JPH0424354B2 - - Google Patents
Info
- Publication number
- JPH0424354B2 JPH0424354B2 JP18987884A JP18987884A JPH0424354B2 JP H0424354 B2 JPH0424354 B2 JP H0424354B2 JP 18987884 A JP18987884 A JP 18987884A JP 18987884 A JP18987884 A JP 18987884A JP H0424354 B2 JPH0424354 B2 JP H0424354B2
- Authority
- JP
- Japan
- Prior art keywords
- inflammatory
- alkyl group
- carbon atoms
- present
- compound
- 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
- 150000003904 phospholipids Chemical class 0.000 claims description 28
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 239000000730 antalgic agent Substances 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 14
- 239000002260 anti-inflammatory agent Substances 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 206010030113 Oedema Diseases 0.000 description 12
- 230000000202 analgesic effect Effects 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 229940121363 anti-inflammatory agent Drugs 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 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 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- -1 etc. Chemical group 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- 238000002329 infrared spectrum Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 238000010998 test method Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- 239000000829 suppository Substances 0.000 description 5
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229960000905 indomethacin Drugs 0.000 description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- UQZZQHGRZPTZME-UHFFFAOYSA-N oxazaphospholidine Chemical class C1CPNO1 UQZZQHGRZPTZME-UHFFFAOYSA-N 0.000 description 4
- 229960002895 phenylbutazone Drugs 0.000 description 4
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 235000010418 carrageenan Nutrition 0.000 description 3
- 229920001525 carrageenan Polymers 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000003205 fragrance Substances 0.000 description 3
- 210000001156 gastric mucosa Anatomy 0.000 description 3
- 208000014617 hemorrhoid Diseases 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000000622 irritating effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 3
- 229940099259 vaseline Drugs 0.000 description 3
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 2
- 229960005274 benzocaine Drugs 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 229940067596 butylparaben Drugs 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 229960003699 evans blue Drugs 0.000 description 2
- 238000010438 heat treatment Methods 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
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229940039717 lanolin Drugs 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- 229960002216 methylparaben Drugs 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 2
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- UDEWPOVQBGFNGE-UHFFFAOYSA-N propyl benzoate Chemical compound CCCOC(=O)C1=CC=CC=C1 UDEWPOVQBGFNGE-UHFFFAOYSA-N 0.000 description 2
- 229940032094 squalane Drugs 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000002511 suppository base Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 239000011345 viscous material Substances 0.000 description 2
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- PJJGZPJJTHBVMX-UHFFFAOYSA-N 5,7-Dihydroxyisoflavone Chemical compound C=1C(O)=CC(O)=C(C2=O)C=1OC=C2C1=CC=CC=C1 PJJGZPJJTHBVMX-UHFFFAOYSA-N 0.000 description 1
- POJWUDADGALRAB-PVQJCKRUSA-N Allantoin Natural products NC(=O)N[C@@H]1NC(=O)NC1=O POJWUDADGALRAB-PVQJCKRUSA-N 0.000 description 1
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 description 1
- 239000011627 DL-alpha-tocopherol Substances 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229960000458 allantoin Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229960000212 aminophenazone Drugs 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000922 anti-bactericidal effect Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000001204 arachidyl 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])C([H])([H])[H] 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 125000002511 behenyl 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])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920006184 cellulose methylcellulose Polymers 0.000 description 1
- 229960002798 cetrimide Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 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
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012153 distilled water 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
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002874 effect on oedema Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229960004369 flufenamic acid Drugs 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 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
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000000755 henicosyl 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])C([H])([H])C([H])([H])[H] 0.000 description 1
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Description
〔産業上の利用分野〕
本発明は燐脂質誘導体およびそれを有効成分と
して含有する消炎鎮痛剤に関する。
〔従来の技術〕
消炎鎮痛剤は大別すると、ステロイド剤、非ス
テロイド剤および消炎酵素剤の３つに分けられる
が、本発明は非ステロイド剤に属するものであ
る。
従来、非ステロイド剤は主なものとしてアスピ
レン、フエニルブタゾン、インドメタシン、フル
フエナム酸、メフエナム酸、イブフエナツク、ア
ミノピリン等が知られている。
〔発明が解決しようとする問題点〕
しかしながら、これら従来の非ステロイド剤は
感染性炎症には無効であり、外用では著しく効果
が弱く、更に副作用の面からは比較的毒性が強
く、しかも胃の刺激作用が強く胃潰瘍を起こしや
すい等の欠点を有していた。
〔問題点を解決するための手段〕
本発明者は、長年燐脂質誘導体の薬理活性を探
索していたところ、今般特定の燐脂質誘導体が抗
炎症、鎮痛および殺菌作用を有し、かつ、胃の刺
激作用が弱く毒性も低いことを見出し、本発明を
完成した。
すなわち本発明は、一般式（）
（式中、R1は炭素数１〜25の直鎖若しくは分岐
のアルキル基、R2は炭素数１〜６の直鎖若しく
は分岐のアルキル基、R3、R4、R5は各々炭素数
１〜６の直鎖若しくは分岐のアルキル基、水素原
子又はアルキル基を示し、Ａは炭素数１〜６のア
ルキレン基を示す）
で表わされる燐脂質誘導体およびそれを含有する
消炎鎮痛剤を提供するものである。
（）式におけるR1としては、例えばメチル、
エチル、ｎ−プロピル、イソプロピル、プチル、
ｔ−ブチル、ペンチル、ヘキシル、ヘプチル、オ
クチル、ノニル、デシル、ウンデシル、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、エイコシル、ヘンエイコシル、ドコシ
ル、トリコシル、テトラコシル、ペンタコシル等
が挙げられ、好ましくは炭素数７以上のアルキル
基、就中、炭素数12〜18のアルキル基が好まし
い。
R3、R4、R5のアラキル基としては、ベンジル、
フエネチル、３−フエニルプロピル、α−フエニ
ル−ｔ−ブチル等々が例示される。
更に、一般式（）は分子中の不斉炭素原子に
基づくあらゆる光学的異性体を包含するものであ
る。
本発明の燐脂質誘導体は次のいずれかの方法に
より製造される。
（製造法１）
