の範囲に包含されるもの
である。
化合物（）およびその塩は優れた血小板活性
化因子（PAF）抑制作用を示し、さらに具体的
にはPAFに起因する血小板凝集、シヨツク（血
圧下降、致死など）およびアレルギーを強力に抑
制する。従つて、化合物（）およびその塩は哺
乳動物における血小板活性化因子に起因する循環
障害疾患、たとえば血栓症、脳卒中（例、脳出
血、脳血栓）、心筋梗塞、狭心症、血栓性静脈炎、
糸球体腎炎、シヨツク（例、エンドトキシンシヨ
ツク、エンドトキシンにより生じる血管内血液凝
固症候群、アナフイラキシーシヨツク）などの疾
病やアレルギーに関連する気管支喘息などの予
防、治療に用いることができる。
化合物（）およびその塩は、親水性、親油性
ともに優れた性状を有し、毒性も低いので、その
まま粉末剤として、または適当な剤形の医薬組成
物として、経口的または非経口的に安全に投与す
ることができる。投与量は投与対象、症状、投与
ルート等によつても異なるが、たとえば成人の血
栓症に対する予防・治療のために経口投与する場
合、化合物（）を１回量として通常約0.1〜20
mg／Kg体重程度、１日１〜３回程度投与するのが
好都合である。さらに詳しくは、血栓症の予防を
目的とする場合、１回量約0.5〜４mg／Kg体重程
度、治療を目的とする場合、１回量約４〜10mg／
Kg体重程度、それぞれ１日１〜３回程度投与する
のが好ましい。
また、たとえばシヨツクに対する予防・治療の
ために使用する場合には、たとえば成人の場合、
静脈注射により投与する時には化合物（）を１
回量として通常の0.1〜20mg／Kg体重程度、好ま
しくは１〜10mg／Kg体重程度、１日１〜３回程度
投与するのが好都合である。また、化合物（）
を１回あたり0.07〜0.7mg／Kg体重／min程度を約
１時間程度、１日１〜３回程度点滴注射により投
与することもできる。他の非経口的投与および経
口的投与の場合もこれに準ずる量が投与される。
シヨツク症状が特に重い場合にはその症状に応じ
て増量して用いてもよい。
上記投与に用いられる医薬組成物は、活性成分
である有効量の化合物（）またはその塩と薬理
学的に許容され得る担体もしくは賦形剤とを含む
ものである。かかる組成物は経口または非経口投
与に適する剤形として提供される。
すなわち、たとえば経口投与のための組成物と
しては、固体または液体の剤形、具体的には錠剤
（糖衣錠、フイルムコーテイング錠を含む）、丸
剤、顆粒剤、散剤、カプセル剤（ソフトカプセル
剤を含む）、シロツプ剤、乳剤、懸濁剤などがあ
げられる。かかる組成物は自体公知の方法によつ
て製造され、制剤分野において通常用いられる担
体もしくは賦形剤を含有するものである。たとえ
ば、錠剤用の担体、賦形剤としては乳糖、でんぷ
ん、庶糖、ステアリン酸マグネシウムなどがあげ
られる。
非経口投与のための組成物としては、たとえば
注射剤、坐剤などがあげられ、注射剤は静脈注射
剤、皮下注射剤、皮内注射剤、筋肉注射剤、点滴
注射剤などの剤型を包含する。かかる注射剤は自
体公知の方法、すなわち化合物（）またはその
塩を通常注射剤に用いられる無菌の水性もしくは
油性液に溶解、懸濁または乳化することによつて
調製される。注射用の水性液としては生理食塩
水、ブドウ糖やその他の補助薬を含む等張液など
があげられ、適当な溶解補助剤、たとえばアルコ
ール（例、エタノール）、ポリアルコール（例、
プロピレングリコール、ポリエチレングリコー
ル）、非イオン性界面活性剤〔例、ポリソルベー
ト80、HCO−50（polyoxyethylene（50mol）
adduct of hydrogenated castor oil）〕などと併
用してもよい。油性液としてはゴマ油、大豆油な
どがあげられ、溶解補助剤として安息香酸ベンジ
ル、ベンジルアルコールなどを併用してもよい。
調製された注射液は通常適当なアンプルに充填さ
れる。直腸投与に用いられる坐剤は、化合物
（）またはその塩を通常の坐薬基剤に混合する
ことによつて調製される。
上記の経口用または非経口用医薬組成物は、活
性成分の投与量に適合するような投薬単位の剤形
に調製されることが好都合である。かかる投薬単
位の剤形としては、錠剤、丸剤、カプセル剤、注
射剤（アンプル）、坐剤などが例示され、それぞ
れの投薬単位剤形当り通常５〜500mg、とりわけ
注射剤では５〜100mg、その他の剤形では10〜250
mgの化合物（）含有されていることが好まし
い。
なお前記した各組成物は、化合物（）との配
合により好ましくない相互作用を生じない限り他
の活性成分を含有していてもよい。
化合物（）は、たとえば以下に示す方法によ
つて製造しうる。
Ａ法
式
〔式中、ＹはCl，BrまたはＩを示し、他の記
号は前記と同意義〕の化合物に、A+に対応する
環状アミン化合物Ａ（）を反応させることによ
り化合物（）を得る。
Ｂ法
式
〔式中、各記号は前記と同意義〕の化合物に置
換されていてもよい環状イミドの活性誘導体を反
応させることにより化合物（）を得る。
Ｃ法
式
〔式中、X′はClまたはBrを示し、他の記号は
前記と同意義〕の化合物に式
HOCH2CH2A+.X- （）
