JPH0240648B2 - KETSUSHOBANKATSUSEIINSHOKUSEIZAI - Google Patents
KETSUSHOBANKATSUSEIINSHOKUSEIZAIInfo
- Publication number
- JPH0240648B2 JPH0240648B2 JP13385581A JP13385581A JPH0240648B2 JP H0240648 B2 JPH0240648 B2 JP H0240648B2 JP 13385581 A JP13385581 A JP 13385581A JP 13385581 A JP13385581 A JP 13385581A JP H0240648 B2 JPH0240648 B2 JP H0240648B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- chloroform
- residue
- compound
- formula
- 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 - Lifetime
Links
- -1 pyridinio group Chemical group 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 150000002314 glycerols Chemical class 0.000 claims description 6
- 239000003848 thrombocyte activating factor antagonist Substances 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 46
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 42
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 150000001875 compounds Chemical class 0.000 description 27
- 239000000203 mixture Substances 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 239000002904 solvent Substances 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 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 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 18
- 108010003541 Platelet Activating Factor Proteins 0.000 description 17
- 238000004519 manufacturing process Methods 0.000 description 16
- 238000010992 reflux Methods 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 238000002347 injection Methods 0.000 description 13
- 239000007924 injection Substances 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- 238000001816 cooling Methods 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 8
- 235000008504 concentrate Nutrition 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 239000003480 eluent Substances 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 210000004623 platelet-rich plasma Anatomy 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229910001958 silver carbonate Inorganic materials 0.000 description 6
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- NYKRTKYIPKOPLK-UHFFFAOYSA-N 1-bromo-2-dichlorophosphoryloxyethane Chemical compound ClP(Cl)(=O)OCCBr NYKRTKYIPKOPLK-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
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000007815 allergy Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- CSGAFRQCVTWGFC-UHFFFAOYSA-N (3-hydroxy-2-methoxypropyl) n-tetradecylcarbamate Chemical compound CCCCCCCCCCCCCCNC(=O)OCC(CO)OC CSGAFRQCVTWGFC-UHFFFAOYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- QWDQYHPOSSHSAW-UHFFFAOYSA-N 1-isocyanatooctadecane Chemical compound CCCCCCCCCCCCCCCCCCN=C=O QWDQYHPOSSHSAW-UHFFFAOYSA-N 0.000 description 2
- LHENQXAPVKABON-UHFFFAOYSA-N 1-methoxypropan-1-ol Chemical compound CCC(O)OC LHENQXAPVKABON-UHFFFAOYSA-N 0.000 description 2
- BWKDAAFSXYPQOS-UHFFFAOYSA-N Benzaldehyde glyceryl acetal Chemical compound O1CC(O)COC1C1=CC=CC=C1 BWKDAAFSXYPQOS-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 208000031481 Pathologic Constriction Diseases 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- JITGUKMVUVBSRU-UHFFFAOYSA-N [3-[2-bromoethoxy(hydroxy)phosphoryl]oxy-2-methoxypropyl] N-octadecylcarbamate Chemical compound CCCCCCCCCCCCCCCCCCNC(=O)OCC(OC)COP(O)(=O)OCCBr JITGUKMVUVBSRU-UHFFFAOYSA-N 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 229940127218 antiplatelet drug Drugs 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
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 2
- OAIVIYSBZFEOIU-UHFFFAOYSA-N chloroform;propan-2-one Chemical compound CC(C)=O.ClC(Cl)Cl OAIVIYSBZFEOIU-UHFFFAOYSA-N 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 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 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 230000036262 stenosis Effects 0.000 description 2
- 208000037804 stenosis Diseases 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- XEZVDURJDFGERA-UHFFFAOYSA-N tricosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCCC(O)=O XEZVDURJDFGERA-UHFFFAOYSA-N 0.000 description 2
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- QCCSFRXLZUBMRQ-UHFFFAOYSA-N (3-hydroxy-2-methoxypropyl) n-decylcarbamate Chemical compound CCCCCCCCCCNC(=O)OCC(CO)OC QCCSFRXLZUBMRQ-UHFFFAOYSA-N 0.000 description 1
- OLIHDTPCDSJDJP-UHFFFAOYSA-N (3-hydroxy-2-methoxypropyl) n-docosylcarbamate Chemical compound CCCCCCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)OC OLIHDTPCDSJDJP-UHFFFAOYSA-N 0.000 description 1
- YISWNDIWGWEDMI-UHFFFAOYSA-N (3-hydroxy-2-methoxypropyl) n-octadecylcarbamate Chemical compound CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)OC YISWNDIWGWEDMI-UHFFFAOYSA-N 0.000 description 1
- PULZKYHSDRUPEJ-UHFFFAOYSA-N (3-hydroxy-2-phenylmethoxypropyl) n-octadecylcarbamate Chemical compound CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)OCC1=CC=CC=C1 PULZKYHSDRUPEJ-UHFFFAOYSA-N 0.000 description 1
- YAXKTBLXMTYWDQ-UHFFFAOYSA-N 1,2,3-butanetriol Chemical compound CC(O)C(O)CO YAXKTBLXMTYWDQ-UHFFFAOYSA-N 0.000 description 1
- PJGSXAZUFMCQKA-UHFFFAOYSA-N 1-bromo-2-dichlorophosphorylethane Chemical compound ClP(Cl)(=O)CCBr PJGSXAZUFMCQKA-UHFFFAOYSA-N 0.000 description 1
- RKOGJKGQMPZCGG-UHFFFAOYSA-N 2-methoxypropane-1,3-diol Chemical compound COC(CO)CO RKOGJKGQMPZCGG-UHFFFAOYSA-N 0.000 description 1
- BKAWJIRCKVUVED-UHFFFAOYSA-N 5-(2-hydroxyethyl)-4-methylthiazole Chemical compound CC=1N=CSC=1CCO BKAWJIRCKVUVED-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 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
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- 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 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- FAGYAKMAKSZGDM-UHFFFAOYSA-N P(=O)(OCC(COC(NCCCCCCCCCC)=O)OC)(OCCC=1SC=C[NH+]1)[O-] Chemical compound P(=O)(OCC(COC(NCCCCCCCCCC)=O)OC)(OCCC=1SC=C[NH+]1)[O-] FAGYAKMAKSZGDM-UHFFFAOYSA-N 0.000 description 1
- MNNXEGTXYMVOIN-UHFFFAOYSA-N P(=O)(OCC(COC(NCCCCCCCCCCCCCC)=O)OC)(OCCC=1SC=C[NH+]1)[O-] Chemical compound P(=O)(OCC(COC(NCCCCCCCCCCCCCC)=O)OC)(OCCC=1SC=C[NH+]1)[O-] MNNXEGTXYMVOIN-UHFFFAOYSA-N 0.000 description 1
- HQBRNFBQPLIEIN-UHFFFAOYSA-N P(=O)(OCC(COC(NCCCCCCCCCCCCCCCCCC)=O)OCC1=CC=CC=C1)(OCCC=1SC=C[NH+]1)[O-] Chemical compound P(=O)(OCC(COC(NCCCCCCCCCCCCCCCCCC)=O)OCC1=CC=CC=C1)(OCCC=1SC=C[NH+]1)[O-] HQBRNFBQPLIEIN-UHFFFAOYSA-N 0.000 description 1
- YVELKZIQKBSNAC-UHFFFAOYSA-N P(=O)(OCC(COC(NCCCCCCCCCCCCCCCCCCCCCC)=O)OC)(OCCC=1SC=C[NH+]1)[O-] Chemical compound P(=O)(OCC(COC(NCCCCCCCCCCCCCCCCCCCCCC)=O)OC)(OCCC=1SC=C[NH+]1)[O-] YVELKZIQKBSNAC-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 229920002472 Starch Polymers 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
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- ZNUVJZDGWJGGJT-UHFFFAOYSA-N [2-methoxy-3-(octadecylcarbamoyloxy)propyl] 2-(1,3-thiazol-3-ium-2-yl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCCCNC(=O)OCC(OC)COP([O-])(=O)OCCC1=[NH+]C=CS1 ZNUVJZDGWJGGJT-UHFFFAOYSA-N 0.000 description 1
- BUYZQHKEDFMULO-UHFFFAOYSA-N [2-methoxy-3-(octadecylcarbamoyloxy)propyl] 2-pyridin-1-ium-1-ylethyl phosphate Chemical compound CCCCCCCCCCCCCCCCCCNC(=O)OCC(OC)COP([O-])(=O)OCC[N+]1=CC=CC=C1 BUYZQHKEDFMULO-UHFFFAOYSA-N 0.000 description 1
