CN1350456A - Pharmaceutical compositions comprising a pyrimidine derivative and cyclodextrin - Google Patents
Pharmaceutical compositions comprising a pyrimidine derivative and cyclodextrin Download PDFInfo
- Publication number
- CN1350456A CN1350456A CN00807523A CN00807523A CN1350456A CN 1350456 A CN1350456 A CN 1350456A CN 00807523 A CN00807523 A CN 00807523A CN 00807523 A CN00807523 A CN 00807523A CN 1350456 A CN1350456 A CN 1350456A
- Authority
- CN
- China
- Prior art keywords
- pyrimidine
- triazol
- ethyl
- compositions
- cyclodextrin
- 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.)
- Pending
Links
- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 40
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
- 150000003230 pyrimidines Chemical class 0.000 title description 3
- 239000000203 mixture Substances 0.000 claims abstract description 92
- 241001465754 Metazoa Species 0.000 claims abstract description 24
- 208000006011 Stroke Diseases 0.000 claims abstract description 19
- 206010015037 epilepsy Diseases 0.000 claims abstract description 19
- -1 racemates Chemical class 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 208000032843 Hemorrhage Diseases 0.000 claims abstract description 7
- 208000019695 Migraine disease Diseases 0.000 claims abstract description 5
- 206010027599 migraine Diseases 0.000 claims abstract description 5
- 239000012453 solvate Substances 0.000 claims abstract description 5
- 206010019196 Head injury Diseases 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 75
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 64
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 61
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 201000010099 disease Diseases 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 230000000324 neuroprotective effect Effects 0.000 claims description 8
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 8
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 6
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 238000012986 modification Methods 0.000 claims description 5
- 230000004048 modification Effects 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 3
- 208000029028 brain injury Diseases 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 3
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 claims description 2
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 2
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 2
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims 1
- 241000282414 Homo sapiens Species 0.000 abstract description 5
- 208000012902 Nervous system disease Diseases 0.000 abstract description 3
- 208000025966 Neurological disease Diseases 0.000 abstract description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract 1
- 206010010904 Convulsion Diseases 0.000 abstract 1
- 208000030886 Traumatic Brain injury Diseases 0.000 abstract 1
- SRNKZYRMFBGSGE-UHFFFAOYSA-N [1,2,4]triazolo[1,5-a]pyrimidine Chemical class N1=CC=CN2N=CN=C21 SRNKZYRMFBGSGE-UHFFFAOYSA-N 0.000 abstract 1
- 239000004090 neuroprotective agent Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 238000000034 method Methods 0.000 description 22
- 239000000243 solution Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 13
- 235000002639 sodium chloride Nutrition 0.000 description 12
- 238000012360 testing method Methods 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 230000006378 damage Effects 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- 239000008187 granular material Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000009834 vaporization Methods 0.000 description 6
- 206010002091 Anaesthesia Diseases 0.000 description 5
- 230000037005 anaesthesia Effects 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 239000006186 oral dosage form Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 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 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 208000028867 ischemia Diseases 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
- 239000001116 FEMA 4028 Substances 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 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 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 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 3
- 230000002421 anti-septic effect Effects 0.000 description 3
- 210000001367 artery Anatomy 0.000 description 3
- 229960004853 betadex Drugs 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000003094 microcapsule Substances 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 230000000926 neurological effect Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 238000001694 spray drying Methods 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N D-Maltose Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920002907 Guar gum Polymers 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229920002774 Maltodextrin Polymers 0.000 description 2
- 239000005913 Maltodextrin Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
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- 238000001035 drying Methods 0.000 description 2
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- 235000010417 guar gum Nutrition 0.000 description 2
- 229960002154 guar gum Drugs 0.000 description 2
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 2
- 229960003132 halothane Drugs 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229940035034 maltodextrin Drugs 0.000 description 2
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 2
- VCANXUAOGIFXHL-UHFFFAOYSA-N methyl 4-(4-chlorophenoxy)-3-oxopentanoate Chemical compound COC(=O)CC(=O)C(C)OC1=CC=C(Cl)C=C1 VCANXUAOGIFXHL-UHFFFAOYSA-N 0.000 description 2
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- IONSZLINWCGRRI-UHFFFAOYSA-N n'-hydroxymethanimidamide Chemical compound NC=NO IONSZLINWCGRRI-UHFFFAOYSA-N 0.000 description 2
- 210000003455 parietal bone Anatomy 0.000 description 2
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
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- 210000003625 skull Anatomy 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
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- 239000011780 sodium chloride Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 229950003937 tolonium Drugs 0.000 description 2
- HNONEKILPDHFOL-UHFFFAOYSA-M tolonium chloride Chemical compound [Cl-].C1=C(C)C(N)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 HNONEKILPDHFOL-UHFFFAOYSA-M 0.000 description 2
- 210000000216 zygoma Anatomy 0.000 description 2
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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Abstract
A pharmaceutical composition comprising a) a 1,2,4-triazolo[1,5-a]pyrimidine derivative of formula (I) including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof b) a cyclodextrin. These compositions are useful in the treatment of migraine, seizures and/or neurological disorders such as epilepsy and/or as neuroprotective agents to protect against conditions such as stroke, brain trauma, head injuries and haemorrhage in animals including human beings.
Description
The present invention relates to contain 1,2, the Pharmaceutical composition of 4-triazol [1,5-a] pyrimidine derivatives and cyclodextrin and relate to they treat and/or prevent migraine, epilepsy, neurological disease such as epilepsy and/or have the disease damaged on the neurological such as apoplexy, brain injury, head injury and hemorrhage in purposes.
In the Western countries, cerebral ischemia is a morbidity and a dead main cause, but remains inadequate and prevention is still the most effective treatment (De Deyn to the Drug therapy of this disease, P.P., De Reuck, J., Deberdt, W., Vlietinck, R., Orgogozo, J.M. (1997) treat acute ischemic apoplexy .Stroke with piracetam, and 28,2347-2352).In the stroke victim of suffering from progressive rather than life-threatening ischemia infringement, provide the medicine of neuroprotective will have profound significance for described treatment of diseases.