〔式中、X-はアニオンを示し、他の記号は前
記と同意義〕の化合物を反応させることにより化
合物（）を得る。
上記Ａ法の反応に用いられる化合物（）の例
としては、ピリジン、チアゾール、オキサゾー
ル、キノリン、イソキノリン、イソチアゾール、
ピリダジン、Ｎ−メチルモルホリン、Ｎ−メチル
ピペラジン、Ｎ−メチルピロリジンなどがあげら
れる。反応は塩基（）を化合物（）に対し１
当量または大過剰（例、50倍モル）に用いて、室
温または加熱下で溶媒の存在下もしくは無溶媒下
に行なう。溶媒としては、メタノール、トルエ
ン、ベンゼン、エーテル、ジオキサン、テトラヒ
ドロフランなどが挙げられる。
Ｂ法の反応に用いられる置換されていてもよい
環状イミドの活性誘導体としてはたとえば、Ｎ−
エトキシカルボニルフタルイミド、Ｎ−メトキシ
カルボニルフタルイミド、Ｎ−エトキシカルボニ
ルサクシンイミド、Ｎ−エトキシカルボニルマレ
インイミドが挙げられる。化合物（）とこれら
の活性誘導体との反応は、アミノ化合物とこれら
の活性誘導体との反応で通常知られている反応条
件に準じておこなうことができる。また反応を促
進するためトリエチルアミンやピリジンなどの塩
基を加えておこなつてもよい。
Ｃ法の反応は、溶媒（例、クロロホルム、ジク
ロルメタン、ピリジン、トルエン、ジオキサン）
の存在下に、化合物（）に対して化合物（）
の当モルまたは1.5倍モル程度の温度を０〜100℃
で作用させることによつて達成される。
以上述べた各製造方法において、反応の進行を
薄層クロマトグラフイーによつて追跡することが
出来、これにより反応条件を適宜決定することが
出来る。
上記方法により製造される化合物の精製は通常
の操作、溶媒抽出、再結晶操作、クロマトグラフ
イー等によつて適宜行われる。
以下に本発明を実施例、実験例および製剤例に
よりさらに具体的に説明するが、本発明の範囲は
これらに限定されるものではない。
実施例 １
３−Ｏ−オクタデシル−２−Ｏ−トシル−１−
Ｏ−トリチルグリセロール
３−Ｏ−オクタデシル−１−Ｏ−トリチルグリ
セロール5.0ｇ（8.52ミリモル）をピリジン９ml
に溶かし塩化トシル1.95ｇ（10.22ミリモル）を
加え、一夜室温にてかきまぜた後減圧下に濃縮乾
固した。残渣を水50ml、ジクロロメタン50mlに溶
かし、ふりまぜてから、ジクロロメタン層を分取
する。有機層は減圧下に濃縮乾固し、残渣をシリ
カゲルカラム（50ｇ）、展開溶媒ｎ−ヘキサン、
酢酸エチル（193：７）にて精製し、無色針状結
晶5.3ｇ（収率83.9％）を得た。
mp52゜〜53℃
実施例 ２
３−オクタデシルオキシ−２−フタルイミド−
１−トリチルオキシプロパン
実施例１で得たトシル体5.3ｇ（7.15ミリモル）
をジメチルスルホキシド53mlに溶かし、フタルイ
ミドカリ10.6ｇを加え浴温115℃、3.5時間かきま
ぜた。反応液を水500mlにあけ、エーテル500mlに
て抽出し、エーテル層は硫酸ナトリウムにて乾か
し減圧下に濃縮乾固した。残渣をシリカゲルカラ
ム（50ｇ）、展開溶媒ｎ−ヘキサン、酢酸エチル
（193：７）にて精製し、無色油状物質3.0ｇ（収
率58.6％）を得た。
TLC〔silicagel，ｎ−Hexane，EtOAc（９：
１）〕Rf＝0.25single spot.
実施例 ３
１−ハイドロキシ−３−オクタデシルオキシ−
２−フタルイミドプロパン
実施例２で得たトリチル体3.0ｇ（4.19ミリモ
ル）を70％酢酸50mlに溶かし、１時間加熱還流し
た。反応液を減圧下に濃縮乾固し、残渣をシリカ
ゲルカラム（40ｇ）ｎ−ヘキサン、酢酸エチル
（４：１）にて精製し、無色針状結晶1.17ｇ（収
率58.9％）を得た。mp90゜〜61℃
TLC〔silicagel，ｎ−Hexane，EtOAc（４：
１）〕Rf＝0.16
IR（KBr）cm-1：3500，3450，2910，2850，
1765，1700，1465，1390，1150，1060，875
実施例 ４
３−オクタデシルオキシ−２−フタルイミドプ
ロピル ２−プロモエチル ホスフエート
実施例３で得たハイドロキシ体1.894ｇ（４ミ
リモル）をベンゼン８mlに溶かし、２−ブロモエ
チル ホスホロジクロリデート1.45ｇ（６ミリモ
ル）、ピリジン0.475ｇ（６ミリモル）を滴下し、
４時間室温にてかきまぜ、反応液を減圧下に濃縮
乾固し残渣を水100mlにあけPH7.0に調整しながら
30分50℃に加熱する。さらに30分加熱還流し、冷
後エーテル60mlに加えて抽出し、エーテル層を減
圧下に濃縮乾固し無色固形物2.64ｇ（収率100％）
を得た。
実施例 ５
３−オクタデシルオキシ−２−フタルイミドプ
ロピル ２−ピリジニオエチル ホスフエート
実施例４で得たプロマイド2.27ｇ（3.55ミリモ
ル）をピリジン20mlに溶かし、浴温60℃２日間加
熱する。反応液を減圧下に濃縮乾固し、残渣をシ
リカゲルカラム（20ｇ）メタノールにて精製し淡
褐色固形物740mg（収率33.3％）を得た。
TLC〔silicagel，CHCl3，MeOH，H2O（65：
25：４）〕Rf＝0.21 single spot.