- UNDOFCPAKWWRTF-UHFFFAOYSA-N [3-(octadecylcarbamoyloxy)-2-phenylmethoxypropyl] 2-pyridin-1-ium-1-ylethyl phosphate Chemical compound C=1C=CC=CC=1COC(COC(=O)NCCCCCCCCCCCCCCCCCC)COP([O-])(=O)OCC[N+]1=CC=CC=C1 UNDOFCPAKWWRTF-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 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
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は新規血小板活性因子抑制剤に関する。
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、血小板凝集を起す化合物としてアデノシ
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
ング法として検索がなされて来た。
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化合
物として、血小板活性因子〔Platelet
Activating Factor（PAF）〕が解明され、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−、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〔ユーロピアン ジ
ヤーナル フアルマコロジー、65巻、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。本発明者らは鋭意検討の結果、（）
式に示される化合物が優れたPAF抑制作用を有
することを見出し、本発明を完成した。
すなわち、本発明は式
〔式中、R1は炭素数10−24のアルキル基を、R2
は炭素数１−４のアルキル基またはアラルキル基
を、A+は炭素数１−４のアルキル基もしくはヒ
ドロキシエチル基で置換されていてもよいピリジ
ニオ基、チアゾリオ基またはイソキノリニオ基を
示す〕で表わされるグリセリン誘導体またはその
塩を含有する血小板活性因子抑制剤に関する。
上記式（）に関し、R1で示される炭素数10
−24のアルキル基は直鎖状もしくは分岐状のいず
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、ジヒドロフイチルな
どがあげられ、なかでも炭素数14−20程度のアル
キル基が好ましい。
R2で示される炭素数１−４のアルキル基とし
ては、たとえばメチル、エチル、プロピル、イソ
プロピル、ブチル、イソブチルなどがあげられ、
なかでもメチルが望ましい。R2で示されるアラ
ルキル基としては、たとえばフエニル−C1-3アル
キル基（例、ベンジル）などがあげられ、そのベ
ンゼン環は、たとえばC1-4アルキル基（例、メチ
ル、エチル、プロピル、イソプロピル）、C1-4ア
ルコキシ基（例、メトキシ、エトキシ、プロポキ
シ）、ハロゲノ基（例、クロロ、ブロモ）、ニトロ
基、アセチル基などの置換基を有していてもよ
い。なお、R2がアラルキル基の化合物（）は
新規化合物である。
A+としてはピリジニオ基、チアゾリオ基およ
びイソキノリニオ基があげられ、これらの基はさ
らにC1-4アルキル基（例、メチル、エチル）また
はヒドロキシエチル基を置換基として有していて
もよい。
なお、化合物（）は生理学的に許容される塩
の形で使用してもよく、かかる塩としては、たと
えば式
〔式中、X-はクロロ、ブロモ、ヨウド、トシル
イオンなどのアニオンを示す〕および
〔式中、M+はアルカリ金属（例、ナトリウム、
カリウム）イオンまたはアルカリ土類金属（例、
カルシウム、マグネシウム）イオンを示す〕で表
わされるような塩があげられる。
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
RS−体のいずれも本発明の範囲に包含されるも
のである。
本発明におけるグリセリン誘導体（）および
その塩は、優れた血小板活性因子（PAF）抑制
作用を示し、さらに具体的にはPAFに起因する
血小板凝集やアレルギーを強力に抑制する。従つ
て、本発明の血小板活性因子抑制剤は、哺乳動物
における血小板凝集に関連する循環障害疾患、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、治療に用いられる。
グリセリン誘導体（）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0.1〜20mg／Kg体重程度、１日約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0.5〜４
mg／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日約１〜３
回程度投与するのが好ましい。
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、製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、筋肉注射剤、点滴注射剤などの剤形を包含す
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
注射液は通常滴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
の塩を通常の坐薬用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（）が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。
本発明のPAF抑制剤に使用するグリセリン誘
導体（）は、たとえば次の方法によつて製造し
得る。
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〕の化合物に式
Ａ （）
〔Ａは窒素を有する異項環〕の化合物を反応させ
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〕の化合物に式
R1−NCO （）
〔式中、R1は前記と同意義〕の化合物を反応さ
せるか、またはホスゲンついで式
R1−NH2 （）
〔式中、R1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、
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
HOCH2CH2+
Ａ
・X- （）
〔式中、X-はハロゲンイオン、OH-、CO3 --、
硫酸イオンなどのアニオンを示し、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、すなわち４級化反応に用いら
れる化合物（）の例としては、ピリジン、チア
ゾール、イソチアゾール、オキサゾール、ピリダ
ジン、キノリン、イソキノリンがあげられる。こ
れらの異項環はさらに前記A+について例示した
置換基を有していてもよい。反応は式（）で表
わされる塩基を化合物（）に対し、１当量また
は大過剰（溶媒として用いる）に用いて、室温ま
たは加熱下（たとえば35〜200℃）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、すなわちカルバミン酸エステル化
は、溶媒としてクロロホルム、ジクロロメタン、
トルエン、ピリジンなどの存在下に（）に対し
１〜10当量の（）を作用させることによつて達
成される。反応温度は０〜150℃程度が好ましい。
（）にホスゲンを作用させる場合、トルエン、
ベンゼン、クロロホルム等の溶媒の存在下に−20
〜室温程度の温度でホスゲンを作用させ、そのま
まもしくは一旦溶存するホスゲンを除去した後、
（）を氷冷または室温下に反応させる。
Ｃ法の反応は、溶媒（例、クロロホルム、ジク
ロロメタン、ピリジン、トルエン、ジオキサン）
の存在下に、（）に対し（）の当モルまたは
1.5倍モル程度を温度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。
上記Ａ、ＢおよびＣ法における各原料化合物
は、たとえば以下に示すような反応経路またはこ
れらに準じて製造しうる。
〔式中、各記号は前記と同意義〕
以下に実験例、製剤例、製造例を示して本発明
をさらに具体的に説明するが、本発明の範囲がこ
れらに限定されるものではない。
実験例
PAF抑制作用
(1) 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Washed
PRP250μlを37℃にて２分撹拌後、0.2〜0.5mM
のCa++液、25μlを加え、さらに30秒撹拌した。
ついで被検薬物を３×10-5Mとなる量を加えさ
らに２分間撹拌後PAF ３×10-7M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。
The present invention relates to a novel platelet activating factor inhibitor. 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 searched for using inhibition of the effects of these compounds as a primary screening method. However, recently, platelet activating factor [ Platelet
Activating Factor (PAF)] was elucidated and its structure was found to be 1-O-alkyl-2-acetyl-Sn-glyceryl-3-phosphorylcholine [Nature, Vol. 285, 193 (1980)] .
PAF has been found to have a different mechanism of action than ADP, TXA 2 , and stronger activity at lower concentrations. In addition, PAF is a powerful chemical messenger for allergies, and is known to have the strongest activity among known compounds when measuring bronchial stenosis, for example [European Journal of Pharmacology, Vol. 65] , 185−192
[1980]. Therefore, if we can find a compound that has an inhibitory effect on PAF, it could become a more effective inhibitor of platelet aggregation in living organisms, and it could also be used to treat other PAF-induced diseases.
For example, it can be an effective suppressant for allergic diseases. As a result of intensive study, the inventors found that ()
The present invention was completed based on the discovery that the compound represented by the formula has an excellent PAF inhibitory effect. That is, the present invention is based on the formula [In the formula, R 1 is an alkyl group having 10-24 carbon atoms, R 2
represents an alkyl group having 1 to 4 carbon atoms or an aralkyl group, and A + represents a pyridinio group, a thiazolio group, or an isoquinolinio group which may be substituted with an alkyl group having 1 to 4 carbon atoms or a hydroxyethyl group. The present invention relates to a platelet activating factor inhibitor containing a glycerin derivative or a salt thereof. Regarding the above formula (), the number of carbon atoms represented by R 1 is 10
The alkyl group at -24 may be linear or branched, such as decyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl,
Examples include icosanyl, docosanyl, dihydrophythyl, etc. Among them, an alkyl group having about 14 to 20 carbon atoms is preferred. Examples of the alkyl group having 1 to 4 carbon atoms represented by R 2 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.
Among these, methyl is preferred. Examples of the aralkyl group represented by R 2 include phenyl-C 1-3 alkyl groups (e.g., benzyl), and the benzene ring is, for example, C 1-4 alkyl groups (e.g., methyl, ethyl, propyl, may have a substituent such as a C 1-4 alkoxy group (eg, methoxy, ethoxy, propoxy), a halogeno group (eg, chloro, bromo), a nitro group, or an acetyl group. Note that the compound () in which R 2 is an aralkyl group is a new compound. Examples of A + include a pyridinio group, a thiazolio group, and an isoquinolinio group, and these groups may further have a C 1-4 alkyl group (eg, methyl, ethyl) or a hydroxyethyl group as a substituent. In addition, the compound () may be used in the form of a physiologically acceptable salt, and such salts include, for example, the formula [In the formula, X - represents an anion such as chloro, bromo, iodo, tosyl ion, etc.] and [In the formula, M + is an alkali metal (e.g., sodium,
potassium) ions or alkaline earth metals (e.g.