Formula A chemical compound
R wherein
1Be one in H or the following group (one or more halogens, cyano group, hydroxyl or the amino optional group that replaces): C
1-6Alkyl, C
1-6Alkoxyl or C
1-6Alkanoyl; R
2And R
3Independently be (one or more halogens, cyano group, hydroxyl or the amino optional group that replaces) a: C in H or the following group
1-6Alkyl, C
1-6Alkoxyl, C
1-6Alkanoyl, C
1-6Alkylthio group, C
1-6Alkyl sulphinyl or C
1-6Alkyl sulphonyl; R
4And R
5Independent is H, C
1-6Alkyl or R
4And R
5The carbon atom that connects with them is C
3-6(each alkyl or cycloalkylidene are optional with one or more halogens, cyano group, hydroxyl, amino or C for cycloalkylidene
1-6Alkyl replaces); And R
6, R
7And R
8Independence is that in H, halogen, hydroxyl, sulfydryl, nitro, cyano group or the following group is (optional by one or more halogens, cyano group, hydroxyl or amino the replacement; And any nitrogen-atoms is optional by one or more C
1-6Alkyl replaces): C
1-6Alkyl, C
1-6Alkanoyl, C
1-6Alkoxyl, C
2-6Alkoxy carbonyl, carboxyl, C
1-6Alkanoyl oxygen base, C
1-6Alkylthio group, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl-amino, sulfamoyl, carbamoyl, C
2-6Alkyl-carbamoyl or C
1-6Alkanoyl amino; Their preparation method and they treat and/or prevent epilepsy, neurological disease such as epilepsy and/or have the disease of neurological infringement such as apoplexy, brain injury, head injury and hemorrhage in purposes be described in WO95/10521 (Knoll AG).The method for preparing these chemical compounds is disclosed in WO98/07724 (Knoll AG).
, described formula A chemical compound has shortcoming, has short plasma half-life behind their water insoluble and oral administration solids in human body.The purposes of these chemical compounds of these results suggest in the treatment apoplexy is restricted.Surprisingly, the invention solves these problems and a kind of potential method for the treatment of apoplexy effectively is provided.
Pharmaceutical composition provided by the invention, it comprises a) formula I chemical compound,
Comprise its pharmaceutically acceptable salt, solvate, racemic modification, enantiomer, diastereomer and their mixture, wherein: R
1Be one in H or the following group (optional): C by one or more halogens, cyano group, hydroxyl or amino the replacement
1-6Alkyl, C
1-6Alkoxyl or C
1-6Alkanoyl; R
2And R
3Independently be (by one or more halogens, cyano group, hydroxyl or amino optional the replacement) a: C in H or the following group
1-6Alkyl, C
1-6Alkoxyl, C
1-6Alkanoyl, C
1-6Alkylthio group, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl or hydroxyl; R
4And R
5Independent is H, C
1-6Alkyl or R
4And R
5The carbon atom that is connected with them engages and is C
3-6(each alkyl or cycloalkylidene are optional with one or more halogens, cyano group, hydroxyl, amino or C for cycloalkylidene
1-6Alkyl replaces); And R
6, R
7And R
8Independence is that in H, halogen, hydroxyl, sulfydryl, nitro, cyano group or the following group (is replaced by one or more halogens, cyano group, hydroxyl or amino choosing wantonly; And any nitrogen-atoms is optional by one or more C
1-6Alkyl replaces): C
1-6Alkyl, C
1-6Alkanoyl, C
1-6Alkoxyl, C
2-6Alkoxy carbonyl, carboxyl, C
1-6Alkanoyl oxygen base, C
1-6Alkylthio group, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl-amino, amino-sulfonyl, carbamoyl, C
2-6Alkyl-carbamoyl or C
1-6Alkanoyl amino; And b) cyclodextrin.
Be appreciated that any group that contains three or three above carbon atom chains as mentioned herein represents that described chain can be the group of straight or branched.For example, alkyl group can comprise propyl group and butyl, and described propyl group comprises n-pro-pyl and isopropyl, and described butyl comprises normal-butyl, sec-butyl, isobutyl group and the tert-butyl group.Specified the total number of carbon atoms for some substituent group, for example C
1-6Expression contains the alkyl group of 1 to 6 carbon atom.When the expression of term " halogen " when this uses fluorine, chlorine, bromine and iodine.When this uses, term " the optional replacement " means optional by one or more groups replacements that are selected from halogen, cyano group, hydroxyl and amino, unless thereafter immediately following a substituent group group catalogue.As benzene ring substitution group R
6, R
7And R
8When being not H, described substituent group can replace attached to any H on the described ring carbon atom and can be positioned at any position of described ring, for example is positioned at maximum three positions in 2,3,4 and/or 5.
Aptly, described compositions is the mixture of formula I chemical compound and cyclodextrin.Described compositions preferably comprises the complex of formula I chemical compound and cyclodextrin.Aptly, the ratio of described complex Chinese style I chemical compound and cyclodextrin at 0.1-1 in the scope of 1-0.1.
Mixture by forming formula I chemical compound or its pharmaceutically acceptable salt and cyclodextrin and water in 10-100 ℃ of temperature range is so that form suspension or solution, thus use then as spray granulation, spray drying, drum drying or cryodesiccated technology remove anhydrate prepare aptly as described in complex.Preferably spray drying is because this method can produce the free flowing granule solid.Preferred especially fluid bed spray drying.
Can be with the mixture of described formula I chemical compound and cyclodextrin or complex preparation becoming well-known solid pharmaceutical formulations, for example tablet, capsule, granule, the powder etc. of described formula I chemical compound and cyclodextrin.Can be carrier with described compositionss of preparation such as effervescent conjugates (effervescent couple), buffer system, sweeting agent, flavoring agent, coloring agent and with the diluent, as saccharide such as glucose, lactose or the sucrose of water soluble.