IR（film）cm- 1：3400，2930，2850，1775，
1710，1635，1490，1465，1395，1250，1100，
1075，1050，760，720
NMR（60MC，CDCl3）δ：
0.88（3H），1.27（32H），3.40（2H），3.80（2H），
4.22（4H），4.60（1H），4.73（2H），7.72（4H），
8.07（2H），8.42（1H），9.08（1H）
実施例 ６
３−オクタデシルオキシ−２−フタルイミドプ
ロピル ２−チアゾリオエチル ホスフエート
実施例４で得たプロマイド2.27ｇをチアゾール
（５ml）とトルエン（５ml）の混液に溶解し、65
℃で７時間加熱した。反応液を減圧下に濃縮乾固
し、残渣をシリカゲルカラムクロマトグラフイー
にて精製し、目的物540mgを得た。
TLC〔silicagel，CHCl3，MeOH，H2O（65：
25：４）〕Rf＝0.22
実施例 ７
３−オクタデシルオキシ−２−アミノ−１−ト
リチルオキシプロパン
３−オクタデシルオキシ−２−フタルイミド−
１−トリチルオキシプロパン6.4ｇをイソプロピ
ルアルコール50mlに溶解し、ヒドラジン水和物４
mlを加えて70℃、１時間加熱した。減圧下反応液
を濃縮乾固し、残渣に酢酸エチルを加え、不溶物
はろ去した。ろ液は濃縮乾固し、シリカゲルクロ
マトグラフイーにより精製した。（溶出液ｎ−ヘ
キサン−酢酸エチル３：１）。淡褐色固体の目的
物4.41ｇ（84％）を得た。
NMR（90MHz，CDCl3）δ.0.87（3H.t）1.25
（32H.m）3.0−3.56（7H.m）7.2−7.5（15H.m）
実施例 ８
３−オクタデシルオキシ−２−（２−カルボキ
シエチルカルボニルアミノ）−１−トリチルオ
キシプロパン
実施例７で得た２−アミノ体2.34ｇ（4mmole
をクロロホルム10mlに溶解し、トリエチルアミン
２ml、無水コハク酸0.48ｇ（4.8mmole）を加え、
１夜加熱還流した。反応液を濃縮乾固し、シリカ
ゲルクロマトグラフイーで精製し（溶出液クロロ
ホルム−メタノール＝20：１）淡褐色固体2.33ｇ
（85％）を得た。
IR（KBr.cm-1）3265，3060，2925，2850，
1730，1680，1648，1550，1490，1470，1455，
1400，1255，1088，1020，705
NMR（90MHz，CDCl3）δ.0.87（3H.t）1.25
（32H.s）2.25−2.75（4H.m）3.0−3.75（6H.m）
4.22（1H.m）5.95（1H.d）7.15−7.50（15H.m）
実施例 ９
３−オクタデシルオキシ−２−スクシンイミド
プロパノール
実施例８で得たカルボン酸体2.21ｇ、酢酸ナト
リウム0.45ｇを無水酢酸10ml中で100℃、２時間
加熱した。反応液を減圧下濃縮し、ｎ−ヘキサン
を加えて不溶物をろ去した。ろ液を濃縮乾固して
３−オクタデシルオキシ−２−スクシンイミド−
１−トリチルオキシプロパノールの粗生成物を得
た。
この粗トリチル体を70％酢酸20ml中100℃、２
時間加熱した。反応液を濃縮乾固し、残渣をシリ
カゲルクロマトグラフイーで精製し（クロロホル
ム−メタノール20：１）無色粉末の目的物1.316
ｇ（95％）を得た。
IR（KBr.cm-1）3525，2970，2925，2850，
1768，1698，1470，1392，1180，1122，1060，
725
NMR（90MHz，CDCl3）δ.0.87（3H.t）1.25
（32H.m）2.71（4H.s）2.9（1H.br）3.40（2H.m）
3.65−4.0（4H.m）4.48（1H.m）
m.p.76〜78℃
実施例 10
３−オクタデシルオキシ−２−スクシンイミド
プロパノール
J.Hajduらの方法〔J.Org.Chem.48．1197−
1202.（1983）〕で合成した３−オクタデシルオキ
シ−２−アミノプロパノール3.43ｇ（10mmole），
およびカルボエトキシスクシンイミド1.73ｇ
（10mmole）を、ジクロルメタン50ml中でかきま
ぜ、氷冷下トリエチルアミン1.01ｇを加えた。室
温にて30時間かきまぜたのち、反応液を濃縮乾固
し、残渣をシリカゲルクロマトグラフイーに付し
て精製した。目的の２−スクシンイミド体894mg
を得た。
スペクトルデータは実施例９で得られたものと
一致した。
実施例 11
３−オクタデシルオキシ−２−スクシンイミド
プロピル２−ブロモエチルホスフエート
３−オクタデシルオキシ−２−スクシンイミド
プロパノール638mg（1.5mmole）をトルエン20ml
に溶解し、冷時、ブロモエチルホスホジクロルデ
ート786mg（3.25mmole）とトリエチルアミン101
mg（3.25mmole）を加え、室温にて４時間かきま
ぜた。水20ml濃塩酸0.5mlを加えて80℃で１時間
かきまぜたのち、溶媒を留去した。残渣をエーテ
ルに溶解し、水洗、濃縮、乾燥して目的のブロム
体939mgを得た。
実施例 12
３−オクタデシルオキシ−２−スクシンイミド
プロピル２−チアゾリオエチルホスフエート
実施例11で得られた粗ブロム体0.30ｇをチアゾ
ール１mlに溶解し、80℃26時間加熱した。反応液
を濃縮乾固し、残渣をシリカゲルクロマトグラフ
イーで精製した。（溶出液メタノールクロロ
ホルム−メタノール水65：25：４）、無色固体状
の目的物121mgを得た。
IR（KBr.cm-1）3410，2850，1775，1550，
1470，1400，1240，1200，1065，830
NMR（90MHz，CDCl3）δ.0.87（3H.t）1.25
（32H.m）2.69（4H.s）3.2−3.5（2H.m）3.5−
4.05（4H.m）4.2（2H.br）4.5（1H.m）4.83（2H.
m）8.20（1H）8.49（1H）10.4（1H）
TLC Rf＝0.24（CHCl3−MeOH−H2O65：
25：４）
実施例 13
３−オクタデシルオキシ−２−マレイミドプロ
パノール
マレイミド495mg（5mmole）およびトリエチ
ルアミン0.70mlをジクロルメタン５mlに溶解し、
氷冷下、クロルギ酸エチル542mg（5mmole）の
ジクロルメタン溶液（５ml）を滴下した。室温に
て１時間かきまぜた後３−オクタデシルオキシ−
２−アミノプロパノール1.37ｇ（4mmole）、ジク
ロルメタン10mlおよびトリエチルアミン0.55ml
（4mmole）を加え、室温で４時間かきまぜた。
反応液を濃縮乾固し、残渣をシリカゲルクロマト
グラフイーに付して精製をおこない（溶出液ｎ−
ヘキサン−酢酸エチル３：１）、さらにｎ−ヘキ
サンより再結晶をおこない、無色針状の目的物
675mgを得た。
IR（KBr.cm-1）3548，2960，2925，2852，
1768，1700，1498，1470，1408，1390，1120，
1058，830，700
NMR（90MHz．CDCl3）δ.0.87（3H.t）1.25
（32H.br−ｓ）2.51（1H.OH），3.39（2H.m）
3.73（2H.d）3.92（2H.t），4.41（1H.m）6.68（2H.
s.maleimide）
TLC Rf＝0.17（ｎ−ヘキサン：酢酸エチル＝
３：１）
m.p.58−60℃
実施例 14
３−オクタデシルオキシ−２−マレイミドプロ
ピル２−チアゾリオエチルホスフエート
実施例13で得た３−オクタデシルオキシ−２−
マレイミドプロパノール（634mg）および２−ブ
ロモエチルホスホリルクロリド（544mg）を用い
実施例11および12と同様に反応をおこない、目的
物を得た。
NMR（CDCl3）δ：0.87（3H.t）1.25（32H.m）
3.2−4.0（6H.m）4.2（2H.m）4.4（1H.m）4.8
（2H.m）6.7（2H.s），8.2，8.5，10.4（3H.