Examples include salts such as those represented by ], which represent calcium and magnesium ions. 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 or a mixture thereof and
Any RS-isomer is included within the scope of the present invention. The glycerin derivative () and its salt in the present invention exhibit an excellent platelet activating factor (PAF) inhibitory effect, and more specifically, strongly inhibit platelet aggregation and allergies caused by PAF. Therefore, the platelet activating factor inhibitor of the present invention can be used to treat circulatory disorders associated with platelet aggregation in mammals, such as thrombosis, stroke (e.g., cerebral hemorrhage, cerebral thrombosis),
It is used to prevent and treat diseases such as myocardial infarction, angina pectoris, thrombophlebitis, and glomerulonephritis, as well as bronchial asthma related to allergies. Glycerin derivatives () and their salts have excellent hydrophilic and lipophilic properties and are low in toxicity, so they can be administered orally or parenterally as a powder or as a pharmaceutical composition in an appropriate dosage form. Can be administered safely. The dose depends on the subject,
Although it varies depending on the symptoms, administration route, etc., for example, when administered orally for the prevention or treatment of thrombosis in adults, the compound () is usually administered at a dose of about 0.1 to 20 mg/Kg body weight per day. It is convenient to administer about 1 to 3 times. More specifically, when the purpose is to prevent thrombosis, a single dose of approximately 0.5 to 4
mg/Kg body weight, for therapeutic purposes, a single dose of approximately 4 to 10 mg/Kg body weight, approximately 1 to 3 mg per day, respectively.
It is preferable to administer the drug several times. 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 pharmaceutically 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. Compositions for parenteral administration include, for example, injections, suppositories, etc., and injections include dosage forms such as intravenous injections, intramuscular injections, and drip injections. 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 solubility aids, such as alcohol (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol, etc.). glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50
(polyoxyethylene (50mol) adduct of
It may be used in combination with 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 ampoules. Suppositories used for rectal administration are prepared by mixing the compound () or its salt 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, mg of compound () is contained. 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 (). The glycerin derivative () used in the PAF inhibitor of the present invention can be produced, for example, by the following method. A method formula [In the formula, Y represents Cl, Br or I, and other symbols have the same meanings as above] to react with a compound of the formula A () [A is a heterocyclic ring having nitrogen] to form a compound () get. B method formula [In the formula, each symbol has the same meaning as above] is reacted with a compound of the formula R 1 -NCO () [In the formula, R 1 has the same meaning as above], or phosgene is then reacted with the compound of the formula R 1 -NH 2 () [In the formula, R 1 has the same meaning as above] to obtain the compound (), C method Formula [ wherein , _ _ 3-- ,
An anion such as a sulfate ion, and other symbols have the same meanings as above] to obtain the compound (). Examples of the compound () used in the reaction of method A, that is, the quaternization reaction, include pyridine, thiazole, isothiazole, oxazole, pyridazine, quinoline, and isoquinoline. These heterocyclic rings may further have the substituents exemplified for A + above. The reaction is carried out using a base represented by the formula () in an amount of 1 equivalent or in large excess (used as a solvent) with respect to the compound (), at room temperature or under heating (e.g. 35 to 200°C), in the presence of a solvent or without a solvent. Do it below. As a solvent,
Examples include methanol, toluene, benzene, ether, dioxane, and tetrahydrofuran. The reaction of method B, that is, carbamate esterification, uses chloroform, dichloromethane,
This is achieved by reacting 1 to 10 equivalents of () with () in the presence of toluene, pyridine, etc. The reaction temperature is preferably about 0 to 150°C.
When phosgene is applied to (), toluene,
-20 in the presence of solvents such as benzene, chloroform, etc.
~ Allow phosgene to act at a temperature around room temperature, either as is or after removing dissolved phosgene,
() are reacted on ice or at room temperature. The reaction of Method C uses a solvent (e.g., chloroform, dichloromethane, pyridine, toluene, dioxane)
In the presence of (), equimolar of () or
This is achieved by applying about 1.5 times the mole at a temperature of 0 to 100°C. 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. Each of the raw material compounds in the above methods A, B, and C can be produced, for example, by the reaction routes shown below or according to these. [In the formula, each symbol has the same meaning as above] The present invention will be explained in more detail by showing experimental examples, formulation examples, and manufacturing examples below, but the scope of the present invention is not limited thereto. Experimental example PAF inhibitory effect (1) PAF inhibitory effect on platelet aggregation [Test method and results] 3.15 as a blood coagulation inhibitor from male rabbits