In treatment was used, compositions of the present invention can be prepared into the Pharmaceutical composition of oral administration, rectally or parenteral.Therefore, for this type of medication, therapeutic combination of the present invention can adopt any known Pharmaceutical composition form.Described compositions can be prepared so that this reactive compound of sustained release, for example this reactive compound of rapid release or slow release with the method that those skilled in the art were familiar with.The pharmaceutically acceptable carrier that is suitable for this based composition is that pharmaceutical field is well-known.Described compositions can contain the reactive compound of about 0.1% to 99% weight and be prepared into unit dosage forms usually.The unit dose of active component preferably from about 1mg to 1000mg, more preferably from about 1mg to 500mg.The excipient that is used to prepare these compositionss is the excipient that the pharmacists field is familiar with.
Compositions of the present invention is preferably with known drug dosage form oral administration.The dosage form of suitable for oral administration administration can comprise tablet, pill, capsule, microcapsule (caplets), comprise multiple granule, powder, elixir, syrup, suspension and the solution of granule, pearl, piller and microencapsulated particles.
Solid oral dosage form such as tablet can be prepared by mixing Pharmaceutical composition of the present invention and following one or more compositions or their mixture: inert diluent such as calcium carbonate, calcium sulfate, compressible sugar, sugar, dextrates (dextrate), dextrin, glucose, the secondary calcium phosphate dihydrate, the Palmic acid tristerin, hydrogenated vegetable oil, Kaolin, lactose, magnesium carbonate, magnesium dioxide, maltodextrin, mannitol, microcrystalline Cellulose, polymethacrylates, potassium chloride, cellulose powder, pregelatinised starch, sodium chloride, Sorbitol, starch, sucrose, the sugar ball, Pulvis Talci and tertiary calcium phosphate; Disintegrating agent, as alginic acid, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, silica sol, cross-linking sodium carboxymethyl cellulose, crospovidone, guar gum, Magnesiumaluminumsilicate, methylcellulose, microcrystalline Cellulose, polacrilin potassium, cellulose powder, pregelatinised starch, sodium alginate, sodium starch glycollate, starch comprises corn starch and agar; Lubricant is as calcium stearate, glyceryl monostearate, Palmic acid tristerin, castor oil hydrogenated, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, Polyethylene Glycol, sodium benzoate, sodium lauryl sulphate, stearyl Fumaric acid sodium, stearic acid, Talcum and zinc stearate; Binding agent, as arabic gum, alginic acid, carbomer, sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, liquid glucose, Magnesiumaluminumsilicate, maltodextrin, methylcellulose, polymethacrylates, polyvidone, pregelatinised starch, sodium alginate, starch comprises corn starch, zein, sugar is (as sucrose, molasses and lactose), and natural and synthetic natural gum are (as the extract of chondrus ocellatus Holmes, Polyethylene Glycol, wax, microcrystalline Cellulose and polyvinylpyrrolidone); Coloring agent is as the pharmaceutically acceptable dyestuff of routine; Sweeting agent and flavoring agent; Antiseptic; One or more pharmaceutically acceptable conjugates (couple) conjugates of a kind of acid and a kind of carbonate or bicarbonate (as comprise), when solid dosage forms was added to the water, this conjugates can foam and help dissolving; With optional other composition known in the art so that produce peroral dosage form with known method such as pressed disc method.
Can prepare solid oral dosage form so that The compounds of this invention is slowly discharged with the method that those skilled in the art were familiar with.The film coating solid oral dosage form that comprises the present composition may be favourable, and this depends on the character of reactive compound.Various materials such as Lac and/or sugar can be used as the coating thing, or modify the physical form of oral formulations in addition.For example, if desired, can enteric coating be provided for tablet and pill with known method, as using Cellulose Acetate Phthalate and/or hydroxypropyl methylcellulose phthalate coating.
Can with the preparation of the method for routine comprise the capsule of the present composition (be added with or do not add excipient) or microcapsule (as hard or soft gel capsule) just like fatty oil and, can provide enteric coating with known method if desired.Can prepare the content of capsule or microcapsule so that reactive compound is slowly discharged with known method.
The pharmaceutical preparation that a kind of particularly preferred liquid oral dosage form is a kind of aqueous solution, described aqueous solution comprises the formula I chemical compound for the treatment of effective dose and is enough to make the cyclodextrin of the amount of formula I compound dissolution that described formula I chemical compound comprises its pharmaceutically acceptable salt, solvate, racemic modification, enantiomer, diastereomer and their mixture as preceding definition.The preferred beta-schardinger dextrin-of described cyclodextrin.Liquid oral dosage form also can comprise one or more sweeting agents, flavoring agent, antiseptic and composition thereof.
Also compositions of the present invention can be mixed with granule or the powder that is added with or is not added with other excipient.The patient can join it in appropriate liquid carrier (as water) before can directly taking in described granule or powder or absorption.Described granule or powder can contain disintegrating agent (the effervescent conjugates that forms as a kind of pharmaceutically acceptable, by a kind of acid and a kind of carbonate or bicarbonate), so that promote the dispersion in liquid media.
Above-mentioned each peroral dosage form can preferably contain the reactive compound of about 1mg to 500mg (as 10mg, 50mg, 100mg, 200mg, 400mg or 500mg).
The present composition can be with the known pharmaceutical dosage form rectally of this type of administering mode, as contains the suppository of stearic fat, semi-synthetic glyceride, cocoa butter or Polyethylene Glycol substrate.
The present composition also can be with the known pharmaceutical dosage form parenteral of this type of administering mode, and as by intravenous administration, described dosage form is as the sterile solution in a kind of suitable solvent.
The present composition also can place intravital chemical compound source to continue the infusion administration by an external source (as by venoclysis) or by one.Endogenous comprise containing remain the implantation bank or the implant of infusion chemical compound, this implantation bank discharges described chemical compound (as by infiltration) constantly.Should in a long time cycle, can transmit the described chemical compound of treatment effective dose in the amount of a reactive compound that exists in endogenous.
For parenteral, particularly intravenous injection, a preferred embodiment of the present invention is a kind of pharmaceutical formulation, said preparation is to comprise the I chemical compound of formula as defined above for the treatment of effective dose and a certain amount of cyclodextrin, described formula I chemical compound comprises its pharmaceutically acceptable salt, solvate, racemic modification, enantiomer, diastereomer and their mixture, and the amount of cyclodextrin is enough to cause the dissolving of described formula I chemical compound.