Thiazolio）
IR（KBr.cm-1（2925，2850，1772，1702，1550，
1470，1240，1065
実施例と同様にして以下の化合物が合成でき
る。
３−オクタデシルオキシ−２−サクシンイミド
プロピル２−ピリジニオエチルホスフエート
３−オクタデシルオキシ−２−サクシンイミド
プロピル２−チアゾリオエチルホスフエート
３−オクタデシルオキシ−２−マレインイミド
プロピル２−ピリジニオエチルホスフエート
３−オクタデシルオキシ−２−マレインイミド
プロピル２−チアゾリオエチルホスフエート
３−ヘキサデシルオキシ−２−フタルイミドプ
ロピル２−ピリジニオエチルホスフエート
３−ヘキサデシルオキシ−２−フタルイミドプ
ロピル２−チアゾリオエチルホスフエート
３−オクタデシルオキシ−２−フタルイミドプ
ロピル２−イソキノリニオエチルホスフエート
３−オクタデシルオキシ−２−フタルイミドプ
ロピル２−キノリニオエチルホスフエート
３−オクタデシルオキシ−２−フタルイミドプ
ロピル２−（Ｎ−メチルピロリジニオ）エチルホ
スフエート
３−オクタデシルオキシ−２−フタルイミドプ
ロピル２−（Ｎ−メチルペラジニオ）エチルホス
フエート
実験例 １
PAF抑制作用
血小板凝集におけるPAF抑制作用
〔試験方法および結果〕
雄性ウサギより、血液凝固防止剤として3.15％
クエン酸（血液９に対して１の割合）を含む注射
筒を用いて、直接採血した。次いで室温下、
1000rpmで10分間遠心分離することにより多血小
板血漿（PRP：Platelet rich plasma）を得た。
PRPをさらに1400rpmにて15分間遠心分離し
Platelet pelletを得、これをCa++free Tyrode
（gelatin0.25％含有）に懸濁し、Washed PRPを
調製した。このWashedPRP250μを37℃にて２
分撹拌後、0.2〜0.5mMのCa++液、25μを加え、
さらに30秒撹拌した。ついで実施例５の化合物を
３×10-5Mとなる量を加えさらに２分間撹拌後
PAF3×10-7Mを加えた。血小板凝集は、凝集計
（理化電機製）で測定した。被検薬物の活性は、
対照PRPにおけるPAFによる最大の光透過度
（最大凝集率）に対する抑制率から求めたところ、
抑制率は70％であつた。
実験例 ２
血小板凝集抑制作用
〔試験方法〕
雄性ウサギより血液凝固防止剤として、3.15％
クエン酸（血液９に対して１の割合）を含む注射
筒を用いて、直接採血した。次いで室温下、
800rpmで10分間遠心分離することにより多血小
板血漿（PRP：Platelet rich plasma）を得た。
残りの血液をさらに3000rpmで10分間遠心して上
清液として乏血小板血漿（PPP：platelet poor
plasma）を分離した。
PPPでPRPを希釈して血小板数を約50万個／μ
に調整した。このPRP250μを37℃で２分撹
拌後、被験薬物を加えさらに２分間撹拌後に
PAF1×10-8Mを加えた。血小板凝集は凝集計
（埋化電機製）で測定した。被験薬物の凝集抑制
活性は、対照PRPにおけるPAFによる最大の光
透過度（最大凝集率）に対する抑制率から求め
た。
〔結果〕
第１表に示す。
The present invention relates to a novel platelet activating factor inhibitor. More specifically, the invention relates to the formula [In the formula, R 1 is an alkyl group having 10 to 24 carbon atoms,
R 2 is an optionally substituted cyclic imide group, A +
represents a cyclic ammonio group) and its salts. Platelet aggregation is considered to be the cause of various cardiovascular disorders, and platelet aggregation inhibitors occupy an important position as pharmaceuticals. Conventionally, adenosine diphosphate (ADP) and arachidonic acid metabolites, particularly thromboxane A 2 (TXA 2 ), have been known as representative compounds that cause platelet aggregation. Therefore, conventional platelet aggregation inhibitors have been tested using inhibition of the effects of these compounds as the first screening method. However, recently, platelet activating factor [ Platelet
Activating Factor (PAF)] and its structure was found to be 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine [Nature, Vol. 285, 193 (1980)]. PAF is
It has been found that it has a different mechanism of action than ADP and TXA 2 and has strong activity at lower concentrations. In addition, PAF is a powerful chemical mediator of allergies, and is known to have the strongest activity among known compounds when measuring bronchial stenosis, for example [European Journal of
Pharmacology, 65 , 185-192 (1980)]. Therefore,
The discovery of compounds that inhibit PAF could serve as more effective inhibitors of platelet aggregation in organisms, and also
It can be an effective inhibitor against diseases caused by PAF, such as allergies. In addition to platelet aggregation, PAF has a strong antihypertensive effect and is thought to act as a shock inducer [European Journal of Pharmacology, 86 ,
403-413 (1983)]. Shocks occur due to various causes such as trauma, bleeding, cardiogenic, and bacterial causes.
However, although the causes are different, the pathological conditions of the shots are almost the same, with circulatory abnormalities such as decreased blood pressure and decreased cardiac output, and metabolic abnormalities such as metabolic acidosis, hyperkalemia, and lactic acidemia observed. For example, in the case of bacterial shots, infections caused by Gram-negative bacilli (E. coli, B. aeruginosa, Klebsiella, etc.) are particularly likely to occur, and endotoxin, a cell wall component of these bacteria, is thought to be the cause. Shocks can actually be induced in animals by injecting them with endoxin. Despite advances in antibiotics and fluid therapy, shots have not improved the mortality rate. Therefore, when a shock is expected, drugs that prevent endotoxin shock are used in combination with antibiotics. For this reason, adrenocortical hormones such as hydrocortisone and dexamethasone are frequently used, but since large amounts are used during the course of a shot, the occurrence of side effects caused by adrenocortical hormones becomes a problem. Anti-inflammatory drugs such as indomethacin are also used, but they not only have side effects such as ulcer formation, but are also not very effective. The present inventors have conducted intensive studies on methods for suppressing the effects of PAF, which is involved in various circulatory disorders and shocks, and have found that the compound represented by formula () has a strong anti-inflammatory effect.