Blood was drawn directly using a syringe containing 1% citric acid (1 part to 9 parts blood). Platelet rich plasma (PRP) was then centrifuged at 1000 rpm for 10 minutes at room temperature.
I got it. The PRP is further centrifuged at 1400 rpm for 15 minutes to obtain a platelet pellet, which is Ca ++ free.
Suspended in Tyrode (containing gelatin 0.25%),
Washed PRP was prepared. This Washed
After stirring 250μl of PRP at 37℃ for 2 minutes, 0.2-0.5mM
25 μl of Ca ++ solution was added and stirred for an additional 30 seconds.
Next, a test drug was added in an amount of 3 x 10 -5 M, and after stirring for an additional 2 minutes, 3 x 10 -7 M of PAF was added.
Platelet aggregation was measured using an aggregometer (manufactured by Rika Denki). The activity of the test drug was determined in the control PRP.
It was determined from the inhibition rate against the maximum light transmittance (maximum aggregation rate) by PAF.
【表】
(2) 気道狭窄におけるPAF抑制作用
体重400g前後の雌雄のHartley系モルモツト
を使用した。Urethane（1.5g／Kg、i.p.）麻酔
下に背位固定し、気管にカニユレ（４脚）の一
脚に挿入し、他の３脚のうち２脚を人工呼吸器
（Harvard apparatus rodent respirator）に
連結した。残りの１脚（側枝）を
bronchospasm transducer7020（Ugo basile）
に連結した。１回送気量、５〜７ml、送気回数
70回／min、肺への負荷圧10cmH2Oとしover
flowする空気量をtransducerを介して
Rectigraph（Rectigrash−8S、三栄測器）上に
記録した。Gallamine triethodide（１mg／Kg
iv）処置後（histamine・2HCl（10μg／Kg）を
静脈内投与し動物の反応性を調べた。生理食塩
水を静脈内投与した対照群にPAF0.3μg／Kg静
脈内投与すると30秒後に最大気道狭窄反応がみ
られ完全閉塞を100％とする時その値は72.8±
4.3％（mean＋Se、ｎ＝６）であつた。製造例
の化合物は0.3および１mg／Kgの２分前静脈
内投与によりPAFの上記反応を各々49および
82％抑制した。
急性毒性
雄性Wistarラツト（４〜６週令；５匹）を用
いた。製造例の化合物を生理食塩水に溶解し
て、尾静脈より100mg／Kgとなるように投与し、
観察を１週間行つた。
試験ラツトは全例とも生存し、観察期間中特に
異常な症状はみられなかつた。
製剤例 １
３−（Ｎ−オクタデシルカルバモイルオキシ）−
２−メトキシプロピル ２−チアゾリオエチルフ
オスフエートの10gを蒸留水、1.0に溶解し、無
菌過後、無菌条件下に１mlづつ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、キシリツトまたはマンニツト100gを含
有する２の注射用蒸留水を無菌的に２mlづつ注
射用アンプルに分注後、溶閉し、1000本に調製す
る。
用時、注射用キシリツト液（またはマンニツト
液）に前者１バイアル分の粉末を溶解して用い
る。
製剤例 ２
錠剤
１錠あたりの使用量として
(1) ３−（Ｎ−オクタデシルカルバモイルオキシ）
−２−メトキシプロピル ２−チアゾリオエチ
ル フオスフエート 100mg
(2) 乳 糖 200mg
(3) コーンスターチ 51mg
(4) ヒドロキシプロピルセルロース ９mg
を常法により混合、顆粒化し、コーンスターチ
（８mg）、ステアリン酸マグネシウム（２mg）と混
和後、打錠して、１錠370mg、直径9.5mmの錠剤と
する。
製剤例 ３
上記２、の錠剤を１錠あたりの使用量として、
ヒドロキシプロピルメチルセルロースフタレート
（14mg）とヒマシ油（１mg）を濃度７％となるよ
うに溶解したアセトン−エタノール（４：６）混
液を用いて、コーテイングを施こすことにより腸
溶性の被覆錠とする。
製造例 １
３−（Ｎ−オクタデシルカルバモイルオキシ）−
２−メトキシプロピル ２−ピリジニオエチル
フオスフエート
１） ｎ−オクタデシルイソシアネート9.7g、β
−メチルグリセロールエーテル3.5gをピリジン
20ml中でまぜ、室温で一晩かきまぜる。反応液
をエーテル300ml、水50mlの混液にあけ、濃塩
酸にて中和する。エーテル層を分離、水洗、乾
燥後、濃縮乾固する。シリカゲルカラムを用い
るクロマトグラフイー（展開溶媒、クロロホル
ム−エーテル １：１）により精製すると、３
−（Ｎ−オクタデシルカルバモイルオキシ）−２
−メトキシ−１−プロパノールの無色結晶8.2g
が得られる。
IR（赤外吸収スペクトル）νNujol nax（cm-1）：3340
1687、
mp 55〜56℃
マススペクトル（ｍ／ｅ）：401（M+）、370（Ｍ
−OCH3）
２） ３−（Ｎ−オクタデシルカルバモイルオキ
シ）−２−メトキシ−１−プロパノール6.0gお
よび２−ブロモエチルホスホロジクロリド4.0g
を四塩化炭素30ml中で18時間加熱還流する。冷
却後、溶媒を減圧下に留去し、水50mlを加え１
時間加熱還流する。冷却後、エーテルで抽出
し、芒硝で脱水後、溶媒を留去すると中間体
（ブロム体）7.1gが得られる。この中間体1.6g
をピリジン16mlに溶解し60℃で一晩加温する。
ピリジンを減圧下に留去し残渣に炭酸銀2g、
メタノール50mlを加えて２時間加熱還流する。
不溶物を過して除き、液を濃縮乾固して得
られる残渣をシリカゲルクロマトグラフイーに
より精製し（流出溶媒：CHCl3：MeOH：
H2O＝65：25：４）、クロロホルム−アセトン
から再沈澱し、目的物393mgを得る。
TLC（薄層クロマト）：Rf＝0.2（CHCl3：
MeOH：H2O＝65：25：４）
IR（KBr）cm-1：3340，1698，1540，1470，
1255，1075，1050
NMR（60MHz、CDCl3）δ：0.7−1.8（35H），
3.44（3H，ｓ，OCH3）、2.9〜4.8（9H，ｍ）、
5.20（2H、broad、CH2+
Ｎ
）、6.16（1H、
broad，CONH）、8.0〜8.8（3H，ｍ，
pyridinio）、9.58（2H，ｍ，pyridinio）
元素分析：C30H55N2O7P・0.5H2O
計算値 Ｃ，60.48；Ｈ，9.48；Ｎ，4.70；
Ｐ，5.20
実測値 Ｃ，60.20；Ｈ，9.28；Ｎ，4.77；
Ｐ，5.30
製造例 ２
３−（Ｎ−オクタデシルカルバモイルオキシ）−
２−メトキシプロピル ２−チアゾリオエチル
フオスフエート
３−（Ｎ−オクタデシルカルバモイルオキシ）−
２−メトキシ−１−プロパノール20.1gおよび２
−ブロモエチルホスホロジクロリド14.5gをベン
ゼン250mlに溶解し、氷冷下ピリジン4.74gを滴下
する。滴下後さらに室温にて６時間撹拌する。減
圧下に溶媒を留去し、残渣に水200mlを加えて１
時間加熱還流する。冷却後エーテルで抽出し、中
間体29gを得る。この中間体をチアゾール20gと
トルエン25mlに溶解し、60℃で３日間加熱する。
溶媒を留去し、残渣をメタノール500mlに溶解し、
炭酸銀20gを加え室温で1.5時間撹拌する。不溶物
を過して除き、液を濃縮し、残渣をシリカゲ
ルクロマトグラフイーにより精製し（流出溶媒：
CHCl3：MeOH：H2O＝65：25：４）目的物5.1g
を得る。
TLC：Rf＝0.2（CHCl3：MeOH：H2O＝65：
25：４）
IR（KBr）cm-1：3400，2920，2851，1701，
1558，1246，1065
NMR（60MHz，CDCl3）δ：0.7−1.8（35H），
3.46（3H，ｓ，OMe），2.9−4.8（9H，ｍ），
5.08（2H，broad），6.30（1H，broad，
CONH），8.55，8.88＆10.93（thiazolio）
元素分析：C28H53N2O7PS.1.5H2O
計算値 Ｃ，54.26；Ｈ，9.11；Ｎ，4.52；
Ｐ，5.00
実測値 Ｃ，54.30；Ｈ，8.90；Ｎ，4.71；
Ｐ，5.03
製造例 ３
３−（Ｎ−デシルカルバモイルオキシ）−２−メ
トキシプロピル ２−チアゾリオエチル フオ
スフエート
１） ｎ−ウンデカン酸25gをトルエン220mlに
溶かし、ジフエニルホスホリルアジド51.6g、
トリエチルアミン28.3mlを加え、室温で3.5時
間撹拌した後、反応液を70mlまで濃縮し、1.5
時間加熱還流する。冷後、β−メチルグリセロ
ールエーテル53.3g、ピリジン155mlを加え、室
温で一夜かきまぜ、濃縮乾固する。残渣をクロ
ロホルムに溶かし水洗、乾燥、濃縮し、シリカ
ゲルによるクロマトグラフイーにより３−（Ｎ
−デシルカルバモイルオキシ）−２−メトキシ
−１−プロパノール20.7g（53％）を得る。
IR（フイルム）3340，2920，2850，1700，
1255，1065，955，748
２） ３−（Ｎ−デシルカルバモイルオキシ）−２
−メトキシ−１−プロパノール289.4mg
（1.0Ymole）、２−ブロモエチルホスホリルジ
クロリド362.8mg（1.5mmole）をベンゼン2.1ml
に溶かし、ピリジン118.7mg（1.5mmole）を加
えて、室温で５時間かきまぜる。反応液を減圧
下に濃縮乾固し残渣に水４mlを加え、90℃、１
時間加熱し、冷後クロロホルム10mlを加えて、
激しくふりまぜ、有機層を分取し、水層はすて
る。有機層を減圧下に濃縮乾固し、残渣にチア
ゾール１mlを加え、50℃、３日かきまぜ、減圧
下に濃縮乾固する。残渣にメタール５ml、
Ag2CO3220mgを加えて室温にて１時間かきま
ぜ、不溶物をろ去後、母液を減圧下に濃縮乾固
する。これをシリカゲル塔（8g）、展開液クロ
ロホルム、メタノール、水（65：25：４）を用
いて精製し、目的物 無色粉末147mg（収率32
％）を得る。
IR（film）cm-1：3320，3080，2930，2850，
1700，1545，1460，1240，1090，1060，950
NMR（30MC，CDCl3）δ：0.93（3H），1.23
（16H），3.13（2H），3.38（3H），3.70〜4.67
（7H），4.96（2H），6.17（1H），8.33（1H），
8.67（1H），10.70（1H）
TLC；クロロホルム、メタノール、水（65：
25：４） Rf＝0.21（１スポツト）
製造例 ４
３−（Ｎ−オクタデシルカルバモイルオキシ）−
２−メトキシプロピル ２−（４−メチル−５
−ヒドロキシエチル基）チアゾリオエチル フ
オスフエート
製造例１で得た３−（Ｎ−オクタデシルカルバ
モイルオキシ）−２−メトキシプロピル ２−ブ
ロモエチルフオスフエート294mg（0.5mmole）、
４−メチル−５−ヒドロキシエチルチアゾール
286.4mg（2.0mmole）をトルエン0.5mlに溶かし、
75℃、３日間加熱する。反応液を減圧下に濃縮乾
固し、残渣をシリカゲル塔（8g）、展開液クロロ
ホルム、メタノール、水（65：25：４）を用いて
精製し、無色粉末85mg（収率26.2％）を得る。
IR（film）cm-1：3300，2920，2850，1700，
1540，1460，1230，1090，1060，1055，930，
850
NMR（60MC，CDCl3）δ：0.90（3H），1.28
（32H），2.57（3H），3.08（6H），3.43（3H），
3.83（6H），4.10（2H），4.33（1H），4.77（1H），
5.78（1H），10.57（1H）
TLC：クロロホルム、メタノール、水（65：
25：４）Rf＝0.33（1spot）
UV（紫外部吸収スペクトル）：λnax MeOH