下式に従つて、グリセリンジアルキルエーテル
（）を塩基の存在下オキシ塩化リンと反応させ
て化合物（）を製造し、次いで化合物（）と
アミン（）を反応させて化合物（）を製造
し、しかるのに化合物（）を酸により開還せし
めて（）式中、R4＝Ｈ、かつR5＝Ｈの目的化
合物（Ia）を得る。
（式中、R1、R2、R3およびＡは前記と同じ）
（製造法２）
下式に従つて、グリセリンジアルキルエーテル
（）を塩基の存在下化合物（）と反応させて
化合物（）を製造し、次いで化合物（）と
R3R4R5Nを反応させて目的化合物（）を得る。
（式中、R1、R2、R3、R4、R5およびＡは前記と
同じ）
本発明の消炎鎮痛剤は、経口投与、注射（静
脈、皮下、筋肉）、外用、坐剤、その他の方法に
より投与することができ、また投与方法に応じた
種々の形態として使用できる。
経口投与の場合、本発明の消炎鎮痛剤は固型製
剤、液体製剤のいずれの剤型で使用することもで
きる。固型製剤としては、例えば錠剤、顆粒剤、
散剤、カプセル剤、糖衣剤等が挙げられる。これ
ら固型製剤には、製剤上一般に使用される糖類、
セルロース類等の賦形剤；でんぷん、ペースト、
メチルセルロース等の結合剤；増量剤、崩壊剤等
の添加物を配合することができる。また、経口用
液体製剤としては、内用水剤、懸濁液剤、乳剤、
シロツプ剤等の形態が可能である。経口投与する
場合の用量は、症状、年令、剤型等により適宜増
減されるが、例えば成人では１日0.1〜1000mg／
Kgの範囲が好ましい。
注射の場合、本発明の消炎鎮痛剤は水溶液、懸
濁剤、油性若しくは水溶性乳剤等の形態とするこ
とができるが、滅菌水又は生理食塩水等の水性液
体媒体に溶解して使用するのが好適である。そし
て必要であれば、一般に使用される溶解剤、安定
化剤、保存剤、等張化剤等を配合することができ
る。この注射液剤は、静脈注射、筋肉注射、皮下
注射等の方法で投与される。投与量は、症状、年
令、剤型、投与方法等により適宜増減されるが、
例えば成人に注射する場合は１日0.01〜1000mg／
Kgの範囲が好ましい。
外用剤として使用する場合、本発明の鎮痛剤は
種々の形態とするができるが、例えばローシヨン
状、乳液状、クリーム状、軟膏状、ステイツク
状、有機溶剤により溶解せしめた溶液状、パツク
状、ゲル状等とするのが好ましい。本発明の消炎
鎮痛剤には、製剤化に際して油性物質、保湿剤、
増粘剤、防腐剤、乳化剤、薬効成分、香料、乳化
安定剤等を併用することができる。また、他の抗
炎症剤、各種植物抽出物等を配合することによ
り、消炎鎮痛、抗炎症効果の向上を図ることがで
きる。外用剤は、例えば成人の場合、本発明化合
物（）を0.01〜10重量％含有せしめたものを当
該部位に局所的に適時、適量塗布すればよい。
坐剤として使用する場合、本発明の消炎鎮痛剤
には坐剤基剤のほかに、任意成分として油性物
質、乳化剤、薬効成分、乳化安定剤等を併用でき
る。また、他の抗炎症剤、各種天然物抽出物等を
配合することにより抗炎症効果の向上を図ること
ができ、更に痔疾治療剤として使用することもで
きる。
〔作用〕
次に本発明化合物（）の薬理効果を試験した
結果を示す。
() 急性毒性
本発明化合物（）は急性毒性試験の結果、
ICR系マウスに対し経口投与で２ｇ／Kg（投与
可能最大量）でも死亡例は認められず、極めて
毒性に低いものである。
() 浮腫抑制作用
ラツト足蹠浮腫に対する抑制作用を下記方法
により試験した。その結果を第１表、第１図及
び第２図に示す。
（試験方法）
体重120〜150ｇの雄性SD系ラツト（５週令）
を用い、１群10匹として試験を行なつた。薬物
を経口投与（第１表、第１図）又は皮膚塗布
（第２図）してから後肢足蹠容積を測定した。
１時間後にカラゲニン（１％、0.1ml）を足蹠
に皮下注射するか、又は１ｍの高さから100ｇ
の分銅を足肢に落下させて起炎刺激を加え、そ
の後一定時間後の足蹠容積の変化を測定した。
なお、浮腫率および浮腫抑制率はそれぞれ次式
により求めた。
浮腫率（％）
＝（起炎刺激後の足蹠容積／起炎刺激前の足蹠容積−
１）×100
浮腫抑制率（％）
＝薬物投与群の浮腫率／コントロールの浮腫率×100
[Industrial Field of Application] The present invention relates to a phospholipid derivative and an anti-inflammatory analgesic agent containing the same as an active ingredient. [Prior Art] Anti-inflammatory analgesics can be broadly classified into three categories: steroids, non-steroids, and anti-inflammatory enzymes, and the present invention belongs to non-steroids. Conventionally, aspiren, phenylbutazone, indomethacin, flufenamic acid, mefenamic acid, ibufenac, aminopyrine, etc. are known as main non-steroidal drugs. [Problems to be solved by the invention] However, these conventional non-steroidal drugs are ineffective against infectious inflammation, are extremely ineffective when used externally, are relatively toxic in terms of side effects, and are harmful to the stomach. It has the disadvantages of being a strong irritant and prone to causing gastric ulcers. [Means for Solving the Problems] The present inventor has been searching for the pharmacological activity of phospholipid derivatives for many years, and has now discovered that a specific phospholipid derivative has anti-inflammatory, analgesic, and bactericidal effects, and has an anti-inflammatory effect on the stomach. The present invention was completed based on the discovery that the irritating effect of the compound is weak and the toxicity is low. That is, the present invention is based on the general formula () (In the formula, R 1 is a straight chain or branched alkyl group having 1 to 25 carbon atoms, R 2 is a straight chain or branched alkyl group having 1 to 6 carbon atoms, and R 3 , R 4 , and R 5 are each a carbon number 1 to 6 linear or branched alkyl group, hydrogen atom or alkyl group, A represents an alkylene group having 1 to 6 carbon atoms) and an anti-inflammatory and analgesic agent containing the same. It is something. As R 1 in formula (), for example, methyl,
Ethyl, n-propyl, isopropyl, butyl,
t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,
Examples thereof include hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, etc., and alkyl groups having 7 or more carbon atoms are preferred, particularly preferred are alkyl groups having 12 to 18 carbon atoms. Examples of the aracyl group for R 3 , R 4 and R 5 include benzyl,
Examples include phenethyl, 3-phenylpropyl, α-phenyl-t-butyl, and the like. Furthermore, the general formula () includes all optical isomers based on asymmetric carbon atoms in the molecule. The phospholipid derivative of the present invention is produced by any of the following methods. (Production method 1) According to the following formula, glycerin dialkyl ether () is reacted with phosphorus oxychloride in the presence of a base to produce compound (), and then compound () and amine () are reacted to produce compound (). Then, compound () is opened with an acid to obtain the target compound (Ia) of the formula (), where R 4 =H and R 5 =H. (In the formula, R 1 , R 2 , R 3 and A are the same as above) (Production method 2) According to the following formula, glycerin dialkyl ether () is reacted with compound () in the presence of a base to produce compound () and then compound () and
R 3 R 4 R 5 N is reacted to obtain the target compound (). (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 and A are the same as above) The anti-inflammatory analgesic of the present invention can be administered orally, by injection (intravenous, subcutaneous, intramuscular), externally, by suppositories, It can be administered by other methods, and can be used in various forms depending on the method of administration. In the case of oral administration, the anti-inflammatory and analgesic agent of the present invention can be used in either a solid preparation or a liquid preparation. Examples of solid preparations include tablets, granules,
Examples include powders, capsules, sugar-coated agents, and the like. These solid preparations contain sugars commonly used in preparations,
Excipients such as cellulose; starch, paste,
Additives such as a binder such as methylcellulose; a filler and a disintegrant may be added. In addition, oral liquid preparations include oral solutions, suspensions, emulsions,
Possible forms include syrup. The dose for oral administration is adjusted depending on the symptoms, age, dosage form, etc., but for example, for adults, it is 0.1 to 1000 mg/day.