They discovered that it has a PAF effect and completed the present invention. Regarding the above formula (), the C 10-24 alkyl group represented by R 1 may be linear or branched, such as decyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosanyl. , docosanil, farnesil, dihydrophythyl, etc., among which C 14-20 alkyl group is preferred. Examples of the cyclic imide group represented by R 2 include a phthalimide group, a succinimide group, and a maleimide group.
It may be substituted with a lower alkoxy group such as methoxy or ethoxy, a halogen group such as chloro or prom, a nitro group, an acetyl group, or the like. As a cyclic ammonio group denoted as A + ,
Examples include pyridinio group, oxazolio group, thiazolio group, isothiazolio group, pyridazinio group, quinolinio group, isoquinolinio group, N-methylmorpholinio group, N-methylpiperidinio group, N-methylpyrrolidinio group, and the like. Further, the compound () is, for example, (a), (
It may also exist in the form of a pharmacologically acceptable salt as represented by b). [In the formula, X - is Cl - , Br - , I - , OH - , CO 2- 3 ,
Anion such as SO 2- 4 , M is an alkali metal (e.g.
Na, K) or alkaline earth metals (e.g., Ca); other symbols have the same meanings as above]. In compound (), there are two types of stereoisomers, R-coordination and S-coordination, with respect to the carbon at the 2-position, and each of them, a mixture thereof, and a racemate are within the scope of the present invention. It is included. Compound () and its salts exhibit excellent platelet activating factor (PAF) inhibitory effects, and more specifically, strongly inhibit platelet aggregation, shock (lower blood pressure, death, etc.) and allergies caused by PAF. Therefore, compound () and its salts are effective against circulatory disorders caused by platelet activating factors in mammals, such as thrombosis, stroke (e.g. cerebral hemorrhage, cerebral thrombosis), myocardial infarction, angina pectoris, thrombophlebitis,
It can be used for the prevention and treatment of diseases such as glomerulonephritis, shock (e.g., endotoxin shock, intravascular blood coagulation syndrome caused by endotoxin, anaphylaxis shock), and bronchial asthma related to allergies. Compound () and its salts have excellent hydrophilic and lipophilic properties and are low in toxicity, so they can be safely used orally or parenterally as a powder or as a pharmaceutical composition in an appropriate dosage form. It can be administered to The dosage varies depending on the subject, symptoms, administration route, etc., but for example, when administered orally for the prevention and treatment of thrombosis in adults, a single dose of compound () is usually about 0.1 to 20
It is convenient to administer about 1 to 3 times a day at a dose of about mg/Kg body weight. More specifically, when the purpose is to prevent thrombosis, the single dose is approximately 0.5 to 4 mg/kg body weight, and when the purpose is treatment, the single dose is approximately 4 to 10 mg/kg body weight.
It is preferable to administer each drug approximately 1 to 3 times a day at a weight of about 1 kg. In addition, when used for the prevention and treatment of shots, for example, in the case of adults,
When administered by intravenous injection, compound ()
It is convenient to administer the drug at the usual dosage of about 0.1 to 20 mg/Kg body weight, preferably about 1 to 10 mg/Kg body weight, about 1 to 3 times a day. Also, the compound ()
It can also be administered by drip injection at a dose of about 0.07 to 0.7 mg/Kg body weight/min for about 1 hour, about 1 to 3 times a day. Similar amounts are administered for other parenteral administrations and oral administrations.
If the symptoms of shock are particularly severe, the dose may be increased depending on the symptoms. The pharmaceutical composition used for the above-mentioned administration contains an effective amount of the active ingredient Compound (2) or a salt thereof and a pharmacologically acceptable carrier or excipient. Such compositions are provided in dosage forms suitable for oral or parenteral administration. That is, for example, compositions for oral administration may include solid or liquid dosage forms, in particular tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules). ), syrups, emulsions, suspensions, etc. Such compositions are produced by methods known per se and contain carriers or excipients commonly used in the pharmaceutical field. For example, carriers and excipients for tablets include lactose, starch, sucrose, and magnesium stearate. Examples of compositions for parenteral administration include injections and suppositories, and injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, and drip injections. include. Such injections are prepared by a method known per se, that is, by dissolving, suspending or emulsifying the compound () or a salt thereof in a sterile aqueous or oily liquid commonly used for injections. Aqueous fluids for injection include physiological saline, isotonic solutions containing dextrose and other adjuvants, and suitable solubilizing agents, such as alcohol (e.g., ethanol), polyalcohols (e.g.,
propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50mol)
It may be used in combination with adduct of hydrogenated castor oil). Examples of the oily liquid include sesame oil and soybean oil, and benzyl benzoate, benzyl alcohol, etc. may be used in combination as a solubilizing agent.
The prepared injection solution is usually filled into suitable ampoules. Suppositories for rectal administration are prepared by mixing the compound () or a salt thereof with a conventional suppository base. The oral or parenteral pharmaceutical compositions described above are conveniently prepared in dosage unit form to suit the dosage of the active ingredient. Examples of such dosage unit dosage forms include tablets, pills, capsules, injections (ampoules), suppositories, etc., and each dosage unit usually contains 5 to 500 mg, particularly 5 to 100 mg for injections, 10-250 for other dosage forms
Preferably, it contains mg of compound (). Note that each of the above-mentioned compositions may contain other active ingredients as long as they do not cause undesirable interactions when mixed with the compound (). Compound () can be produced, for example, by the method shown below. A method formula [In the formula, Y represents Cl, Br or I, and the other symbols have the same meanings as above] is reacted with a cyclic amine compound A() corresponding to A + to obtain the compound (). B method formula Compound () is obtained by reacting the active derivative of an optionally substituted cyclic imide with the compound [wherein each symbol has the same meaning as above]. C method formula [In the formula, X' represents Cl or Br , and the other symbols have the same meanings as above ] to the compound of formula HOCH 2 CH 2 A + . [Symbols have the same meanings as above] to obtain the compound (). Examples of compounds () used in the reaction of method A above include pyridine, thiazole, oxazole, quinoline, isoquinoline, isothiazole,
Examples include pyridazine, N-methylmorpholine, N-methylpiperazine, and N-methylpyrrolidine. The reaction is to add base () to compound () at 1
The reaction is carried out using an equivalent amount or a large excess (for example, 50 times the mole) at room temperature or under heating in the presence of a solvent or in the absence of a solvent. Examples of the solvent include methanol, toluene, benzene, ether, dioxane, and tetrahydrofuran. Examples of active derivatives of optionally substituted cyclic imides used in the reaction of method B include N-
Examples include ethoxycarbonyl phthalimide, N-methoxycarbonyl phthalimide, N-ethoxycarbonyl succinimide, and N-ethoxycarbonyl maleimide. The reaction between the compound () and these active derivatives can be carried out according to reaction conditions commonly known for reactions between amino compounds and these active derivatives. Further, a base such as triethylamine or pyridine may be added to accelerate the reaction. The reaction of Method C uses a solvent (e.g., chloroform, dichloromethane, pyridine, toluene, dioxane)
In the presence of compound () for compound ()
Temperature of equivalent mole or 1.5 times mole of 0 to 100℃
This is achieved by acting on In each of the production methods described above, the progress of the reaction can be tracked by thin layer chromatography, and thereby the reaction conditions can be appropriately determined. Purification of the compound produced by the above method is carried out as appropriate by conventional operations, solvent extraction, recrystallization, chromatography, etc. The present invention will be explained in more detail below using Examples, Experimental Examples, and Formulation Examples, but the scope of the present invention is not limited thereto. Example 1 3-O-octadecyl-2-O-tosyl-1-
O-tritylglycerol 5.0 g (8.52 mmol) of 3-O-octadecyl-1-O-tritylglycerol was dissolved in 9 ml of pyridine.