222mμ、262mμ
製造例 ５
３−（Ｎ−オクタデシルカルバモイルオキシ）−
２−メトキシプロピル ２−イソキノリニオエ
チル フオスフエート
製造例１で得たブロム体すなわち３−（Ｎ−オ
クタデシルカルバモイルオキシ）−２−メトキシ
プロピル ２−ブロモエチル フオスフエート
294mg（0.5mmole）、イソキノリン258.3mg
（2.0mmole）をトルエン0.5mlに溶かし、75℃、
３日間加熱する。反応液を減圧下に濃縮乾固し、
残渣をシリカゲル塔（8g）、展開液、クロロホル
ム、メタノール、水（65：25：４）を用いて精製
し、無色粉末140mg（収率44％）を得る。
IR（film）cm-1：3320，2920，2850，1700，
1640，1530，1460，1240，1095，1060，930，
820
NMR（60MC，CDCl3）δ：0.88（3H），1.27
（35H），3.13（2H），3.32（3H），3.3〜3.8（2H），
3.93（1H），4.07（8H），4.63（1H），5.30（1H），
6.00（1H），8.00（3H），8.50（1H），8.57（1H），
9.10（1H），10.70（1H）
TLC：クロロホルム、メタノール、水（65：
25：４）Rf＝0.47（1spot）
UV：λnax MeOH233mμ、279mμ、340mμ
製造例 ６
３−（Ｎ−オクタデシルカルバモイルオキシ）−
２−ベンジルオキシプロピル ２−チアゾリオ
エチル フオスフエート
１） １，３−ベンジリデングリセロール27g、
ベンジルクロリド45g、Et4NI300mg、50％
NaOH60mlおよびベンゼン240mlをまぜて40時
間加熱還流する。ベンゼン層を分離し、50％
NaOH60mlとEt4NI300mgを加えてさらに20時
間加熱還流する。ベンゼン層を分離、水洗し、
濃縮する。残渣をシリカゲルクロマトグラフイ
ーにて精製し（流出溶媒、ベンゼン）、１，３
−ベンジリデングリセロール β−ベンジルエ
ーテル36g（収率89％）を得る。mp73〜75℃
２） 前記の方法で得られるエーテル体33gを水
35mlと酢酸140mlの混液に溶解し、窒素気流中、
１時間加熱還流する。減圧下に溶媒を留去し、
残渣をシリカゲルクロマトグラフイーにて精製
し（展開溶媒、エーテル）、β−ベンジルグリ
セロール19.6g（収率88％）を得る。
NMR（CDCl3）δ：3.14（2H，OH），3.3〜3.9
（5H）、4.60（2H，PhCH2−）、7.34（5H，
PhCH2−）
３） β−ベンジルグリセロール3.64gをピリジ
ン20mlに溶解し、これにイソシアン酸オクタデ
シル5.9gを加え、室温にて一晩かきまぜる。ピ
リジンを留去し、残渣に希塩酸とクロロホルム
を加える。クロロホルム層を分離し、脱水、濃
縮する。残渣をシリカゲルクロマトグラフイー
にて精製し（流出溶媒、クロロホルム−エーテ
ル、10：１）、主生成物をｎ−ヘキサンから再
結晶し、３−（Ｎ−オクタデシルカルバモイル
オキシ）−２−ベンジルオキシ−１−プロパノ
ール4.1gを得る。mp52−54℃
４） ３−（Ｎ−オクタデシルカルバモイルオキ
シ）−２−ベンジルオキシ−１−プロパノール
3.1gおよび２−ブロモエチルホスホロジクロリ
デート2.9gをベンゼン50mlに溶解し、氷冷下ピ
リジン0.96gを滴下する。さらに室温にて1.5時
間撹拌後、ベンゼンを留去し、残渣に水50mlを
加え、45分間加熱還流する。冷後、クロロホル
ムで抽出し、濃縮乾固し、白色粉末（ブロム
体）5.3gを得る。この中から3.0gを取り、チア
ゾール６mlに溶解し、60℃で３日間加温する。
溶媒を留去し、メタノール40ml、炭酸銀3.1gを
加えて室温で１時間撹拌後、不溶物を去し、
液を濃縮乾固、残渣をシリカゲルクロマトグ
ラフイーにより精製し（流出溶媒：CHCl3：
MeOH：H2O＝65：25：４）目的物811mgを得
る。
IR（KBr）cm-1：3340，2920，2850，1695，
1462，1230，1055
NMR（60MHz、CDCl3）δ：0.7−1.8（35H），
2.9〜4.9（11H，ｍ），4.62（2H，ｓ，−
CH2Ph）、6.0（1H，broad，CONH）、7.30
（5H，ｓ，Ph）、8.21，8.44＆10.73（3H，
thiazolio）
元素分析：C34H57N2O7SP・2H2O
計算値 Ｃ，57.93；Ｈ，8.72；Ｎ，3.97；
Ｐ，4.39
実測値 Ｃ，58.00；Ｈ，8.91；Ｎ，3.97；
Ｐ，4.22
製造例 ７
３−（Ｎ−オクタデシルカルバモイルオキシ）−
２−ベンジルオキシプロピル ２−ピリジニオ
エチル フオスフエート
製造例６で得られる中間体（ブロム体）2.3gを
ピリジン12mlに溶解し、60℃で16時間加温する。
減圧下にピリジンを留去し、残渣に炭酸銀2.3gと
メタノール30mlを加え、１時間加熱還流する。不
溶物を去し、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より精製し（流出溶
媒：CHCl3：MeOH：H2O＝65：25：４）目的
物770mgを得る。
TLC：Rf＝0.35（CHCl3：MeOH：H2O＝65：
25：４）
外吸収スペクトル（KBr）cm-1：2910，2840，
1695，1245，1070
NMR（60MHz，CDCl3）δ：0.8−1.8（35H），
2.7〜5.1（13H），6.10（1H，broad，CONH），
7.27（5H，ｓ，Ph），7.66〜8.47（3H，broad，
pyridinio），9.10（2H，broad，pyridinio）
元素分析：C36H59N2O7P・1.5H2O
計算値 Ｃ，62.68；Ｈ，9.06；Ｎ，4.06
実測値 Ｃ，62.80；Ｈ，8.80；Ｎ，4.47
製造例 ８
３−（Ｎ−ドコシルカルバモイルオキシ）−２−
メトキシプロピル ２−チアゾリオエチル フ
オスフエート
１） トリコサン酸7.08g（２×10-2モル）を無水
トルエン70mlおよびトリエチルアミン3.6mlの
混合液に溶かし、室温下にジフエニルホスホリ
ルアジド6.6g（2.4×10-2モル）を滴下する。３
時間室温で撹拌した後、反応液を減圧下1/3量
に濃縮する。この反応液を1.5時間還流、冷後、
ピリジン30mlおよび２−メトキシ−１，３−プ
ロピレングリコール7.84g（7.4×10-2モル）を加
えて室温一夜撹拌する。反応液を減圧下濃縮乾
固し、残渣に水を加えてクロロホルムで抽出す
る。クロロホルム層を水洗後、Na2SO4で乾燥
する。溶媒留去し、残渣をシリカゲル（100g）
でカラムクロマトグラフイーをおこない精製す
る。クロロホルム流出分画液を濃縮乾固して、
３−（Ｎ−ドコシルカルバモイルオキシ）−２−
メトキシ−１−プロパノールの無色粉末4.3g
（47％）を得る。
IR（KBr）：3350（NH，OH），2920（CH），
2850（CH），1685（−NHCOO−），1530（−
NHCOO−）
２） ３−（Ｎ−ドコシルカルバモイルオキシ）−
２−メトキシ−１−プロパノール2.74gおよび
２−ブロモエチルホスホロジクロリデート
1.89gをベンゼン20mlに溶解し、ピリジン0.62g
を滴下し、室温にて2.5時間撹拌する。ベンゼ
ンを留去し、水を加えて１時間30分加熱還流を
行なう。冷後クロロホルム抽出し、濃縮乾固す
る。残渣にチアゾール6.4mlを加え60℃で77.5
時間加温する。反応液を乾固し、残渣にメタノ
ール80mlおよび炭酸銀2.15gを加えて１時間加
熱還流する。熱時過、液を濃縮乾固し粗生
成物を得る。シリカゲルを用いるクロマトグラ
フイーにより精製し（流出溶媒：CHCl3−
MeOH−H2O，65：25：４）、クロロホルム−
アセトン混液より再結晶して目的物0.41g（10.5
％）を得る。
IR（KBr）cm-1：2920，2850，1700，1245，
1065
元素分析 C32H61N2O7PS・2H2O
計算値 Ｃ，56.12；Ｈ，9.57；Ｎ，4.09；
Ｐ，4.52；Ｓ，4.68
実測値 Ｃ，56.14；Ｈ，9.47；Ｎ，4.07；
Ｐ，4.68；Ｓ，4.24
製造例 ９
３−（Ｎ−テトラデシルカルバモイルオキシ）−
２−メトキシプロピル ２−チアゾリオエチル
フオスフエート
１） ペンタデカン酸20gを乾燥トルエン200ml
に溶解し、ジフエニルホスホリルアジド27.3g、
トリエチルアミン14.9mlを加え、室温で５時間
撹拌、反応液を減圧濃縮し、１時間、加熱還流
する。冷後、β−メチルグリセロールエーテル
32.8g、乾燥ピリジン124mlを加え、室温で一晩
かきまぜる。濃縮乾固し、クロロホルムに溶解
し、水洗、乾燥し、シリカゲルによるクロマト
グラフイー（溶出液；クロロホルム）で精製
し、２−メトキシ−３−（Ｎ−テトラデシルカ
ルバモイルオキシ）−１−プロパノール9.43g
（33％）を得る。
IRνKBr nax（cm-1）1695
２） ２−メトキシ−３−（Ｎ−テトラデシルカ
ルバモイルオキシ）−１−プロパノール5.18gお
よび２−ブロモエチルホスホロジクロリデート
5.44gをベンゼン73mlに溶解し、ピリジン1.78g
を滴下し、室温にて２時間撹拌する。ベンゼン
を留去し、水を加えて１時間30分加熱還流す
る。冷後クロロホルム抽出し、濃縮乾固する。
残渣にチアゾール７mlを加え60℃で60時間加温
する。反応液を乾固し、残渣にメタノール90ml
および炭酸銀8gを加えて１時間加熱還流する。
熱時過、液を濃縮乾固し、残渣をシリカゲ
ルを用いるクロマトグラフイーにより精製す
る。クロロホルム−アセトン混液より再結晶し
て目的物0.4g（５％）を得る。
IR（KBr）cm-1：2920，2850，1700，1230，
1050
元素分析：C24H45N2O7PS・2H2O
計算値 Ｃ，50.33；Ｈ，8.27；Ｎ，4.89；
Ｐ，5.41；S5.60
実測値 Ｃ，50.35；Ｈ，8.20；Ｎ，4.76；
Ｐ，5.38；Ｓ，4.84[Table] (2) PAF inhibitory effect on airway stenosis Male and female Hartley guinea pigs weighing approximately 400 g were used. Urethane (1.5g/Kg, ip) was placed in the dorsal position under anesthesia, one leg of the cannula (four legs) was inserted into the trachea, and two of the other three legs were placed on a ventilator (Harvard apparatus rodent respirator). Connected. The remaining leg (lateral branch)
bronchospasm transducer7020 (Ugo basile)
connected to. Air volume per time, 5-7ml, number of air injections
70 times/min, load pressure to the lungs is 10 cmH 2 O and over
The amount of air flowing through the transducer
It was recorded on a Rectigraph (Rectigrash-8S, Sanei Sokki). Gallamine triethodide (1mg/Kg
iv) After treatment (histamine・2HCl (10 μg/Kg) was administered intravenously to examine the animal's reactivity. When 0.3 μg/Kg of PAF was intravenously administered to a control group that had been intravenously administered with physiological saline, the maximum level was reached after 30 seconds. When airway constriction reaction is observed and complete obstruction is taken as 100%, the value is 72.8±
It was 4.3% (mean+Se, n=6). The compound of the production example was administered intravenously at doses of 0.3 and 1 mg/Kg 2 minutes before to induce the above-mentioned reactions in PAF, 49 and 49 respectively.