Kg range is preferred. In the case of injection, the anti-inflammatory and analgesic agent of the present invention can be in the form of an aqueous solution, suspension, oil-based or water-soluble emulsion, etc.; is suitable. If necessary, commonly used solubilizers, stabilizers, preservatives, tonicity agents, etc. can be added. This injection solution is administered by intravenous injection, intramuscular injection, subcutaneous injection, or the like. The dosage may be adjusted depending on symptoms, age, dosage form, administration method, etc.
For example, when injecting into adults, 0.01 to 1000 mg/day
Kg range is preferred. When used as an external preparation, the analgesic of the present invention can be in various forms, such as lotion, emulsion, cream, ointment, stick, solution dissolved in an organic solvent, pack, Preferably, it is in the form of a gel or the like. The anti-inflammatory analgesic of the present invention includes oily substances, humectants,
Thickeners, preservatives, emulsifiers, medicinal ingredients, fragrances, emulsion stabilizers, etc. can be used in combination. Furthermore, by incorporating other anti-inflammatory agents, various plant extracts, etc., the anti-inflammatory analgesic and anti-inflammatory effects can be improved. For example, in the case of an adult, an external preparation containing 0.01 to 10% by weight of the compound () of the present invention may be applied locally to the relevant area in an appropriate amount at a timely manner. When used as a suppository, the anti-inflammatory and analgesic agent of the present invention may contain optional ingredients such as an oily substance, an emulsifier, a medicinal ingredient, an emulsion stabilizer, etc. in addition to the suppository base. Furthermore, by incorporating other anti-inflammatory agents, various natural product extracts, etc., the anti-inflammatory effect can be improved, and it can also be used as a therapeutic agent for hemorrhoids. [Effect] Next, the results of testing the pharmacological effects of the compound () of the present invention will be shown. () Acute toxicity The compound of the present invention () has the following acute toxicity test results:
No deaths were observed even when administered orally to ICR mice at 2 g/Kg (maximum dose that can be administered), indicating extremely low toxicity. () Suppressive effect on edema The suppressive effect on rat footpad edema was tested by the following method. The results are shown in Table 1, Figures 1 and 2. (Test method) Male SD rats weighing 120-150g (5 weeks old)
The test was conducted using 10 animals per group. After the drug was administered orally (Table 1, Figure 1) or applied to the skin (Figure 2), the volume of the hind paw was measured.
After 1 hour, carrageenin (1%, 0.1 ml) is injected subcutaneously into the footpad or 100 g from a height of 1 m.
A weight was dropped onto the foot to apply an inflammatory stimulus, and changes in footpad volume were then measured after a certain period of time.
The edema rate and edema suppression rate were calculated using the following formulas. Edema rate (%) = (Footpad volume after inflammatory stimulation / Footpad volume before inflammatory stimulation -
1) × 100 Edema suppression rate (%) = Edema rate of drug administration group / Edema rate of control × 100
【表】
＊ 実施例２で得た化合物を意味する。以下
同様。
第１表および第１図から明らかな如く、本発明
化合物は経口投与において抗炎症作用があり、
また第２図から明らかな如く、皮膚塗布した場
合にも効果を有する。
() 血管と透過性に対する作用
本発明化合物（）の血管透過性に対する作
用を下記方法により試験した。その結果を第３
図に示す。
（試験方法）
Whittle法に準じて行なつた。
体重20〜25ｇのICR系マウスを第３図に示す
薬剤で前処理し、30分後にエバンスブルー（１
％、0.1ml／10ｇ）を尾静脈より注射し、更に
その直後に0.6％酢酸0.1ml／10ｇ腹腔内注射す
る。酢酸注射20分後に屠殺し、蒸溜水５mlを腹
腔内注射したのち開復、採水した。これを過
後590ｍμに於る吸光度を求め、検量線から漏
出色素量を求めた。
第３図から明らかな如く、本発明化合物
（）はフエニルブタゾンやインドメタシン匹
敵する抗炎症作用を有する。
() 他の抗炎症剤との相乗作用
本発明化合物（）を他の抗炎症剤と併用し
た場合の効果につき下記方法により試験した。
その結果を第２表に示す。
（試験方法）
浮腫抑制試験（）と同様にモルモツトの足
にカラゲニンを皮下注射し、下記第２表に示す
薬剤のカラゲニン浮腫に対する作用を試験し
た。なお、抗炎症剤としてはフエニルブタゾン
又はインドメタシンを用いた。[Table] *Means the compound obtained in Example 2. Same below.