It may be useful using described reactive compound with the form of very little microgranule in some compositions, the microgranule that for example uses fluid energy mill to obtain.
If desired, active component adaptive on described reactive compound and other pharmacology is mixed.
The present composition can be suitable as neuroprotective, avoids the disease such as apoplexy so that animal comprises the mankind, and is used for the treatment of epilepsy and such as the sacred disease of epilepsy.Confirm the therapeutic activity of described compositions by the whole bag of tricks at the intravital pharmacological experiment of standard laboratory animal.
Therefore; the present invention provides a kind of on the other hand and treats epilepsy and/or as the method for the sacred disease of epilepsy and/or a kind of method of neuroprotective is provided; so that comprising the mankind, animal avoids disease such as apoplexy; this method comprises the Pharmaceutical composition of the patient treatment effective dose that needs, and described compositions contains the formula I reactive compound and the cyclodextrin for the treatment of effective dose.Therefore, described compositions of the present invention is used to suppress epilepsy and/or as the sacred disease of epilepsy and/or as neuroprotective, avoids the disease as apoplexy so that animal comprises the mankind.Described compositions of the present invention also can be used for treatment and prevention of migraine.
The accurate amount of the reactive compound that gives in above-mentioned treatment simultaneously will depend on many factors, as severity of disease, patient's age and medical history in the past and always in the pharmacists, doctor or the veterinary's that carry out reasonable power to make decision scope, when the administration of human time-like, the suitable daily dose of described reactive compound is typically about 1mg to 5000mg, be more typically about 5mg to 1000mg, in one day according to single dose or divided dose in single or divided doses.Preferred oral administration or venoclysis.
Compositions of the present invention can be used for auxiliary treatment; has active compounds for treating epilepsy and/or as the sacred disease of epilepsy and/or as neuroprotective with one or more; avoid disease so that animal comprises the mankind, and be used for the treatment of and prevent to comprise the migraine of human animal as apoplexy.Should be appreciated that; when the preventive use that comprises described reactive compound and Pharmaceutical composition treated in term when this uses; described compositions comprises a kind of reactive compound for the treatment of effective dose; so that prevention avoids the disease as apoplexy as the outbreak of the sacred disease of epilepsy or as neuroprotective so that animal comprises the mankind.Described reactive compound and/or comprise a kind of Pharmaceutical composition for the treatment of the effective dose reactive compound or compositions can be used to provide a kind of therapeutical effect of partial and/or system.
Also have; the invention provides the purposes of Pharmaceutical composition of the present invention when the preparation medicine on the other hand; described medicine is used for the treatment of epilepsy and/or as the sacred disease of epilepsy and/or be used for neuroprotective, avoids disease and/or treatment and the prevention of stroke as apoplexy so that animal comprises the mankind.
The particular compound of formula I is: 7-[1-(4-fluorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-bromine phenoxy group) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-cyano-benzene oxygen) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-4-trifluoromethylphenopendant) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-methoxyl group phenoxy group) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-(Trifluoromethoxy)benzene oxygen base) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-acetyl group phenoxy group) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-{1-[4-(methyl mercapto) phenoxy group] ethyl }-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-methylsulfinyl phenoxy group) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-sulfonyloxy methyl phenoxyl) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-{1-[4-(ethylmercapto group) phenoxy group) ethyl }-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(3-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(2,4 difluorobenzene oxygen base) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(2, the 4-dichlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(3, the 4-dichlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(2-chloro-4-fluorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-chlorophenoxy) ethyl]-the 2-methyl isophthalic acid, 2,4-triazol [1,5-a] pyrimidine; 7-(4-chlorophenoxy methyl)-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-chlorophenoxy)-1-Methylethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-chlorophenoxy) propyl group]-1,2,4-triazol [1,5-a] pyrimidine; And 7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine-5-alcohol; And their stereoisomer and its pharmaceutically acceptable salt.
The instantiation of the stereoisomer of formula I chemical compound is: (+)-7-[1-(4-fluorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; (-)-7-[1-(4-fluorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; (+)-7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; (-)-7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; (+)-7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine-5-alcohol; (-)-7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine-5-alcohol; And pharmaceutically acceptable salt.
Preferred formula I chemical compound is 7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine and 7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine-5-alcohol, comprise their racemic modification, enantiomer and composition thereof, and pharmaceutically acceptable salt.Preferred formula I chemical compound is (R)-7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine and (S)-7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine and pharmaceutically acceptable salt thereof.A most preferred formula I chemical compound is (R)-7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine and pharmaceutically acceptable salt thereof.(R)-and 7-[1-(4-chlorophenoxy) ethyl]-1,2, the free alkali of 4-triazol [1,5-a] pyrimidine has minus optical rotation.
Can be according to the description preparation I compound among WO95/10521 (Knoll AG) and the WO98/07724 (Knoll AG).
Suitable cyclodextrin is selected from alpha-cyclodextrin, beta-schardinger dextrin-or gamma-cyclodextrin.Suitable beta-schardinger dextrin-comprises beta-schardinger dextrin-, methyl-beta-schardinger dextrin-, 2-hydroxyethyl-beta-schardinger dextrin-, 2-hydroxypropyl-beta-schardinger dextrin-, 3-hydroxypropyl-beta-schardinger dextrin-, 2,3-dihydroxypropyl-beta-schardinger dextrin-, TM-, 6-O-alpha-D-glucose group-beta-cyclodextrin, 6-O-α-D-malt sugar group-beta-cyclodextrin, two malt sugar group-beta-cyclodextrins, the glucosulfone group-beta-cyclodextrin, G 3-, carboxymethyl-beta-cyclodextrin, carboxyethyl-beta-schardinger dextrin-, seven (heptakis)-(2,6-two-O-methyl)-beta-schardinger dextrin-, seven-(2,3,6-three-O-methyl)-beta-schardinger dextrin-, beta-schardinger dextrin-sulfo group butyl ether (is described in US 5,376,645 and US 5, in 134,127).Suitable gamma-cyclodextrin comprises 2-hydroxypropyl-gamma-cyclodextrin.Preferred cyclodextrin is a beta-schardinger dextrin-.Preferred cyclodextrin is methyl-beta-schardinger dextrin-or 2-hydroxypropyl-beta-schardinger dextrin-.Most preferred cyclodextrin is 2-hydroxypropyl-beta-schardinger dextrin-.