It was suppressed by 82%. Acute Toxicity Male Wistar rats (4-6 weeks old; 5 rats) were used. The compound of the production example was dissolved in physiological saline and administered through the tail vein at a dose of 100 mg/Kg.
Observations were conducted for one week. All test rats survived, and no abnormal symptoms were observed during the observation period. Formulation example 1 3-(N-octadecylcarbamoyloxy)-
Dissolve 10 g of 2-methoxypropyl 2-thiazolioethyl phosphate in distilled water, 1.0 g, and after sterilization, dispense 1 ml each into 1000 vials under aseptic conditions, freeze-dry, and seal tightly after drying. . On the other hand, aseptically dispense 2 ml of the distilled water for injection containing 100 g of xyrite or mannitrate into ampoules for injection, and melt and seal the ampoules to make 1000 ampoules. When using, dissolve one vial of the former powder in an injection xyrite solution (or mannite solution). Formulation Example 2 Tablet Usage amount per tablet: (1) 3-(N-octadecylcarbamoyloxy)
-2-Methoxypropyl 2-thiazolioethyl phosphate 100mg (2) Lactose 200mg (3) Cornstarch 51mg (4) Hydroxypropyl cellulose 9mg were mixed and granulated using a conventional method, and mixed with cornstarch (8mg) and magnesium stearate (2mg). After that, it is compressed into tablets each weighing 370 mg and having a diameter of 9.5 mm. Formulation Example 3 The usage amount per tablet of 2 above is as follows:
Enteric-coated tablets are prepared by coating with an acetone-ethanol (4:6) mixture in which hydroxypropyl methylcellulose phthalate (14 mg) and castor oil (1 mg) are dissolved to a concentration of 7%. Production example 1 3-(N-octadecylcarbamoyloxy)-
2-methoxypropyl 2-pyridinioethyl phosphate 1) n-octadecyl isocyanate 9.7g, β
-3.5g of methylglycerol ether in pyridine
Mix in 20ml and stir overnight at room temperature. Pour the reaction solution into a mixture of 300 ml of ether and 50 ml of water, and neutralize with concentrated hydrochloric acid. The ether layer is separated, washed with water, dried, and concentrated to dryness. When purified by chromatography using a silica gel column (developing solvent: chloroform-ether 1:1), 3
-(N-octadecylcarbamoyloxy)-2
-8.2g of colorless crystals of methoxy-1-propanol
is obtained. IR (infrared absorption spectrum) ν Nujol nax (cm -1 ): 3340
1687, mp 55-56℃ Mass spectrum (m/e): 401 (M + ), 370 (M
-OCH 3 ) 2) 6.0 g of 3-(N-octadecylcarbamoyloxy)-2-methoxy-1-propanol and 4.0 g of 2-bromoethylphosphorodichloride
is heated to reflux in 30 ml of carbon tetrachloride for 18 hours. After cooling, the solvent was distilled off under reduced pressure, and 50 ml of water was added.
Heat to reflux for an hour. After cooling, the mixture is extracted with ether, dehydrated with Glauber's salt, and the solvent is distilled off to obtain 7.1 g of an intermediate (bromine compound). 1.6g of this intermediate
Dissolve in 16 ml of pyridine and warm at 60°C overnight.
Pyridine was distilled off under reduced pressure, leaving 2 g of silver carbonate in the residue.
Add 50 ml of methanol and heat under reflux for 2 hours.
Insoluble matters were removed by filtration, the liquid was concentrated to dryness, and the resulting residue was purified by silica gel chromatography (eluent solvent: CHCl 3 :MeOH:
H 2 O = 65:25:4) and reprecipitation from chloroform-acetone to obtain 393 mg of the desired product. TLC (thin layer chromatography): Rf = 0.2 (CHCl 3 :
MeOH: H 2 O = 65:25:4) IR (KBr) cm -1 : 3340, 1698, 1540, 1470,
1255, 1075, 1050 NMR (60MHz, CDCl3 ) δ: 0.7−1.8 (35H),
3.44 (3H, s, OCH 3 ), 2.9-4.8 (9H, m),
5.20 (2H, broad, CH 2+ N ), 6.16 (1H,
broad, CONH), 8.0-8.8 (3H, m,
pyridinio), 9.58 (2H, m, pyridinio) Elemental analysis: C 30 H 55 N 2 O 7 P・0.5H 2 O Calculated value C, 60.48; H, 9.48; N, 4.70; P, 5.20 Actual value C, 60.20 ; H, 9.28; N, 4.77; P, 5.30 Production example 2 3-(N-octadecylcarbamoyloxy)-
2-Methoxypropyl 2-thiazolioethyl phosphate 3-(N-octadecylcarbamoyloxy)-
2-methoxy-1-propanol 20.1g and 2
- Dissolve 14.5 g of bromoethyl phosphorodichloride in 250 ml of benzene, and add 4.74 g of pyridine dropwise under ice cooling. After the addition, the mixture was further stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and 200 ml of water was added to the residue.
Heat to reflux for an hour. After cooling, extraction with ether yields 29 g of intermediate. This intermediate is dissolved in 20 g of thiazole and 25 ml of toluene and heated at 60°C for 3 days.
The solvent was distilled off, the residue was dissolved in 500 ml of methanol,
Add 20g of silver carbonate and stir at room temperature for 1.5 hours. Insoluble matters were removed by filtration, the liquid was concentrated, and the residue was purified by silica gel chromatography (eluent solvent:
CHCl 3 :MeOH:H 2 O=65:25:4) Target 5.1g
get. TLC: Rf=0.2 ( CHCl3 :MeOH: H2O =65:
25:4) IR (KBr) cm -1 : 3400, 2920, 2851, 1701,
1558, 1246, 1065 NMR (60MHz, CDCl3 ) δ: 0.7−1.8 (35H),
3.46 (3H, s, OMe), 2.9−4.8 (9H, m),
5.08 (2H, broad), 6.30 (1H, broad,
CONH), 8.55, 8.88 & 10.93 (thiazolio) Elemental analysis: C 28 H 53 N 2 O 7 PS.1.5H 2 O Calculated value C, 54.26; H, 9.11; N, 4.52; P, 5.00 Actual value C, 54.30; H, 8.90; N, 4.71; P, 5.03 Production example 3 3-(N-decylcarbamoyloxy)-2-methoxypropyl 2-thiazolioethyl phosphate 1) Dissolve 25 g of n-undecanoic acid in 220 ml of toluene and diphenylphosphoryl. Azide 51.6g,
After adding 28.3 ml of triethylamine and stirring at room temperature for 3.5 hours, the reaction solution was concentrated to 70 ml.