As is clear from Table 1 and Figure 1, the compound of the present invention has an anti-inflammatory effect upon oral administration;
Furthermore, as is clear from FIG. 2, it is also effective when applied to the skin. () Effect on blood vessels and permeability The effect of the compound of the present invention () on blood vessel permeability was tested by the following method. The result is the third
As shown in the figure. (Test method) Testing was conducted according to the Whittle method. ICR mice weighing 20 to 25 g were pretreated with the drugs shown in Figure 3, and 30 minutes later, Evans blue (1
%, 0.1 ml/10 g) was injected through the tail vein, and immediately thereafter, 0.6% acetic acid was injected intraperitoneally (0.1 ml/10 g). The animals were sacrificed 20 minutes after the acetic acid injection, and 5 ml of distilled water was injected intraperitoneally, and the animals were opened and water was collected. After passing through this, the absorbance at 590 mμ was determined, and the amount of leaked dye was determined from the calibration curve. As is clear from FIG. 3, the compound of the present invention () has an anti-inflammatory effect comparable to that of phenylbutazone and indomethacin. () Synergistic effect with other anti-inflammatory agents The effect of the compound of the present invention () when used in combination with other anti-inflammatory agents was tested by the following method.
The results are shown in Table 2. (Test method) Carrageenin was subcutaneously injected into the paws of guinea pigs in the same manner as in the edema suppression test (), and the effects of the drugs shown in Table 2 below on carrageenan edema were tested. Note that phenylbutazone or indomethacin was used as the anti-inflammatory agent.
【表】
第２表から明らかな如く、本発明化合物（）
と非ステロイド系抗炎症剤との間に相乗作用が
認められた。
() 鎮痛作用
下記方法により本発明化合物（）の鎮痛作
用を試験した。その結果を第４図に示す。
（試験方法）
Koster法に準じて行なつた。
体重20〜25ｇのICR系マウスを第４図に示す
薬剤で処置し、30分後に0.6％酢酸0.1ml／10ｇ
を腹腔内注射した。その後、20分間に生じる苦
悶症状（stretching movement）を呈した回数
を測定した。
第４図から明らかな如く、本発明化合物
（）はフエニルブタゾンやインドメタシンに
匹敵する鎮痛作用を有する。
() 胃粘膜刺激作用
下記方法により本発明化合物（）の胃粘膜
に対する刺激作用を試験した。その結果の第３
表に示す。
（試験方法）
体重120〜150ｇの雄性SD系ラツト（５週令）
を用い、１晩絶食後、第３表に示す薬物を経口
投与し、24時間後にクロロホルムにより致死さ
せ、胃より摘出して開き肉眼観察すると同時に
写真撮影した。肉眼観察により異常部位の数と
刺激の強さを調べた。なお、刺激の強さは次の
基準で評価した。
−：正常 ±：少し出血 ＋：はつきりと出血
：ビラン ：潰瘍[Table] As is clear from Table 2, the compounds of the present invention ()
A synergistic effect was observed between the drug and non-steroidal anti-inflammatory drugs. () Analgesic effect The analgesic effect of the compound of the present invention () was tested by the following method. The results are shown in FIG. (Test method) Testing was conducted according to the Koster method. ICR mice weighing 20 to 25 g were treated with the drugs shown in Figure 4, and 30 minutes later, 0.1 ml/10 g of 0.6% acetic acid was administered.
was injected intraperitoneally. Thereafter, the number of times the subjects exhibited stretching movements over a 20-minute period was measured. As is clear from FIG. 4, the compound of the present invention () has an analgesic effect comparable to that of phenylbutazone and indomethacin. () Stimulating effect on gastric mucosa The stimulating effect of the compound of the present invention () on gastric mucosa was tested by the following method. The third result
Shown in the table. (Test method) Male SD rats weighing 120-150g (5 weeks old)
After an overnight fast, the drugs listed in Table 3 were administered orally, and 24 hours later the animals were killed with chloroform, removed from their stomachs, opened, and visually observed and photographed at the same time. The number of abnormal areas and the intensity of stimulation were examined by visual observation. The strength of stimulation was evaluated using the following criteria. -: Normal ±: Slight bleeding +: Punching and bleeding: Violence: Ulcer
【表】【table】
【表】
第４表から明らかな如く、本発明化合物（）
は胃粘膜の刺激作用は弱く、また他の抗炎症剤
の刺激作用を緩和する作用を有する。
() 抗菌作用
試験管内稀釈試験法により、本発明化合物
（）の下記第４表に示す菌株に対する阻害作
用を調べ、最小阻害濃度（MIC）の概略値を
求めた。[Table] As is clear from Table 4, the compounds of the present invention ()
has a weak irritating effect on the gastric mucosa, and also has the effect of alleviating the irritating effects of other anti-inflammatory drugs. () Antibacterial activity The inhibitory effect of the compounds of the present invention () on the bacterial strains shown in Table 4 below was investigated by an in vitro dilution test method, and the approximate value of the minimum inhibitory concentration (MIC) was determined.