A Pharmaceutical composition that preferred embodiment is a kind of aqueous solution form of the present invention, said composition comprise a) the treatment effective dose, as the formula I chemical compound and the b of preceding definition) beta-schardinger dextrin-.
Surprisingly, a kind of formula I chemical compound that comprises, (R)-7-[1-(4-chlorophenoxy) ethyl particularly]-1,2,4-triazol [1,5-a] compositions of pyrimidine and 2-hydroxypropyl-beta-schardinger dextrin-is useful especially, because compare with the compositions that contains other cyclodextrin, its dissolubility increases and the reduction of unfavorable toxicity.This based composition provides aqueous solution by intravenous injection or lasting infusion administration can for the patient suffer stroke.This based composition can provide a kind of important pre-treatment (major advance) when the apoplexy that treatment must be handled rapidly.Can think that these compositionss are a kind of special selections that may make up that are selected from formula I chemical compound and cyclodextrin, described combination has the unexistent favourable character of the combination beyond thought, that other is possible.
The Pharmaceutical composition that preferred embodiment of the present invention is a kind of aqueous solution form, said composition comprise a) the treatment effective dose, as the formula I chemical compound and the b of preceding definition) 2-hydroxypropyl-beta-schardinger dextrin-.
The Pharmaceutical composition that the most preferred embodiment of the present invention is a kind of aqueous solution form, said composition comprise a) the treatment effective dose, as the formula I chemical compound of preceding definition, its concentration in the scope of 0.1-30%w/v and b) 2-hydroxypropyl-beta-schardinger dextrin-, its concentration is in the scope of 5-75%w/v.The remainder that should be appreciated that described compositions is generally and adds to 100% water, and can have other pharmaceutically acceptable additive such as antiseptic, antioxidant, antimicrobial, flavoring agent etc. according to the level that those skilled in the art were familiar with.Formula I chemical compound preferably exists with the concentration of 1-30%w/v scope, as 10-20%w/v and 12-18%w/v, more preferably with the concentration range of 0.5-5%w/v with most preferably exist with the concentration range of 1-3%w/v.The concentration of 2-hydroxypropyl-beta-schardinger dextrin-is preferably in the scope of 20-50%w/v and more preferably in the scope at 30-40%w/v.
A particularly preferred embodiment according to the invention is a kind of Pharmaceutical composition of aqueous solution form, said composition comprises: a) (the R)-7-[1-in the 0.1-30%w/v scope (4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine and b) 2-hydroxypropyl-beta-schardinger dextrin-in the 5-75%w/v scope.(R)-and 7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] preferred concentration of pyrimidine is in the scope of 1-30%w/v, as 10-20%w/v, most preferably in the scope of 12-18%w/v, more preferably in the concentration range of 0.5-5%w/v and most preferably in the concentration range at 1-3%w/v.
The concentration of 2-hydroxypropyl-beta-schardinger dextrin-is preferably in the scope of 20-50%w/v and more preferably in the scope at 30-40%w/v.
By the following effect that studies confirm that described compositions of the present invention.Method i) mesencephalic arteries (MCA) obturation
Make male Sprague-Dawley rat (300-350g) anesthesia with the halothane in the oxygen (1000ml/min).Also keep anesthesia with the induced anesthesia of 5% (v/v) halothane with the face shield of a concentration 2.25-2.5%.Make the body temperature of animal maintain 37 ± 0.5 ℃ by the method for using a thermostatically controlled heating operation blanket.Mid point between right eye and auris dextra is done an incision of scalp.Fibre bundle planar separation temporalis at it is also extracted out so that expose cheekbone and squamosa cheekbone.Scrape muscle from bone and form tissue so that to changeing the hole point location with connecing.Adopt microsurgical technique, carry out fusion (fusion) point of craniotomy to two skull with No. 5 knob dental drills, a rostrad.Carrying out conventional wiping with Sterile Saline makes the skull cooling avoid cerebral cortex is caused pyrolytic damage.With 25g hypodermic needle tendency top at cerebral dura mater and pia-arachnoid upper cut in case form a hook and with the tweezers of exquisiteness from the surface of cortex dilazep gently.(GU Manufacturing Company London) carries out electric cautery to the mesencephalic arteries that exposes and is entering under the aortic bifurcation of cortex bundle of parietal bone and volume second mesencephalic arteries that exposes is carried out electric cautery under nasal fossa with bipolar transthermia.Abandoned belonging to the hemorrhage animal of MCA obturation in the research.Cutting off MCA with a micro-scissors at two points separates so that guarantee vascular.Carefully carry out to avoid that non-specific injury is caused on corticocerebral surface.At last, the skin with temporalis and overlaying returns food original position and stitching.According to following operation, animal is placed in the cage in the absorbent paper and under the 60W bulb that comes from a redness soft warm, allows it recover consciousness.After recovery, animal is accumulated in (n=4-6) in the cage.Surgery duration is 15-20 minute and makes animal regains consciousness in 10-15 minute in addition behind arterial occlusion.Ii) medication preparation
Increase (-)-7-[1-(4-chlorophenoxy) ethyl with two kinds of different cyclodextrin solutions (Research Biochemicals Inc.) at first]-1,2,4-triazol [1,5-a] pyrimidine (after this being called test compound), the dissolving of 2-hydroxypropyl-beta-schardinger dextrin-and methyl-beta-schardinger dextrin-.Join test compound in every kind of cyclodextrin solution (35%w/v aqueous solution) and in ultrasonic water bath supersound process 5-10 minute, avoid solution warm.Described chemical compound is soluble in 2-hydroxypropyl-beta-schardinger dextrin-solution, and approximately concentration is 15mg/ml (being to 15mg/ml from 0.1) and about concentration methyl-beta-schardinger dextrin-is 40mg/ml.2-hydroxypropyl-beta-schardinger dextrin-has been selected in this research, because animal can not tolerate the peritoneal injection of methyl-beta-schardinger dextrin-.The iii) processing of animal
Use two treated animals; The MCA obturation adds test chemical compound (n=11) and the MCA obturation adds vehicle (n=12).Before the MCA obturation and recover after 6 days weighing animal immediately.By being placed in the sterile saline solution that in the ultrasonic water bath test compound is dissolved in 35% w/v 2-hydroxypropyl-beta-schardinger dextrin-, making concentration is 15mg/l.With the pH regulator to 7.4 of media and drying solution and during Therapy lasted with them 4 ℃ of storages.Solidify and broke off back six minutes at MCA, give test compound or the isopyknic vehicle of animal peritoneal injection 35mg/kg.After this according to 20mg/kg at interval 12 hours to animals administer 36 hours.The iv) histopathology assessment of ischemia infringement
After recovering 6 days, with Sagatal (intraperitoneal 85mg/kg, Rhone Merieux) makes Animal Anesthesia and see through the pit of the stomach (trans-cardially) perfusion 3 minutes, use phosphate buffered saline (PBS) (pH7.4) the solution perfusion 15 minutes of 4% cold formaldehyde subsequently with cold (4 ℃) phosphate buffered saline (PBS) liquid (Oxoid).Remove brains and fix at least 48 hours at the 4C dipping.