To the solution was added 1.95 g (10.22 mmol) of tosyl chloride, stirred overnight at room temperature, and then concentrated to dryness under reduced pressure. Dissolve the residue in 50 ml of water and 50 ml of dichloromethane, stir, and separate the dichloromethane layer. The organic layer was concentrated to dryness under reduced pressure, and the residue was applied to a silica gel column (50 g), developing solvent n-hexane,
Purification with ethyl acetate (193:7) gave 5.3 g (yield: 83.9%) of colorless needle crystals. mp52° to 53°C Example 2 3-octadecyloxy-2-phthalimide
1-Trityloxypropane 5.3 g (7.15 mmol) of the tosyl compound obtained in Example 1
was dissolved in 53 ml of dimethyl sulfoxide, 10.6 g of potash phthalimide was added, and the mixture was stirred at a bath temperature of 115°C for 3.5 hours. The reaction solution was poured into 500 ml of water, extracted with 500 ml of ether, and the ether layer was dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified using a silica gel column (50 g) and a developing solvent of n-hexane and ethyl acetate (193:7) to obtain 3.0 g of a colorless oil (yield: 58.6%). TLC [silicagel, n-Hexane, EtOAc (9:
1)] Rf = 0.25 single spot. Example 3 1-Hydroxy-3-octadecyloxy-
2-phthalimidopropane 3.0 g (4.19 mmol) of the trityl compound obtained in Example 2 was dissolved in 50 ml of 70% acetic acid and heated under reflux for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified using a silica gel column (40 g) with n-hexane and ethyl acetate (4:1) to obtain 1.17 g of colorless needle crystals (yield 58.9%). mp90°～61℃ TLC [silicagel, n-Hexane, EtOAc (4:
1)] Rf = 0.16 IR (KBr) cm -1 : 3500, 3450, 2910, 2850,
1765, 1700, 1465, 1390, 1150, 1060, 875 Example 4 3-octadecyloxy-2-phthalimidopropyl 2-promoethyl phosphate 1.894 g (4 mmol) of the hydroxy compound obtained in Example 3 was dissolved in 8 ml of benzene, and 2 - 1.45 g (6 mmol) of bromoethyl phosphorodichloridate and 0.475 g (6 mmol) of pyridine were added dropwise,
Stir at room temperature for 4 hours, concentrate the reaction solution to dryness under reduced pressure, and pour the residue into 100 ml of water while adjusting the pH to 7.0.
Heat to 50°C for 30 minutes. The mixture was further heated under reflux for 30 minutes, and after cooling, it was added to 60 ml of ether for extraction, and the ether layer was concentrated to dryness under reduced pressure to give 2.64 g of colorless solid (yield: 100%).
I got it. Example 5 3-Octadecyloxy-2-phthalimidopropyl 2-pyridinioethyl phosphate 2.27 g (3.55 mmol) of the bromide obtained in Example 4 was dissolved in 20 ml of pyridine and heated at a bath temperature of 60°C for 2 days. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified using a silica gel column (20 g) and methanol to obtain 740 mg (yield 33.3%) of a pale brown solid. TLC [silicagel, CHCl 3 , MeOH, H 2 O (65:
25:4)] Rf=0.21 single spot. IR (film) cm - 1 : 3400, 2930, 2850, 1775,
1710, 1635, 1490, 1465, 1395, 1250, 1100,
1075, 1050, 760, 720 NMR (60MC, CDCl3 ) δ: 0.88 (3H), 1.27 (32H), 3.40 (2H), 3.80 (2H),
4.22 (4H), 4.60 (1H), 4.73 (2H), 7.72 (4H),
8.07 (2H), 8.42 (1H), 9.08 (1H) Example 6 3-octadecyloxy-2-phthalimidopropyl 2-thiazolioethyl phosphate 2.27 g of the bromide obtained in Example 4 was mixed with thiazole (5 ml) and toluene (5 ml). Dissolve in mixed solution, 65
Heated at ℃ for 7 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 540 mg of the target product. TLC [silicagel, CHCl 3 , MeOH, H 2 O (65:
25:4)] Rf=0.22 Example 7 3-octadecyloxy-2-amino-1-trityloxypropane 3-octadecyloxy-2-phthalimide-
Dissolve 6.4 g of 1-trityloxypropane in 50 ml of isopropyl alcohol, and dissolve hydrazine hydrate 4
ml was added and heated at 70°C for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, ethyl acetate was added to the residue, and insoluble materials were filtered off. The filtrate was concentrated to dryness and purified by silica gel chromatography. (Eluent n-hexane-ethyl acetate 3:1). 4.41 g (84%) of the target product was obtained as a light brown solid. NMR (90MHz, CDCl 3 ) δ.0.87 (3H.t) 1.25
(32H.m) 3.0-3.56 (7H.m) 7.2-7.5 (15H.m) Example 8 3-octadecyloxy-2-(2-carboxyethylcarbonylamino)-1-trityloxypropane Obtained in Example 7 2.34g (4mmole) of 2-amino compound
Dissolve in 10 ml of chloroform, add 2 ml of triethylamine and 0.48 g (4.8 mmole) of succinic anhydride,
The mixture was heated to reflux overnight. The reaction solution was concentrated to dryness and purified by silica gel chromatography (eluent: chloroform-methanol = 20:1) to obtain 2.33 g of light brown solid.