叙上の如く、本発明の消炎鎮痛剤は、経口、注
射、皮膚塗布、坐剤等として適用することによ
り、抗炎症、解熱、鎮痛効果を発揮するものであ
り、極めて安全性が高く、刺激作用の少ない、全
く新しい基本構造を有する消炎鎮痛剤である。
〔実施例〕
次に参考例および実施例を挙げて本発明を説明
する。
参考例 １
オキシ塩化リン4.6ｇとヘキサン10mlを５℃で
撹拌しながら、これにトリエチルアミン3.0ｇお
よびトリクレン20mlの混合溶液を加える。ここ
に、１−Ｏ−オクタデシル−３−Ｏ−メチルグリ
セリン7.2ｇおよびトリクレン80mlの混合溶液を
０〜５℃、30分で滴下する。滴下終了後、室温で
２〜３時間撹拌し、次いで析出したトリエチルア
ミン塩酸塩を濾去し、溶媒を40℃以下で留去する
と無色液体の目的物（ａ）10.5ｇを得る（収
率：定量的）。
IRスペクトル（液膜）：
2930、2860、1455、1290、1110〜1100、1000br
cm-1
PMRスペクトル（CDCl3）δ：
0.81（3H、ｔ、5.0Hz）、1.18（32H）、3.31（3H、
ｓ）、3.2〜3.8（7H、ｍ）
参考例 ２
参考例１で得られた（ａ）10.5ｇをTHF50
mlに溶解し、０℃で撹拌しつつＮ−メチルエタノ
ールアミン1.82ｇ、トリエチルアミン8.8ｇ、
THF50mlの溶液を30分で滴下する。滴下終了後、
室温にもどし、TLCで原料の消失を確認した後、
トリエチルアミン塩酸塩を濾去し、溶媒を40℃以
下で留去する。残留物をｎ−ヘキサンより再結晶
すると、目的とするオキサアサホスホリジン誘導
体（va）（mp38〜39°）5.2ｇを得る（収率：50
％）。
IRスペクトル（KBr）：
2925、2850、1460、1375、1270、1190、1100、
1000、930、830cm-1
PMRスペクトル（CDCl3）δ：
0.88（3H、ｔ、5.0Hz）、1.30（32H）、2.72（3H、
ｄ、10Hz）、3.38（3H、ｓ）3.0〜4.9（11H、ｍ）
元素分析値（C25H52NO5P）
実測値 C62.86 H10.97 N2.93
計算値 C62.93 H10.89 N3.21
参考例 ３
１−Ｏ−オクタデシル−３−Ｏ−メチルグリセ
リン（ａ）35.8ｇ、ベンゼン100mlトリエチル
アミン12.1ｇを室温下混合撹拌しつつ、２−クロ
ロ−２−オキサ−１，４，５−ジオキサホスホラ
ン（）14.3ｇのベンゼン100ml溶液を0.5時間で
滴下する。滴下終了後、室温で６時間撹拌したの
ち、トリエチルアミン塩酸塩を濾去、溶媒留去す
る。残渣にｎ−ヘキサン100mlを加え、再結晶を
行なう。得られた結晶をｎ−ヘキサン100mlに溶
解し、飽和食塩水200mlで洗浄する。ｎ−ヘキサ
ン層を分液乾燥後、ｎ−ヘキサンを留去すると目
的とする無色結晶の目的物（ａ）（mp50〜50.5
℃）30.0ｇを得る（収率：65％）。
IRスペクトル（液膜）：
2920、2850、1455、1285、1105、1020、925、
840cm-1
PMRスペクトル（CDCl3）δ：
0.86（3H、ｔ、5.0Hz）、1.27（32H）、3.35（3H、
ｓ）、3.3〜4.4（11H、ｍ）
元素分析値（C24H49O6P）
計算値 C62.06 H10.63
実測値 C62.35 H10.59
実施例 １
参考例２で得られたオキサアザホスホラン誘導
体（Va）5.2ｇをイソプロパノール30mlに溶解さ
せ、室温下、１規定塩酸10mlを加えて２時間撹拌
する。反応生成物をアセトン100mlに注ぎ、生成
した白色沈澱を濾取し、アセトン洗浄後乾燥する
と淡黄色結晶の目的物（Ib）（mp58〜59℃）2.9
ｇを得る（収率：50％）。
IRスペクトル（KBr）：
2920、2850、3200〜2600、1460、1220、1160〜
900、820、790、720cm-1
PMRスペクトル（CDCl3）δ：
0.85（3H、ｔ、5.0Hz）、1.28（32H）、2.70（3H、
br）、3.37（3H、ｓ）3.3〜4.7（13H、br）
元素分析値（C25H54NO6P・2H2O）
計算値 C56.47 H11.00 N2.63
実測値 C56.76 H10.81 N2.34
実施例 ２
オキサアザホスホリジン誘導体（Vb）2.5ｇを
イソプロパノール25mlに溶解させ、室温下、１規
定塩酸５mlを加えて２時間撹拌する。反応生成物
をアセトン100mlに注ぎ、生成した白色沈澱を濾
取し、アセトン洗浄後乾燥すると淡黄色結晶の目
的物（Ic）（mp76.5〜78℃）1.5ｇを得る（収率：
58％）。
IRスペクトル（KBr）：
3400、3100〜2600br、2915、2850、1460、
1210、170〜900、790cm-1
PMRスペクトル（CDCl3）δ：
0.89（3H、ｔ、5.0Hz）、1.29（28H）、2.70（3H、
br）、3.35（3H、ｓ）3.30〜4.70（13H、br）
元素分析値（C23H50NO6P・H2O）
計算値 C56.88 H10.79 N2.88
実測値 C56.83 H10.49 N2.94
実施例 ３
オキサアザホスホリジン誘導体（Vc）87.0ｇ
をイソプロパノール1000mlに溶解し、−50℃で撹
拌する。ここに６規定塩酸34ｇを0.5時間で滴下
し、−50℃で2.5時間撹拌後、溶媒留去し更に、エ
ーテル500mlを加えて撹拌する。不溶物を濾去し、
エーテルを留去すると淡黄色粘稠物が得られる。
これをシリカゲルクロマトグラフイー〔1000ｇ、
クロロホルム−メタノール（５：１）の混合溶
媒〕により精製すると淡黄色粘稠物の目的物
（Ib）11.5ｇを得る〔（）からの総収率14％〕。
IRスペクトル（液膜）：
3400、3100〜2400br、2920、2850、1455、
1225、1100〜960br、790、745cm-1
PMRスペクトル（CDCl3）δ：
0.86（3H、ｔ、5.0Hz）、1.24（20H）、2.76（3H、
br）、3.35（3H、br ｓ）3.30〜4.70（13H、br）
元素分析値（C19H42NO6P・H2O）
計算値 C53.13 H10.33 N3.26
実測値 C53.11 H10.22 N3.14
実施例 ４
参考例３で得られたホスホラン誘導体（ａ）
4.6ｇをアセトニトリル60mlに溶解し、ベンジル
アミン1.1ｇを加え、65〜70℃で24時間撹拌する。
次いで不溶物を濾去し、溶媒を留去する。残渣を
アセトンから再結晶して淡黄色結晶の目的物
（Ie）（mp37〜39℃）4.4ｇを得る（収率77％）。
PMR（CDCl3）δ：
0.87（3H、ｔ、5.0Hz）、1.24（32H）、3.23（3H、
ｓ）、3.35〜4.15（15H、br）7.2〜8.6（5H、ｍ）
元素分析値（C31H58NO6P）
計算値 C65.12 H10.22 N2.45
実測値 C64.83 H10.20 N2.71
実施例 ５