Heat to reflux for an hour. After cooling, add 53.3 g of β-methylglycerol ether and 155 ml of pyridine, stir overnight at room temperature, and concentrate to dryness. The residue was dissolved in chloroform, washed with water, dried, concentrated, and 3-(N
20.7 g (53%) of -decylcarbamoyloxy)-2-methoxy-1-propanol are obtained. IR (Film) 3340, 2920, 2850, 1700,
1255, 1065, 955, 748 2) 3-(N-decylcarbamoyloxy)-2
-Methoxy-1-propanol 289.4mg
(1.0 Ymole), 362.8 mg (1.5 mmole) of 2-bromoethylphosphoryl dichloride and 2.1 ml of benzene.
Add 118.7 mg (1.5 mmole) of pyridine and stir at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, 4 ml of water was added to the residue, and the mixture was heated at 90°C for 1
After heating for an hour and cooling, add 10ml of chloroform.
Shake vigorously, separate the organic layer, and discard the aqueous layer. The organic layer is concentrated to dryness under reduced pressure, 1 ml of thiazole is added to the residue, stirred at 50°C for 3 days, and concentrated to dryness under reduced pressure. 5ml of metal in the residue,
Add 220 mg of Ag 2 CO 3 and stir at room temperature for 1 hour. After filtering off insoluble matter, the mother liquor is concentrated to dryness under reduced pressure. This was purified using a silica gel column (8 g) and a developing solution of chloroform, methanol, and water (65:25:4), and the target product was 147 mg of colorless powder (yield: 32
%). IR (film) cm -1 : 3320, 3080, 2930, 2850,
1700, 1545, 1460, 1240, 1090, 1060, 950 NMR (30MC, CDCl3 ) δ: 0.93 (3H), 1.23
(16H), 3.13 (2H), 3.38 (3H), 3.70~4.67
(7H), 4.96 (2H), 6.17 (1H), 8.33 (1H),
8.67 (1H), 10.70 (1H) TLC; Chloroform, methanol, water (65:
25:4) Rf=0.21 (1 spot) Production example 4 3-(N-octadecylcarbamoyloxy)-
2-methoxypropyl 2-(4-methyl-5
-hydroxyethyl group) thiazolioethyl phosphate 294 mg (0.5 mmole) of 3-(N-octadecylcarbamoyloxy)-2-methoxypropyl 2-bromoethyl phosphate obtained in Production Example 1,
4-Methyl-5-hydroxyethylthiazole
Dissolve 286.4 mg (2.0 mmole) in 0.5 ml of toluene,
Heat at 75℃ for 3 days. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified using a silica gel column (8 g) and a developing solution of chloroform, methanol, and water (65:25:4) to obtain 85 mg of colorless powder (yield 26.2%). . IR (film) cm -1 : 3300, 2920, 2850, 1700,
1540, 1460, 1230, 1090, 1060, 1055, 930,
850 NMR (60MC, CDCl3 ) δ: 0.90 (3H), 1.28
(32H), 2.57 (3H), 3.08 (6H), 3.43 (3H),
3.83 (6H), 4.10 (2H), 4.33 (1H), 4.77 (1H),
5.78 (1H), 10.57 (1H) TLC: Chloroform, methanol, water (65:
25:4) Rf=0.33 (1spot) UV (ultraviolet absorption spectrum): λ nax MeOH 222mμ, 262mμ Production example 5 3-(N-octadecylcarbamoyloxy)-
2-Methoxypropyl 2-isoquinolinioethyl phosphate Bromine compound obtained in Production Example 1, namely 3-(N-octadecylcarbamoyloxy)-2-methoxypropyl 2-bromoethyl phosphate
294mg (0.5mmole), Isoquinoline 258.3mg
(2.0 mmole) in 0.5 ml of toluene, 75℃,
Heat for 3 days. The reaction solution was concentrated to dryness under reduced pressure.
The residue was purified using a silica gel column (8 g), a developing solution, chloroform, methanol, and water (65:25:4) to obtain 140 mg (yield: 44%) of a colorless powder. IR (film) cm -1 : 3320, 2920, 2850, 1700,
1640, 1530, 1460, 1240, 1095, 1060, 930,
820 NMR (60MC, CDCl 3 ) δ: 0.88 (3H), 1.27
(35H), 3.13 (2H), 3.32 (3H), 3.3~3.8 (2H),
3.93 (1H), 4.07 (8H), 4.63 (1H), 5.30 (1H),
6.00 (1H), 8.00 (3H), 8.50 (1H), 8.57 (1H),
9.10 (1H), 10.70 (1H) TLC: Chloroform, methanol, water (65:
25:4) Rf=0.47 (1spot) UV:λ nax MeOH 233mμ, 279mμ, 340mμ Production example 6 3-(N-octadecylcarbamoyloxy)-
2-benzyloxypropyl 2-thiazolioethyl phosphate 1) 1,3-benzylidene glycerol 27g,
Benzyl chloride 45g, Et 4 NI 300mg, 50%
Mix 60 ml of NaOH and 240 ml of benzene and heat under reflux for 40 hours. Separate the benzene layer and 50%
Add 60 ml of NaOH and 300 mg of Et 4 NI, and heat under reflux for an additional 20 hours. Separate the benzene layer, wash with water,
Concentrate. The residue was purified by silica gel chromatography (eluent solvent: benzene), and 1,3
-Benzylidene glycerol 36 g (yield 89%) of β-benzyl ether are obtained. mp73-75℃ 2) Add 33g of ether obtained by the above method to water.
Dissolve in a mixture of 35 ml and 140 ml of acetic acid, under a nitrogen stream,
Heat to reflux for 1 hour. The solvent was distilled off under reduced pressure,
The residue was purified by silica gel chromatography (developing solvent, ether) to obtain 19.6 g (yield: 88%) of β-benzylglycerol. NMR ( CDCl3 ) δ: 3.14 (2H, OH), 3.3-3.9
(5H), 4.60 (2H, PhCH 2 −), 7.34 (5H,
PhCH 2 −) 3) Dissolve 3.64 g of β-benzylglycerol in 20 ml of pyridine, add 5.9 g of octadecyl isocyanate, and stir overnight at room temperature. Pyridine is distilled off, and dilute hydrochloric acid and chloroform are added to the residue. Separate the chloroform layer, dry and concentrate. The residue was purified by silica gel chromatography (eluent: chloroform-ether, 10:1), and the main product was recrystallized from n-hexane to give 3-(N-octadecylcarbamoyloxy)-2-benzyloxy- 4.1 g of 1-propanol is obtained. mp52-54℃ 4) 3-(N-octadecylcarbamoyloxy)-2-benzyloxy-1-propanol
3.1 g and 2.9 g of 2-bromoethylphosphorodichloridate are dissolved in 50 ml of benzene, and 0.96 g of pyridine is added dropwise under ice cooling. After further stirring at room temperature for 1.5 hours, benzene was distilled off, 50 ml of water was added to the residue, and the mixture was heated under reflux for 45 minutes. After cooling, extract with chloroform and concentrate to dryness to obtain 5.3 g of white powder (bromine compound). Take 3.0g of this, dissolve it in 6ml of thiazole, and heat it at 60°C for 3 days.
The solvent was distilled off, 40 ml of methanol and 3.1 g of silver carbonate were added, and after stirring at room temperature for 1 hour, insoluble materials were removed.
The liquid was concentrated to dryness, and the residue was purified by silica gel chromatography (eluent solvent: CHCl 3 :
MeOH:H 2 O = 65:25:4) 811 mg of the target product was obtained. IR (KBr) cm -1 : 3340, 2920, 2850, 1695,
1462, 1230, 1055 NMR (60MHz, CDCl3 ) δ: 0.7−1.8 (35H),
2.9~4.9 (11H, m), 4.62 (2H, s, -
CH 2 Ph), 6.0 (1H, broad, CONH), 7.30
(5H, s, Ph), 8.21, 8.44 & 10.73 (3H,
thiazolio) Elemental analysis: C 34 H 57 N 2 O 7 SP・2H 2 O Calculated value C, 57.93; H, 8.72; N, 3.97; P, 4.39 Actual value C, 58.00; H, 8.91; N, 3.97; P ,4.22 Production example 7 3-(N-octadecylcarbamoyloxy)-
2-Benzyloxypropyl 2-pyridinioethyl phosphate 2.3 g of the intermediate (bromine compound) obtained in Production Example 6 is dissolved in 12 ml of pyridine and heated at 60°C for 16 hours.