(85%). IR (KBr.cm -1 ) 3265, 3060, 2925, 2850,
1730, 1680, 1648, 1550, 1490, 1470, 1455,
1400, 1255, 1088, 1020, 705 NMR (90MHz, CDCl 3 ) δ.0.87 (3H.t) 1.25
(32H.s) 2.25−2.75 (4H.m) 3.0−3.75 (6H.m)
4.22 (1H.m) 5.95 (1H.d) 7.15-7.50 (15H.m) Example 9 3-octadecyloxy-2-succinimidopropanol 2.21g of the carboxylic acid compound obtained in Example 8 and 0.45g of sodium acetate were anhydrous. It was heated in 10 ml of acetic acid at 100°C for 2 hours. The reaction solution was concentrated under reduced pressure, n-hexane was added, and insoluble matter was filtered off. The filtrate was concentrated to dryness to give 3-octadecyloxy-2-succinimide.
A crude product of 1-trityloxypropanol was obtained. This crude trityl compound was dissolved in 20 ml of 70% acetic acid at 100℃ for 2 hours.
heated for an hour. The reaction solution was concentrated to dryness, and the residue was purified by silica gel chromatography (chloroform-methanol 20:1) to obtain the desired product 1.316 as a colorless powder.
g (95%) was obtained. IR (KBr.cm -1 ) 3525, 2970, 2925, 2850,
1768, 1698, 1470, 1392, 1180, 1122, 1060,
725 NMR (90MHz, CDCl 3 ) δ.0.87 (3H.t) 1.25
(32H.m) 2.71 (4H.s) 2.9 (1H.br) 3.40 (2H.m)
3.65-4.0 (4H.m) 4.48 (1H.m) mp76-78℃ Example 10 3-octadecyloxy-2-succinimidopropanol Method of J. Hajdu et al. [J.Org.Chem. 48 . 1197−
1202. (1983)] 3.43 g (10 mmole) of 3-octadecyloxy-2-aminopropanol,
and carboethoxysuccinimide 1.73g
(10 mmole) was stirred in 50 ml of dichloromethane, and 1.01 g of triethylamine was added under ice cooling. After stirring at room temperature for 30 hours, the reaction solution was concentrated to dryness, and the residue was purified by silica gel chromatography. Target 2-succinimide compound 894mg
I got it. The spectral data were consistent with that obtained in Example 9. Example 11 3-Octadecyloxy-2-succinimidopropyl 2-bromoethyl phosphate 638 mg (1.5 mmole) of 3-octadecyloxy-2-succinimidopropanol was added to 20 ml of toluene.
Dissolved in cold, bromoethylphosphodichlordate 786 mg (3.25 mmole) and triethylamine 101
mg (3.25 mmole) was added and stirred at room temperature for 4 hours. After adding 20ml of water and 0.5ml of concentrated hydrochloric acid and stirring at 80°C for 1 hour, the solvent was distilled off. The residue was dissolved in ether, washed with water, concentrated, and dried to obtain 939 mg of the desired bromine compound. Example 12 3-octadecyloxy-2-succinimidopropyl 2-thiazolioethyl phosphate 0.30 g of the crude bromine compound obtained in Example 11 was dissolved in 1 ml of thiazole and heated at 80°C for 26 hours. The reaction solution was concentrated to dryness, and the residue was purified by silica gel chromatography. (eluent methanol chloroform - methanol water 65:25:4) to obtain 121 mg of the target product as a colorless solid. IR (KBr.cm -1 ) 3410, 2850, 1775, 1550,
1470, 1400, 1240, 1200, 1065, 830 NMR (90MHz, CDCl 3 ) δ.0.87 (3H.t) 1.25
(32H.m) 2.69 (4H.s) 3.2−3.5 (2H.m) 3.5−
4.05 (4H.m) 4.2 (2H.br) 4.5 (1H.m) 4.83 (2H.
m) 8.20 (1H) 8.49 (1H) 10.4 (1H) TLC Rf=0.24 (CHCl 3 −MeOH−H 2 O65:
25:4) Example 13 3-octadecyloxy-2-maleimidopropanol 495 mg (5 mmole) of maleimide and 0.70 ml of triethylamine were dissolved in 5 ml of dichloromethane,
A dichloromethane solution (5 ml) containing 542 mg (5 mmole) of ethyl chloroformate was added dropwise under ice cooling. After stirring at room temperature for 1 hour, 3-octadecyloxy-
1.37 g (4 mmole) of 2-aminopropanol, 10 ml of dichloromethane and 0.55 ml of triethylamine
(4 mmole) and stirred at room temperature for 4 hours.
The reaction solution was concentrated to dryness, and the residue was purified by silica gel chromatography (eluent n-
Hexane-ethyl acetate 3:1) and then recrystallized from n-hexane to obtain colorless needle-like target product.
Obtained 675 mg. IR (KBr.cm -1 ) 3548, 2960, 2925, 2852,
1768, 1700, 1498, 1470, 1408, 1390, 1120,
1058, 830, 700 NMR (90MHz. CDCl 3 ) δ.0.87 (3H.t) 1.25
(32H.br-s) 2.51 (1H.OH), 3.39 (2H.m)
3.73 (2H.d) 3.92 (2H.t), 4.41 (1H.m) 6.68 (2H.
s.maleimide) TLC Rf=0.17 (n-hexane:ethyl acetate=
3:1) mp58-60℃ Example 14 3-octadecyloxy-2-maleimidopropyl 2-thiazolioethyl phosphate 3-octadecyloxy-2- obtained in Example 13
A reaction was carried out in the same manner as in Examples 11 and 12 using maleimidopropanol (634 mg) and 2-bromoethylphosphoryl chloride (544 mg) to obtain the desired product. NMR ( CDCl3 ) δ: 0.87 (3H.t) 1.25 (32H.m)
3.2−4.0 (6H.m) 4.2 (2H.m) 4.4 (1H.m) 4.8
(2H.m) 6.7 (2H.s), 8.2, 8.5, 10.4 (3H.