実施例１〜４で得られた燐脂質（Ib）、（Ic）、
（Id）、（Ie）10mgを生理食塩水１mlに溶かし、無
菌操作で１％溶液として、過、アンプル封入滅
菌処理を行ない、注射剤を調製した。
実施例 ６
実施例１〜４で得られた燐脂質（Ib）、（Ic）、
（Id）、（Ie）50mgを結晶セルロース630mg、カルボ
キシメチルセルロースナトリウム塩と良く混合し
たのち打錠して錠剤を製造した。
実施例 ７
燐脂質（Ib） 1.0重量部
プレドニゾロン 0.05
アミノ安息香酸エチル 1.00
セトリミド 0.1
卵黄レシチン 5.0
イソカカオ（花王石鹸(株)製、坐剤基剤）
バランス
計100
〜を60℃にて加温し、よく混合したのち、
1.5ｇ宛坐剤製造用鋳型にて製剤化する。
実施例 ８
燐脂質（Id） 1.00重量部
ヒドロコルチゾン 0.05
酢酸dl−トコフエロール 1.00
アラントイン 1.00
アミノ安息香酸エチル 1.50
イソカカオ（実施例７と同じ） バランス
計100
〜を60℃にて加温し、よく混合したのち１
ｇ宛坐剤製造用鋳型にて製剤化する。
実施例 ９
ワセリン 10.0重量部
ラノリン 4.5
イソプロピル・ミリステート 5.0
ステアリルアルコール 5.0
流動パラフイン 4.5
安息香酸プロピルエステル 0.1
ソルビタンモノステアレート 2.0
グリセロールモノステアレート 2.0
ポリオキシエチレンソルビタンモノステアレ
ート 1.5
安息香酸メチルエステル 0.1
燐脂質（Ic） 1.0
精製水 バランス
計100
を70℃で加温してゆるやかにかきまぜなが
ら、同じく70℃に加温した〜を徐々に添加
し乳化する。次いで、これを冷却して痔疾軟膏と
する。
実施例 10
燐脂質（Ie） 1.0重量部
シリコーン 25.0
ホホバ油 25.0
スクワレン バランス
計100
を50℃に加温し、を添加して充分溶解さ
せたのち、を加えよく混合する。本発明品は、
スプレーボトルに充填し、次の方法にて使用す
る。すなわち、痔疾患者において排便後トイレツ
トペーパー等で通常の拭き取りをしたのち、本発
明品を用いて拭き取り仕上げをしたり、また、入
浴後、本発明品を用いて肛門周辺部をぬぐう等の
方法にて使用する。
実施例 11
グリセリン 4.0重量部
燐脂質（Ic） 1.0
ポリオキシエチレン硬化ヒマシ油 1.5
エタノール 10.0
ピロリドンカルボン酸ナトリウム 2.0
香料 微量
精製水 残量
計100.0
実施例 12
Ｗ／Ｏクリーム型抗炎症剤：
燐脂質（Ie） 1.0重量部
セタノール 0.5
ワセリン 6.0
ソルビタンセスキオレート 2.0
コレステロール 0.6
液状ラノリン 4.0
イソプロピルパルミテート 8.0
スクワラン 10.0
固型パラフイン 4.0
ブチルパラベン 0.1
メチルパラベン 0.1
グリセリン 3.0
香料 0.2
精製水 バランス
計100
実施例 13
Ｏ／Ｗクリーム型抗炎症剤：
ステアリン 2.0重量部
燐脂質（Ib） 1.0
セタノール 4.0
ワセリン 5.0
スクワラン 8.0
硬化パーム油 4.0
ポリオキシエチレンソルビタンモノステアレ
ート（20E.O） 1.4
親油型モノステアリン酸グリセリン 2.4
ブチルパラベン 0.1
メチルパラベン 0.1
グリセリン 3.0
(12) ジプロピレングリコール 3.0
〓 Ｌ−アルギニン 10.0
水酸化カリウム 0.2
精製水 バランス
計100.0
実施例 14
軟膏型抗炎症例：
燐脂質（Id） 1.0重量部
白色ワセリン 99.0
計100.0
実施例 15
液剤型抗炎症剤
燐脂質（Id） 1.0重量部
エタノール 99.0
100.0
As mentioned above, the anti-inflammatory and analgesic agent of the present invention exhibits anti-inflammatory, antipyretic, and analgesic effects when administered orally, by injection, by application to the skin, or as a suppository, and is extremely safe and non-irritating. It is an anti-inflammatory analgesic with a completely new basic structure and less action. [Example] Next, the present invention will be described with reference to Reference Examples and Examples. Reference example 1 While stirring 4.6 g of phosphorus oxychloride and 10 ml of hexane at 5°C, add a mixed solution of 3.0 g of triethylamine and 20 ml of trichlene. A mixed solution of 7.2 g of 1-O-octadecyl-3-O-methylglycerin and 80 ml of trichlene was added dropwise thereto at 0 to 5°C over 30 minutes. After the dropwise addition is completed, the mixture is stirred at room temperature for 2 to 3 hours, and then the precipitated triethylamine hydrochloride is filtered off, and the solvent is distilled off at below 40°C to obtain 10.5 g of the target product (a) as a colorless liquid (yield: quantitative). target). IR spectrum (liquid film): 2930, 2860, 1455, 1290, 1110~1100, 1000br
cm -1 PMR spectrum (CDCl 3 ) δ: 0.81 (3H, t, 5.0Hz), 1.18 (32H), 3.31 (3H,
s), 3.2 to 3.8 (7H, m) Reference example 2 10.5g of (a) obtained in Reference Example 1 was added to THF50
1.82 g of N-methylethanolamine, 8.8 g of triethylamine, while stirring at 0°C.