At coronal plane according to the thickness of the interval of 250 μ m and 30tm with a vibratome (General Scientific, Series 1000) with brain section and use 0.2% Toluidine blue staining.On 13 planes from estimate the scope of local hemorrhage injury at interval according to 500 μ m to-3.3mm with respect to bregma+2.7mm.Micro slide is placed on (CarlZeiss on the slide illumination apparatus; 17.5x amplify) and with the region description of infringement on stereotactic big mind map.Measure the volume that damages the zone and calculate infringement with the analysis (GraphPad Prism) of calculating with an image analyzer.Write down all sections and do not know that by one the operator of processing method measures the size of damage.The v) statistical analysis of data
Analyze the assessment of histologic lesion and the variation of rat body weight with dual factors ANOVA.Quote all data according to meansigma methods ± average difference.The result
Animal does not show neurological defective, as because the epilepsy that causes of MCA obturation or hemiparesis and handle with test compound and only to show slight sedation, and a 5-6 after initial administration hour especially.Because because hemorrhage that the incomplete obturation of MCA causes ironed in electricity consumption, after from anesthesia, recovering, put to death immediately for two in 25 rats of sum.There is not animal because of handling dead with vehicle or test compound.I) damage of the histopathology after the MCA obturation
Because the pale zone that has tangible boundary edges between tissue health and infringement, being presented at has the ischemia injury in the brain sections of Toluidine blue staining.
Because the infringement that the MCA obturation causes mainly is to have parietal bone, Reil's island, volume and forelimb cortex zone.Also find infringement in the perimeter that the tail shell is arranged.This is to be caused by the infringement second time that compressing causes, compressing is owing to have edema at cortex and corpus callosum.Therefore can infer do not have tremulous pulse to replenish to tail shell tip is arranged like this for the position of obturation.
When in ischemia infringement back assessment in the time of 6 days, when with only give vectorial rat relatively the time, with test compound (post-MCAO 60 minutes; 35mg/kg ip+20mg/kg * 3) handle rat, can make the infringement volume reduce by 40%.For the rat infringement volume of handling with vehicle is 72.0 ± 7.9mm
3And damage volume for the animal of handling with test compound is 43.6 ± 4.9mm
3
In a comparative study, use the suspension (post-MCAO 15 minutes of test compound by oral gavage; 50mg/kg * 3) handle rat.When with the matched group (82.6 ± 6.47mm that handles with vehicle
3) compare, this test compound makes infringement volume (56.9 ± 6.1mm
3) reduced by 31%.
These results prove that the known than before compositions of compositions of the present invention is favourable.In detail, the solution of formula I chemical compound is useful, and is because more effective than suspension, bigger and have lower dosage and administration late after the MCA obturation as the volume that reduces infringement.Also may overcome half-life according to pharmaceutical solutions of the present invention at the weak point of human body Chinese style I chemical compound.In addition, this type of pharmaceutical solutions can be by the intravenous infusion administration that continues, and intravenous infusion administration is useful especially when the treatment apoplexy.
Set forth the present invention by following examples, these embodiment only provide by way of example.The end-product of each embodiment carries out characterized in order to following method: gas liquid chromatography, high performance liquid chromatography (HPLC), elementary analysis, nuclear magnetic resonance spectrometry and infrared spectrometry.