Pyridine was distilled off under reduced pressure, 2.3 g of silver carbonate and 30 ml of methanol were added to the residue, and the mixture was heated under reflux for 1 hour. Insoluble matter was removed, the liquid was concentrated to dryness, and the residue was purified by silica gel chromatography (eluent solvent: CHCl 3 :MeOH:H 2 O=65:25:4) to obtain 770 mg of the desired product. TLC: Rf=0.35 ( CHCl3 :MeOH: H2O =65:
25:4) External absorption spectrum (KBr) cm -1 : 2910, 2840,
1695, 1245, 1070 NMR (60MHz, CDCl3 ) δ: 0.8−1.8 (35H),
2.7~5.1 (13H), 6.10 (1H, broad, CONH),
7.27 (5H, s, Ph), 7.66-8.47 (3H, broad,
pyridinio), 9.10 (2H, broad, pyridinio) Elemental analysis: C 36 H 59 N 2 O 7 P・1.5H 2 O Calculated value C, 62.68; H, 9.06; N, 4.06 Actual value C, 62.80; H, 8.80 ;N, 4.47 Production Example 8 3-(N-docosylcarbamoyloxy)-2-
Methoxypropyl 2-thiazolioethyl phosphate 1) Dissolve 7.08 g (2 x 10 -2 mol) of tricosanoic acid in a mixture of 70 ml of anhydrous toluene and 3.6 ml of triethylamine, and add 6.6 g (2.4 x 10 -2 mol) of diphenylphosphoryl azide at room temperature. ). 3
After stirring at room temperature for an hour, the reaction solution was concentrated to 1/3 volume under reduced pressure. This reaction solution was refluxed for 1.5 hours, and after cooling,
Add 30 ml of pyridine and 7.84 g (7.4 x 10 -2 mol) of 2-methoxy-1,3-propylene glycol and stir at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After washing the chloroform layer with water, it is dried with Na 2 SO 4 . Evaporate the solvent and transfer the residue to silica gel (100g)
Perform column chromatography to purify. The chloroform effluent fraction was concentrated to dryness.
3-(N-docosylcarbamoyloxy)-2-
4.3g colorless powder of methoxy-1-propanol
(47%). IR (KBr): 3350 (NH, OH), 2920 (CH),
2850 (CH), 1685 (-NHCOO-), 1530 (-
NHCOO-) 2) 3-(N-docosylcarbamoyloxy)-
2-methoxy-1-propanol 2.74g and 2-bromoethylphosphorodichloridate
Dissolve 1.89g in 20ml of benzene and 0.62g of pyridine.
was added dropwise and stirred at room temperature for 2.5 hours. Benzene was distilled off, water was added, and the mixture was heated under reflux for 1 hour and 30 minutes. After cooling, extract with chloroform and concentrate to dryness. Add 6.4ml of thiazole to the residue and heat to 77.5 at 60°C.
Warm for an hour. The reaction solution was dried, 80 ml of methanol and 2.15 g of silver carbonate were added to the residue, and the mixture was heated under reflux for 1 hour. After heating, the solution was concentrated to dryness to obtain a crude product. Purified by chromatography using silica gel (effluent solvent: CHCl 3 −
MeOH- H2O , 65:25:4), chloroform-
Recrystallize from acetone mixture to obtain 0.41 g (10.5
%). IR (KBr) cm -1 : 2920, 2850, 1700, 1245,
1065 Elemental analysis C 32 H 61 N 2 O 7 PS・2H 2 O Calculated value C, 56.12; H, 9.57; N, 4.09; P, 4.52; S, 4.68 Actual value C, 56.14; H, 9.47; N, 4.07 ; P, 4.68; S, 4.24 Production example 9 3-(N-tetradecylcarbamoyloxy)-
2-methoxypropyl 2-thiazolioethyl phosphate 1) 20g of pentadecanoic acid and 200ml of dry toluene
27.3 g of diphenylphosphoryl azide, dissolved in
Add 14.9 ml of triethylamine, stir at room temperature for 5 hours, concentrate the reaction solution under reduced pressure, and heat under reflux for 1 hour. After cooling, β-methylglycerol ether
Add 32.8g and 124ml of dry pyridine and stir overnight at room temperature. Concentrate to dryness, dissolve in chloroform, wash with water, dry, and purify by chromatography on silica gel (eluent: chloroform) to obtain 9.43 g of 2-methoxy-3-(N-tetradecylcarbamoyloxy)-1-propanol.
(33%). IRν KBr nax (cm -1 ) 1695 2) 5.18 g of 2-methoxy-3-(N-tetradecylcarbamoyloxy)-1-propanol and 2-bromoethylphosphorodichloridate
Dissolve 5.44g in 73ml of benzene and 1.78g of pyridine.
was added dropwise and stirred at room temperature for 2 hours. Benzene was distilled off, water was added, and the mixture was heated under reflux for 1 hour and 30 minutes. After cooling, extract with chloroform and concentrate to dryness.
Add 7 ml of thiazole to the residue and heat at 60°C for 60 hours. Dry the reaction solution and add 90ml of methanol to the residue.
Then add 8 g of silver carbonate and heat under reflux for 1 hour.
After heating, the solution is concentrated to dryness, and the residue is purified by chromatography using silica gel. Recrystallization from a chloroform-acetone mixture yields 0.4 g (5%) of the desired product. IR (KBr) cm -1 : 2920, 2850, 1700, 1230,
1050 Elemental analysis: C 24 H 45 N 2 O 7 PS・2H 2 O Calculated value C, 50.33; H, 8.27; N, 4.89; P, 5.41; S5.60 Actual value C, 50.35; H, 8.20; N, 4.76; P, 5.38; S, 4.84
Claims (1)
は炭素数１−４のアルキル基またはアラルキル基
を、A+は炭素数１−４のアルキル基もしくはヒ
ドロキシエチル基で置換されていてもよいピリジ
ニオ基、チアゾリオ基またはイソキノリニオ基を
示す〕で表わされるグリセリン誘導体またはその
塩を含有する血小板活性因子抑制剤。 ２ グリセリン誘導体が３−（Ｎ−オクタデシル
カルバモイルオキシ）−２−メトキシプロピル２
−チアゾリオエチル フオスフエートである、特
許請求の範囲第１項記載の血小板活性因子抑制
剤。[Claims] 1 formula [In the formula, R 1 is an alkyl group having 10-24 carbon atoms, R 2
represents an alkyl group having 1 to 4 carbon atoms or an aralkyl group, and A + represents a pyridinio group, a thiazolio group, or an isoquinolinio group which may be substituted with an alkyl group having 1 to 4 carbon atoms or a hydroxyethyl group. Platelet activating factor inhibitor containing a glycerin derivative or its salt. 2 Glycerin derivative is 3-(N-octadecylcarbamoyloxy)-2-methoxypropyl 2
- The platelet activating factor inhibitor according to claim 1, which is thiazolioethyl phosphate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13385581A JPH0240648B2 (en) | 1981-08-25 | 1981-08-25 | KETSUSHOBANKATSUSEIINSHOKUSEIZAI |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13385581A JPH0240648B2 (en) | 1981-08-25 | 1981-08-25 | KETSUSHOBANKATSUSEIINSHOKUSEIZAI |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5835116A JPS5835116A (en) | 1983-03-01 |
| JPH0240648B2 true JPH0240648B2 (en) | 1990-09-12 |
Family
ID=15114604
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13385581A Expired - Lifetime JPH0240648B2 (en) | 1981-08-25 | 1981-08-25 | KETSUSHOBANKATSUSEIINSHOKUSEIZAI |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0240648B2 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6045518A (en) * | 1983-08-22 | 1985-03-12 | Takeda Chem Ind Ltd | Antishock agent |
| US4650791A (en) * | 1984-01-11 | 1987-03-17 | Takedo Chemical Industries, Ltd. | Certain 3-alkoxy-2-cyclic-imido-propyl-phosphate-ethyl-cyclic ammonium hydroxide inner salts which inhibit activities of platelet activating factor |
| US4863941A (en) * | 1985-06-18 | 1989-09-05 | Hoffmann-La Roche Inc. | Glycerol derivatives |
| ES2013834A6 (en) * | 1989-01-30 | 1990-06-01 | Uriach & Cia Sa J | New 4-substituted 2-alkoxytetrahydrofuran derivatives. |
| ES2010145A6 (en) * | 1989-03-02 | 1989-10-16 | Uriach & Cia Sa J | 2-picolylamine derivates. |
| ES2062943B1 (en) * | 1993-03-23 | 1995-11-16 | Uriach & Cia Sa J | NEW DERIVATIVES OF (2-METHYL-3-PIRIDIL) CYANOMETILPIPERAZINES. |
-
1981
- 1981-08-25 JP JP13385581A patent/JPH0240648B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5835116A (en) | 1983-03-01 |
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