Add a solution of 50 ml of THF dropwise over 30 minutes. After the dripping is finished,
After returning to room temperature and confirming disappearance of raw materials by TLC,
Triethylamine hydrochloride is filtered off and the solvent is distilled off at below 40°C. The residue is recrystallized from n-hexane to obtain 5.2 g of the desired oxaasaphospholidine derivative (va) (mp38-39°) (yield: 50
%). IR spectrum (KBr): 2925, 2850, 1460, 1375, 1270, 1190, 1100,
1000, 930, 830 cm -1 PMR spectrum (CDCl 3 ) δ: 0.88 (3H, t, 5.0Hz), 1.30 (32H), 2.72 (3H,
d, 10Hz), 3.38 (3H, s) 3.0 to 4.9 (11H, m) Elemental analysis value (C 25 H 52 NO 5 P) Actual value C62.86 H10.97 N2.93 Calculated value C62.93 H10.89 N3.21 Reference example 3 While stirring 35.8 g of 1-O-octadecyl-3-O-methylglycerin (a) and 12.1 g of triethylamine in 100 ml of benzene at room temperature, 2-chloro-2-oxa-1,4,5-dioxaphosphorane ( ) A solution of 14.3 g of benzene in 100 ml is added dropwise over 0.5 hours. After the addition was completed, the mixture was stirred at room temperature for 6 hours, and then triethylamine hydrochloride was filtered off and the solvent was distilled off. Add 100 ml of n-hexane to the residue and perform recrystallization. The obtained crystals are dissolved in 100 ml of n-hexane and washed with 200 ml of saturated saline. After separating and drying the n-hexane layer, when the n-hexane is distilled off, the desired colorless crystal object (a) (mp50-50.5
℃) to obtain 30.0 g (yield: 65%). IR spectrum (liquid film): 2920, 2850, 1455, 1285, 1105, 1020, 925,
840cm -1 PMR spectrum (CDCl 3 ) δ: 0.86 (3H, t, 5.0Hz), 1.27 (32H), 3.35 (3H,
s), 3.3 to 4.4 (11H, m) Elemental analysis value (C 24 H 49 O 6 P) Calculated value C62.06 H10.63 Actual value C62.35 H10.59 Example 1 5.2 g of the oxaazaphosphorane derivative (Va) obtained in Reference Example 2 is dissolved in 30 ml of isopropanol, and 10 ml of 1N hydrochloric acid is added at room temperature, followed by stirring for 2 hours. Pour the reaction product into 100 ml of acetone, collect the white precipitate by filtration, wash with acetone, and dry to obtain the desired product (Ib) as pale yellow crystals (mp 58-59℃) 2.9
g (yield: 50%). IR spectrum (KBr): 2920, 2850, 3200~2600, 1460, 1220, 1160~
900, 820, 790, 720 cm -1 PMR spectrum (CDCl 3 ) δ: 0.85 (3H, t, 5.0Hz), 1.28 (32H), 2.70 (3H,
br), 3.37 (3H, s) 3.3~4.7 (13H, br) Elemental analysis value (C 25 H 54 NO 6 P・2H 2 O) Calculated value C56.47 H11.00 N2.63 Actual value C56.76 H10 .81 N2.34 Example 2 2.5 g of oxaazaphospholidine derivative (Vb) is dissolved in 25 ml of isopropanol, 5 ml of 1N hydrochloric acid is added at room temperature, and the mixture is stirred for 2 hours. Pour the reaction product into 100 ml of acetone, collect the formed white precipitate by filtration, wash with acetone and dry to obtain 1.5 g of the target product (Ic) (mp 76.5-78°C) as pale yellow crystals (yield:
58%). IR spectrum (KBr): 3400, 3100~2600br, 2915, 2850, 1460,
1210, 170-900, 790 cm -1 PMR spectrum ( CDCl3 ) δ: 0.89 (3H, t, 5.0Hz), 1.29 (28H), 2.70 (3H,
br), 3.35 (3H, s) 3.30 to 4.70 (13H, br) Elemental analysis value (C 23 H 50 NO 6 P・H 2 O) Calculated value C56.88 H10.79 N2.88 Actual value C56.83 H10 .49 N2.94 Example 3 Oxaazaphospholidine derivative (Vc) 87.0g
Dissolve in 1000 ml of isopropanol and stir at -50°C. To this, 34 g of 6N hydrochloric acid was added dropwise over 0.5 hours, and after stirring at -50°C for 2.5 hours, the solvent was distilled off, and then 500 ml of ether was added and stirred. Filter off insoluble matter,
When the ether is distilled off, a pale yellow viscous substance is obtained.
This was subjected to silica gel chromatography [1000g,
Purification using a mixed solvent of chloroform and methanol (5:1)] yielded 11.5 g of the target compound (Ib) as a pale yellow viscous substance [total yield from (2): 14%]. IR spectrum (liquid film): 3400, 3100~2400br, 2920, 2850, 1455,
1225, 1100~960br, 790, 745cm -1 PMR spectrum ( CDCl3 ) δ: 0.86 (3H, t, 5.0Hz), 1.24 (20H), 2.76 (3H,
br), 3.35 (3H, br s) 3.30 to 4.70 (13H, br) Elemental analysis value (C 19 H 42 NO 6 P・H 2 O) Calculated value C53.13 H10.33 N3.26 Actual value C53.11 H10.22 N3.14 Example 4 Phosphorane derivative (a) obtained in Reference Example 3
Dissolve 4.6 g in 60 ml of acetonitrile, add 1.1 g of benzylamine, and stir at 65-70°C for 24 hours.