Thiazolio) IR (KBr.cm -1 (2925, 2850, 1772, 1702, 1550,
1470, 1240, 1065 The following compounds can be synthesized in the same manner as in Examples. 3-octadecyloxy-2-succinimidopropyl 2-pyridinioethyl phosphate 3-octadecyloxy-2-succinimidopropyl 2-thiazolioethyl phosphate 3-octadecyloxy-2-maleimidopropyl 2-pyridinio Ethyl phosphate 3-octadecyloxy-2-maleimidopropyl 2-thiazolioethyl phosphate 3-hexadecyloxy-2-phthalimidopropyl 2-pyridinioethyl phosphate 3-hexadecyloxy-2-phthalimidopropyl 2- Thiazolioethyl phosphate 3-octadecyloxy-2-phthalimidopropyl 2-isoquinolinioethyl phosphate 3-octadecyloxy-2-phthalimidopropyl 2-quinolinioethyl phosphate 3-octadecyloxy-2-phthalimidopropyl 2 -(N-methylpyrrolidinio)ethyl phosphate 3-octadecyloxy-2-phthalimidopropyl 2-(N-methylpyrrolidinio)ethyl phosphate Experimental example 1 PAF inhibitory effect PAF inhibitory effect on platelet aggregation [Test method and results] Male From rabbit, 3.15% as anticoagulant
Blood was drawn directly using a syringe containing citric acid (ratio of 1 part to 9 parts blood). Then at room temperature,
Platelet rich plasma (PRP) was obtained by centrifugation at 1000 rpm for 10 minutes.
Centrifuge the PRP for another 15 minutes at 1400 rpm.
Get Platelet pellet and use it as Ca ++ free Tyrode
(containing 0.25% gelatin) to prepare Washed PRP. This WashedPRP250μ was heated to 37℃.
After stirring for minutes, add 0.2-0.5mM Ca ++ solution, 25μ,
Stirred for an additional 30 seconds. Next, the compound of Example 5 was added in an amount of 3 x 10 -5 M, and after stirring for an additional 2 minutes.
PAF3×10 -7 M was added. Platelet aggregation was measured using an aggregometer (manufactured by Rika Denki). The activity of the test drug is
As determined from the inhibition rate of the maximum light transmittance (maximum aggregation rate) by PAF in control PRP,
The suppression rate was 70%. Experimental example 2 Platelet aggregation inhibitory effect [Test method] 3.15% as a blood coagulation inhibitor from male rabbits
Blood was drawn directly using a syringe containing citric acid (ratio of 1 part to 9 parts blood). Then at room temperature,
Platelet rich plasma (PRP) was obtained by centrifugation at 800 rpm for 10 minutes.
The remaining blood was further centrifuged at 3000 rpm for 10 minutes to obtain platelet poor plasma (PPP) as a supernatant.
plasma) was separated. Dilute PRP with PPP to increase platelet count to approximately 500,000/μ
Adjusted to. After stirring this PRP250μ for 2 minutes at 37℃, add the test drug and stirring for another 2 minutes.
PAF1×10 -8 M was added. Platelet aggregation was measured using an aggregometer (manufactured by Ukaede Denki). The aggregation inhibitory activity of the test drug was determined from the inhibition rate with respect to the maximum light transmittance (maximum aggregation rate) by PAF in control PRP. [Results] Shown in Table 1.
【表】
製剤例
３−オクタデシルオキシ−２−フタルイミドプ
ロピル２−ピリジニオエチルホスフエート10ｇを
蒸留水、1.0に溶解し、無菌過後、無菌条件
下に１mlずつ1000本のバイアルに分注し、凍結乾
燥を行ない乾燥後密栓する。
一方、キシリトールまたはマンニトール100ｇ
を含有する２の注射用蒸留水を無菌的に２mlず
つ注射用アンプルに分注後、熔閉し、1000本に調
整する。
用時、注射用キシリトール液（またはマンニト
ール液）に前者１バイアル分の粉末を溶解して用
いる。[Table] Formulation example 10 g of 3-octadecyloxy-2-phthalimidopropyl 2-pyridinioethyl phosphate was dissolved in distilled water, 1.0 g, and after sterilization, 1 ml each was dispensed into 1000 vials under aseptic conditions. Freeze-dry and seal tightly after drying. Meanwhile, 100g of xylitol or mannitol
Aseptically dispense 2 ml of distilled water for injection containing 2 into ampoules for injection, and then melt and close the ampoules to make 1000 ampoules. When using, dissolve one vial of the former powder in xylitol solution (or mannitol solution) for injection.
Claims (1)
R2は置換されていてもよい環状イミド基を、A+
は環状アンモニオ基を示す〕で表わされるリン脂
質またはその塩。[Claims] 1 formula [In the formula, R 1 is an alkyl group having 10 to 24 carbon atoms,
R 2 is an optionally substituted cyclic imide group, A +
represents a cyclic ammonio group] or a salt thereof.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP403084A JPS60146894A (en) | 1984-01-11 | 1984-01-11 | Phospholipid |
| US06/689,730 US4650791A (en) | 1984-01-11 | 1985-01-08 | Certain 3-alkoxy-2-cyclic-imido-propyl-phosphate-ethyl-cyclic ammonium hydroxide inner salts which inhibit activities of platelet activating factor |
| DE8585300133T DE3563968D1 (en) | 1984-01-11 | 1985-01-09 | Phospholipids, their production and use |
| AT85300133T ATE35993T1 (en) | 1984-01-11 | 1985-01-09 | PHOSPHOLIPIDES, THEIR PRODUCTION AND USE. |
| EP85300133A EP0148777B1 (en) | 1984-01-11 | 1985-01-09 | Phospholipids, their production and use |
| CA000471815A CA1276638C (en) | 1984-01-11 | 1985-01-10 | Phospholipids, their production and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP403084A JPS60146894A (en) | 1984-01-11 | 1984-01-11 | Phospholipid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60146894A JPS60146894A (en) | 1985-08-02 |
| JPH048432B2 true JPH048432B2 (en) | 1992-02-17 |
Family
ID=11573559
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP403084A Granted JPS60146894A (en) | 1984-01-11 | 1984-01-11 | Phospholipid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60146894A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2556849B2 (en) * | 1986-02-13 | 1996-11-27 | 三共株式会社 | Glycerin derivative |
| JP2542396B2 (en) * | 1987-08-12 | 1996-10-09 | 三共株式会社 | Glycerin derivative |
-
1984
- 1984-01-11 JP JP403084A patent/JPS60146894A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60146894A (en) | 1985-08-02 |
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