According to be attached to by reference herein WO95/10521 (Knoll AG) and the description of WO98/07724 (Knoll AG) prepare other chemical compound of the present invention.Cyclodextrin is from the disclosed method preparation of the commercial list of references that can obtain or quote with Chemical Reviews (1998) 98,1474-2076 and this paper.Embodiment 11a) 60-70 ℃, stir under, the mixture of 2-(4-chlorophenoxy) propanoic acid (30.0g) in toluene (300ml) joined in toluene (150ml) solution of thionyl chloride (22.0ml) and dimethyl formamide (2ml).Stirred this mixture 18 hours at 70-80 ℃, vapourisation under reduced pressure obtains acyl chlorides then.Under nitrogen, dichloromethane (90ml) solution of Meldrum ' s acid (23.5g) is cooled to 0-5 ℃ and add pyridine (33ml) at 0-5 ℃.Dichloromethane (90ml) solution of the acyl chlorides for preparing above being added dropwise in this mixture maintains the temperature at below 5 ℃.Stirred this mixture 1 hour at 0-5 ℃, then stirring at room 18 hours.Diluting this mixture with dichloromethane (150ml) also washs successively with 2M hydrochloric acid, saturated sodium bicarbonate solution and water.With 5M hcl acidifying bicarbonate washing liquid and be extracted in the dichloromethane.With these dichloromethane extraction liquid and initial dichloromethane solution merging and dry and evaporation, obtain rough intermediate Meldrum ' s acid derivative.Under refluxing, make this derivant boiling 6 hours, then at room temperature, use the hydrogen chloride solution (10ml) of methanolizing to keep 66 hours with methanol (400ml).The described mixture of vapourisation under reduced pressure also distributes residue between ethyl acetate and water.The separating ethyl acetate layer with saturated sodium bicarbonate solution, salt water washing and drying and reduction vaporization, obtains a kind of grease, and it is distilled under fine vacuum.By quick this distillation of post color popularize law purification on silica gel, use petroleum ether, b.p.60-80 ℃/ethyl acetate as mobile phase obtains as a kind of buttery 4-(4-chlorophenoxy)-3-oxopentanoic acid methyl ester at 20: 1.B) stirring joins guanidine hydrochloride (1.87g) in ethanol (15ml) solution of sodium (0.41g) down.Stir this mixture 15 minutes, and in this mixture, added ethanol (15ml) solution of 4-(4-chlorophenoxy)-3-oxopentanoic acid methyl ester (5.0g) then.Stir this mixture and boiling 16 hours under refluxing.Cool off described mixture, vapourisation under reduced pressure obtains a kind of solid to doing then.Ground this solid 1 hour with the water (10ml) that contains glacial acetic acid (2ml) and dichloromethane (20ml), filter then.Water (20ml), the residue that obtains with washed with dichloromethane obtains 2-amino-4-[1-(4-chlorophenoxy) ethyl then]-the 6-hydroxy pyrimidine, m.p.125 ℃.C) stir 2-amino-4-[1-(4-chlorophenoxy) ethyl base]-mixture of 6-hydroxy pyrimidine (0.5g), dimethyl formamide dimethyl acetal (0.5ml) and toluene (5ml) and under refluxing, seething with excitement 8 hours.Evaporated this mixture 8 hours.Also vapourisation under reduced pressure is extremely dried to allow this mixture at room temperature place 24 hours, obtains a kind of solid, grinds this solid and filtration with ether, obtains being solid described amidine.D) be dissolved in the methanol (10ml) sodium hydride (60% is dispersed in the 62mg in the mineral oil, by having removed mineral oil with the gasoline washing) and adding oxammonium hydrochloride. (0.12g).Stirred described mixture 5 minutes, and joined at c then) in the amidino groups pyrimidine (0.5g) that obtains.At room temperature stirred described mixture 72 hours, vapourisation under reduced pressure obtains a kind of residue to doing then, washes this residue and dry with water, obtains formamidoxime (formamidoxine).E) stir from d) product (5.0g) and polyphosphoric acid (100g) and in steam bath, heated 4 hours.Allow this mixture be cooled to room temperature, add ice (100g) and ethyl acetate (100ml) then.Drip water (cumulative volume 100ml) solution of potassium carbonate (110g) so that neutralize this mixture with the time more than 15 minutes.Separate this mixture and use the ethyl acetate extraction water layer.Dry ethyl acetate layer that merges and evaporation obtain a kind of solid, through this solid of silica gel rapid column chromatography method purification, as mobile phase, obtain 7-[1-(4-chlorophenoxy) ethyl with methylene chloride (75: 3)]-1,2,4-triazol [l, 5-a] pyrimidine-5-alcohol, m.p.190 ℃.
Embodiment 2
According to the described preparation of WO95/10521 (-)-7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine.
Dissolubility is measured
Embodiment 1 | Embodiment 2 | |
Water | <33μg/ml | ?125-170μg/ml |
35%w/v methyl-beta-schardinger dextrin-aqueous solution | 2mg/ml | ?40mg/ml |
35%w/v 2-hydroxypropyl-beta-schardinger dextrin-aqueous solution | 1mg/ml | ?15mg/ml |
35%w/v 2-hydroxypropyl-gamma-cyclodextrin aqueous solution | <62μg/ml | ?6mg/ml |
Claims (18)
1. Pharmaceutical composition, said composition comprises a) a kind of formula I chemical compound
Comprise its pharmaceutically acceptable salt, solvate, racemic modification, enantiomer, diastereomer and their mixture, wherein: R
1Be one in H or the following group (optional): C by one or more halogens, cyano group, hydroxyl or amino the replacement
1-6Alkyl, C
1-6Alkoxyl or C
1-6Alkanoyl; R
2And R
3Independently be (optional) a: C in H or the following group by one or more halogens, cyano group, hydroxyl or amino the replacement
1-6Alkyl, C
1-6Alkoxyl, C
1-6Alkanoyl, C
1-6Alkylthio group, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl or hydroxyl; R
4And R
5Independent is H, C
1-6Alkyl or R
4And R
5The carbon atom that connects with them is C
3-6(each alkyl or cycloalkylidene are optional by one or more halogens, cyano group, hydroxyl, amino or C for cycloalkylidene
1-6Alkyl replaces); And R
6, R
7And R
8Independence is that in H, halogen, hydroxyl, sulfydryl, nitro, cyano group or the following group is (optional by one or more halogens, cyano group, hydroxyl or amino the replacement; And any nitrogen-atoms is optional by one or more C
1-6Alkyl replaces): C
1-6Alkyl, C
1-6Alkanoyl, C
1-6Alkoxyl, C
2-6Alkoxy carbonyl, carboxyl, C
1-6Alkanoyl oxygen base, C
1-6Alkylthio group, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl-amino, sulfamoyl, carbamoyl, C
2-6Alkyl-carbamoyl or C
1-6Alkanoyl amino; And b) a kind of cyclodextrin.
2. the compositions of claim 1, wherein said compositions is the mixture of formula I chemical compound and cyclodextrin.
3. the compositions of claim 1, wherein said compositions comprises the complex of formula I chemical compound and cyclodextrin.