Next, insoluble matter is filtered off and the solvent is distilled off. The residue is recrystallized from acetone to obtain 4.4 g of the target compound (Ie) (mp 37-39°C) as pale yellow crystals (yield 77%). PMR (CDCl 3 ) δ: 0.87 (3H, t, 5.0Hz), 1.24 (32H), 3.23 (3H,
s), 3.35~4.15 (15H, br) 7.2~8.6 (5H, m) Elemental analysis value (C 31 H 58 NO 6 P) Calculated value C65.12 H10.22 N2.45 Actual value C64.83 H10.20 N2.71 Example 5 Phospholipids (Ib), (Ic), obtained in Examples 1 to 4
An injection was prepared by dissolving 10 mg of (Id) and (Ie) in 1 ml of physiological saline, making a 1% solution using aseptic techniques, and sterilizing the solution by filtration and sealing in ampoules. Example 6 Phospholipids (Ib), (Ic), obtained in Examples 1 to 4
Tablets were produced by thoroughly mixing 50 mg of (Id) and (Ie) with 630 mg of crystalline cellulose and carboxymethyl cellulose sodium salt, and then compressing the mixture. Example 7 Phospholipid (Ib) 1.0 parts by weight Prednisolone 0.05 Ethyl aminobenzoate 1.00 Cetrimide 0.1 Egg yolk lecithin 5.0 Isocacao (manufactured by Kao Soap Co., Ltd., suppository base)
After heating the balance meter 100 ~ at 60℃ and mixing well,
Formulate into a 1.5g suppository mold. Example 8 Phospholipid (Id) 1.00 parts by weight Hydrocortisone 0.05 dl-tocopherol acetate 1.00 Allantoin 1.00 Ethyl aminobenzoate 1.50 Isocacao (same as Example 7) Balance meter 100 After heating ~ at 60℃ and mixing well 1
Formulate the product using a mold for manufacturing suppositories. Example 9 Vaseline 10.0 parts by weight Lanolin 4.5 Isopropyl myristate 5.0 Stearyl alcohol 5.0 Liquid paraffin 4.5 Benzoic acid propyl ester 0.1 Sorbitan monostearate 2.0 Glycerol monostearate 2.0 Polyoxyethylene sorbitan monostearate 1.5 Benzoic acid methyl ester 0.1 Phospholipid (Ic) 1.0 Purified water Balance meter 100 is heated to 70℃, and while stirring gently, gradually add ~, which was also heated to 70℃, to emulsify. This is then cooled to form a hemorrhoid ointment. Example 10 Phospholipid (Ie) 1.0 parts by weight Silicone 25.0 Jojoba oil 25.0 Squalene Balance meter 100 is heated to 50°C, and after it is sufficiently dissolved, is added and mixed well. The product of this invention is
Fill a spray bottle and use as follows. That is, after a person with hemorrhoid disease has defecated, he or she normally wipes with toilet paper, etc., and then uses the product of the present invention to finish wiping, or after taking a bath, uses the product of the present invention to wipe the area around the anus. Used in Example 11 Glycerin 4.0 parts by weight Phospholipid (Ic) 1.0 Polyoxyethylene hydrogenated castor oil 1.5 Ethanol 10.0 Sodium pyrrolidonecarboxylate 2.0 Fragrance Trace amount Purified water Total amount 100.0 Example 12 W/O cream type anti-inflammatory agent: Phospholipid ( Ie) 1.0 parts by weight Setanol 0.5 Vaseline 6.0 Sorbitan sesquiolate 2.0 Cholesterol 0.6 Liquid lanolin 4.0 Isopropyl palmitate 8.0 Squalane 10.0 Solid paraffin 4.0 Butylparaben 0.1 Methylparaben 0.1 Glycerin 3.0 Fragrance 0.2 Purified water Balance meter 100 implementation Example 13 O/W cream type Anti-inflammatory agents: Stearin 2.0 parts by weight Phospholipid (Ib) 1.0 Setanol 4.0 Vaseline 5.0 Squalane 8.0 Hydrogenated palm oil 4.0 Polyoxyethylene sorbitan monostearate (20E.O) 1.4 Lipophilic glyceryl monostearate 2.4 Butylparaben 0.1 Methylparaben 0.1 Glycerin 3.0 (12) Dipropylene glycol 3.0 〓 L-Arginine 10.0 Potassium hydroxide 0.2 Purified water Balance meter 100.0 Example 14 Ointment type anti-inflammatory example: Phospholipid (Id) 1.0 parts by weight White petrolatum 99.0 Total 100.0 Example 15 Liquid formulation Anti-inflammatory agent Phospholipid (Id) 1.0 parts by weight Ethanol 99.0 100.0
第１図はラツトに本発明化合物（）を経口投
与した場合の浮腫率の経時変化を示す図面、第２
図はラツトの足蹠浮腫に本発明化合物（）を塗
布した場合の浮腫率の経時変化を示す図面、第３
図はWhittle法による血管透過性試験における腹
水中のエバンスブルーの吸光度を示す図面、第４
図はKoster法における苦悶数を示す図面である。
Figure 1 is a diagram showing the time course of the edema rate when the compound of the present invention () was orally administered to rats;
Figure 3 shows the change in edema rate over time when the compound of the present invention () is applied to the footpad edema of rats.
The figure shows the absorbance of Evans blue in ascites in a vascular permeability test using the Whittle method.
The figure is a diagram showing the number of agonies in the Koster method.
Claims (1)
のアルキル基、R2は炭素数１〜６の直鎖若しく
は分岐のアルキル基、R3、R4、R5は各々炭素数
１〜６の直鎖若しくは分岐のアルキル基、水素原
子又はアルキル基を示し、Ａは炭素数１〜６のア
ルキレン基を示す） で表わされる燐脂質誘導体。 ２ 一般式（） （式中、R1は炭素数１〜25の直鎖若しくは分岐
のアルキル基、R2は炭素数１〜６の直鎖若しく
は分岐のアルキル基、R3、R4、R5は各々炭素数
１〜６の直鎖若しくは分岐のアルキル基、水素原
子又はアルキル基を示し、Ａは炭素数１〜６のア
ルキレン基を示す） で表わされる燐脂質誘導体を有効成分として含有
する消炎鎮痛剤。[Claims] 1 General formula () (In the formula, R 1 is a straight chain or branched alkyl group having 1 to 25 carbon atoms, R 2 is a straight chain or branched alkyl group having 1 to 6 carbon atoms, and R 3 , R 4 , and R 5 are each a carbon number 1-6 linear or branched alkyl group, hydrogen atom or alkyl group, and A represents an alkylene group having 1-6 carbon atoms. 2 General formula () (In the formula, R 1 is a straight chain or branched alkyl group having 1 to 25 carbon atoms, R 2 is a straight chain or branched alkyl group having 1 to 6 carbon atoms, and R 3 , R 4 , and R 5 are each a carbon number An anti-inflammatory analgesic agent containing as an active ingredient a phospholipid derivative represented by the following formula (representing a linear or branched alkyl group, hydrogen atom, or alkyl group having 1 to 6 carbon atoms, and A representing an alkylene group having 1 to 6 carbon atoms).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18987884A JPS6168494A (en) | 1984-09-11 | 1984-09-11 | Phospholipid derivative and antiphlogistic analgesic |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18987884A JPS6168494A (en) | 1984-09-11 | 1984-09-11 | Phospholipid derivative and antiphlogistic analgesic |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6168494A JPS6168494A (en) | 1986-04-08 |
| JPH0424354B2 true JPH0424354B2 (en) | 1992-04-24 |
Family
ID=16248687
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP18987884A Granted JPS6168494A (en) | 1984-09-11 | 1984-09-11 | Phospholipid derivative and antiphlogistic analgesic |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6168494A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6838452B2 (en) * | 2000-11-24 | 2005-01-04 | Vascular Biogenics Ltd. | Methods employing and compositions containing defined oxidized phospholipids for prevention and treatment of atherosclerosis |
| CN115448945A (en) * | 2021-06-08 | 2022-12-09 | 恒大新能源技术(深圳)有限公司 | Halogenated phosphate and preparation method and application thereof |
-
1984
- 1984-09-11 JP JP18987884A patent/JPS6168494A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6168494A (en) | 1986-04-08 |
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