4. each compositions in the aforementioned claim, wherein said formula I chemical compound is selected from: 7-[1-(4-fluorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-bromine phenoxy group) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-cyano-benzene oxygen) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-4-trifluoromethylphenopendant) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-methoxyl group phenoxy group) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-(Trifluoromethoxy)benzene oxygen base) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-acetyl group phenoxy group) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-{1-[4-(methyl mercapto) phenoxy group] ethyl }-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-methylsulfinyl phenoxy group) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-sulfonyloxy methyl phenoxyl) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-{1-[4-(ethylmercapto group) phenoxy group) ethyl }-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(3-chlorophenoxy) ethyl)-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(2,4 difluorobenzene oxygen base) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(2, the 4-dichlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(3, the 4-dichlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(2-chloro-4-fluorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-chlorophenoxy) ethyl]-the 2-methyl isophthalic acid, 2,4-triazol [1,5-a] pyrimidine; 7-(4-chlorophenoxy methyl)-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-chlorophenoxy)-1-Methylethyl]-1,2,4-triazol [1,5-a] pyrimidine; 7-[1-(4-chlorophenoxy) propyl group]-1,2,4-triazol [1,5-a] pyrimidine; And 7-[1-(4-chlorophenoxy) ethyl]-1,2, pure and mild their stereoisomer and the pharmaceutically acceptable salt thereof of 4-triazol [1,5-a] pyrimidine-5-.
5. each a kind of compositions in the aforementioned claim, wherein said formula I chemical compound is selected from: (+)-7-[1-(4-fluorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; (-)-7-[1-(4-fluorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; (+)-7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; (-)-7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine; (+)-7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine-5-alcohol; (-)-7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine-5-alcohol; With its pharmaceutically acceptable salt.
6. each a kind of compositions in the aforementioned claim, wherein said formula I chemical compound are (R)-7-[1-(4-chlorophenoxy) ethyl]-1,2,4-triazol [1,5-a] pyrimidine.
7. the compositions of the aqueous solution form of claim 1, described compositions comprise a) treatment effective dose as each defined formula I chemical compound and b in the claim 1 to 6) cyclodextrin.
8. each compositions in the aforementioned claim, wherein said cyclodextrin is selected from alpha-cyclodextrin, beta-schardinger dextrin-or gamma-cyclodextrin.
9. each compositions in the aforementioned claim, wherein said cyclodextrin is a beta-schardinger dextrin-.
10. the compositions of claim 9, wherein said cyclodextrin is methyl-beta-schardinger dextrin-or 2-hydroxypropyl-beta-schardinger dextrin-.
11. the compositions of claim 9, wherein said cyclodextrin are 2-hydroxypropyl-beta-schardinger dextrin-.
12. the compositions of the aqueous solution form of claim 1, described compositions comprise a) the treatment effective dose as each defined formula I chemical compound in the claim 1 to 6, its concentration in the scope of 0.1-30%w/v and b) the 2-hydroxypropyl-beta-schardinger dextrin-of concentration in the 5-75%w/v scope.
13. the compositions of claim 12, wherein said formula I compound concentrations is in the scope of 1-3%w/v.
14. the compositions of claim 12 or claim 13, wherein the concentration of 2-hydroxypropyl-beta-schardinger dextrin-is in the scope of 30-40%w/v.
15. each compositions in the aforementioned claim, said composition is by orally using.
16. each compositions in the claim 12 to 14, said composition is used for venoclysis.
17. each compositions comprises among the mankind animal and suppresses epilepsy and/or sacred disease such as epilepsy and/or make the purposes that avoids such as in apoplexy, brain injury, head injury and the hemorrhage disease as neuroprotective in the aforementioned claim.
18. the purposes of each compositions in treatment and prevention of migraine in the aforementioned claim.
Applications Claiming Priority (2)
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GBGB9906126.9A GB9906126D0 (en) | 1999-03-18 | 1999-03-18 | Pharmaceutical formulations |
GB9906126.9 | 1999-03-18 |
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Family
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CN00807523A Pending CN1350456A (en) | 1999-03-18 | 2000-03-06 | Pharmaceutical compositions comprising a pyrimidine derivative and cyclodextrin |
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EP (1) | EP1161243A2 (en) |
JP (1) | JP2002539261A (en) |
CN (1) | CN1350456A (en) |
AU (1) | AU3286700A (en) |
CA (1) | CA2367040A1 (en) |
GB (1) | GB9906126D0 (en) |
MX (1) | MXPA01009384A (en) |
WO (1) | WO2000056336A2 (en) |
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US11821118B2 (en) | 2018-03-23 | 2023-11-21 | Bast Fibre Technologies Inc. | Nonwoven fabric comprised of crimped bast fibers |
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GB9906130D0 (en) * | 1999-03-18 | 1999-05-12 | Knoll Ag | Compounds for use in therapy |
GB9914743D0 (en) * | 1999-06-24 | 1999-08-25 | Knoll Ag | Therapeutic agents |
CN113874377A (en) | 2019-05-13 | 2021-12-31 | 埃科莱布美国股份有限公司 | 1,2, 4-triazolo [1,5-a ] pyrimidine derivatives as copper corrosion inhibitors |
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DE3346123A1 (en) * | 1983-12-21 | 1985-06-27 | Janssen Pharmaceutica, N.V., Beerse | PHARMACEUTICAL PREPARATIONS OF SUBSTANCES MEDICAL OR UNSTABLE IN WATER AND METHOD FOR THE PRODUCTION THEREOF |
GB9321162D0 (en) * | 1993-10-13 | 1993-12-01 | Boots Co Plc | Therapeutic agents |
-
1999
- 1999-03-18 GB GBGB9906126.9A patent/GB9906126D0/en not_active Ceased
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2000
- 2000-03-06 JP JP2000606241A patent/JP2002539261A/en not_active Withdrawn
- 2000-03-06 EP EP00910780A patent/EP1161243A2/en not_active Withdrawn
- 2000-03-06 MX MXPA01009384A patent/MXPA01009384A/en unknown
- 2000-03-06 WO PCT/EP2000/001940 patent/WO2000056336A2/en not_active Application Discontinuation
- 2000-03-06 AU AU32867/00A patent/AU3286700A/en not_active Abandoned
- 2000-03-06 CN CN00807523A patent/CN1350456A/en active Pending
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US11821118B2 (en) | 2018-03-23 | 2023-11-21 | Bast Fibre Technologies Inc. | Nonwoven fabric comprised of crimped bast fibers |
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CA2367040A1 (en) | 2000-09-28 |
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AU3286700A (en) | 2000-10-09 |
EP1161243A2 (en) | 2001-12-12 |
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