CA2367040A1 - Pharmaceutical compositions comprising a pyrimidine derivative and cyclodextrin - Google Patents
Pharmaceutical compositions comprising a pyrimidine derivative and cyclodextrin Download PDFInfo
- Publication number
- CA2367040A1 CA2367040A1 CA002367040A CA2367040A CA2367040A1 CA 2367040 A1 CA2367040 A1 CA 2367040A1 CA 002367040 A CA002367040 A CA 002367040A CA 2367040 A CA2367040 A CA 2367040A CA 2367040 A1 CA2367040 A1 CA 2367040A1
- Authority
- CA
- Canada
- Prior art keywords
- triazolo
- ethyl
- pyrimidine
- cyclodextrin
- composition according
- 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.)
- Abandoned
Links
- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 74
- 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 29
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 18
- 150000003230 pyrimidines Chemical class 0.000 title 1
- 239000000203 mixture Substances 0.000 claims abstract description 87
- -1 racemates Chemical class 0.000 claims abstract description 41
- 241001465754 Metazoa Species 0.000 claims abstract description 23
- 238000011282 treatment Methods 0.000 claims abstract description 22
- 208000006011 Stroke Diseases 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 206010010904 Convulsion Diseases 0.000 claims abstract description 11
- 208000012902 Nervous system disease Diseases 0.000 claims abstract description 10
- 208000025966 Neurological disease Diseases 0.000 claims abstract description 10
- 206010015037 epilepsy Diseases 0.000 claims abstract description 9
- 241000282414 Homo sapiens Species 0.000 claims abstract description 8
- 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 claims abstract description 6
- 239000004090 neuroprotective agent Substances 0.000 claims abstract description 6
- 208000019695 Migraine disease Diseases 0.000 claims abstract description 5
- 206010027599 migraine Diseases 0.000 claims abstract description 5
- 206010019196 Head injury Diseases 0.000 claims abstract description 4
- 208000032843 Hemorrhage Diseases 0.000 claims abstract description 4
- 208000030886 Traumatic Brain injury Diseases 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 73
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- FCEPUTGEUCVRRI-UHFFFAOYSA-N 7-[1-(4-chlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C=1C=NC2=NC=NN2C=1C(C)OC1=CC=C(Cl)C=C1 FCEPUTGEUCVRRI-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- FCEPUTGEUCVRRI-SECBINFHSA-N 7-[(1r)-1-(4-chlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound O([C@H](C)C=1N2N=CN=C2N=CC=1)C1=CC=C(Cl)C=C1 FCEPUTGEUCVRRI-SECBINFHSA-N 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 238000001802 infusion Methods 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 5
- CJEBZUWYGIVECV-UHFFFAOYSA-N 7-[1-(4-chlorophenoxy)ethyl]-1h-[1,2,4]triazolo[1,5-a]pyrimidin-5-one Chemical compound C=1C(=O)N=C2N=CNN2C=1C(C)OC1=CC=C(Cl)C=C1 CJEBZUWYGIVECV-UHFFFAOYSA-N 0.000 claims description 4
- 238000001990 intravenous administration Methods 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 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
- UAKRICMNLSRISL-UHFFFAOYSA-N 1-[4-[1-([1,2,4]triazolo[1,5-a]pyrimidin-7-yl)ethoxy]phenyl]ethanone Chemical compound C=1C=NC2=NC=NN2C=1C(C)OC1=CC=C(C(C)=O)C=C1 UAKRICMNLSRISL-UHFFFAOYSA-N 0.000 claims description 2
- BEWOAZYLVJYVMO-UHFFFAOYSA-N 4-[1-([1,2,4]triazolo[1,5-a]pyrimidin-7-yl)ethoxy]benzonitrile Chemical compound C=1C=NC2=NC=NN2C=1C(C)OC1=CC=C(C#N)C=C1 BEWOAZYLVJYVMO-UHFFFAOYSA-N 0.000 claims description 2
- AONXGEYUTVOOOO-UHFFFAOYSA-N 7-[(4-chlorophenoxy)methyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C1=CC(Cl)=CC=C1OCC1=CC=NC2=NC=NN12 AONXGEYUTVOOOO-UHFFFAOYSA-N 0.000 claims description 2
- KZXQJKAJKRZZDK-UHFFFAOYSA-N 7-[1-(2,4-difluorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C=1C=NC2=NC=NN2C=1C(C)OC1=CC=C(F)C=C1F KZXQJKAJKRZZDK-UHFFFAOYSA-N 0.000 claims description 2
- KNFQKACFWUSMOB-UHFFFAOYSA-N 7-[1-(2-chloro-4-fluorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C=1C=NC2=NC=NN2C=1C(C)OC1=CC=C(F)C=C1Cl KNFQKACFWUSMOB-UHFFFAOYSA-N 0.000 claims description 2
- HDLHXYFXJHGDOR-UHFFFAOYSA-N 7-[1-(3,4-dichlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C=1C=NC2=NC=NN2C=1C(C)OC1=CC=C(Cl)C(Cl)=C1 HDLHXYFXJHGDOR-UHFFFAOYSA-N 0.000 claims description 2
- ZRVJOPMTANXDOX-UHFFFAOYSA-N 7-[1-(3-chlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C=1C=NC2=NC=NN2C=1C(C)OC1=CC=CC(Cl)=C1 ZRVJOPMTANXDOX-UHFFFAOYSA-N 0.000 claims description 2
- DDCKRPUTULJVPC-UHFFFAOYSA-N 7-[1-(4-bromophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C=1C=NC2=NC=NN2C=1C(C)OC1=CC=C(Br)C=C1 DDCKRPUTULJVPC-UHFFFAOYSA-N 0.000 claims description 2
- KFSMQDIGWKNFBO-UHFFFAOYSA-N 7-[1-(4-chlorophenoxy)ethyl]-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C=1C=NC2=NC(C)=NN2C=1C(C)OC1=CC=C(Cl)C=C1 KFSMQDIGWKNFBO-UHFFFAOYSA-N 0.000 claims description 2
- VFMPGXYNNSGZBT-UHFFFAOYSA-N 7-[1-(4-chlorophenoxy)propyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C=1C=NC2=NC=NN2C=1C(CC)OC1=CC=C(Cl)C=C1 VFMPGXYNNSGZBT-UHFFFAOYSA-N 0.000 claims description 2
- JCGNIAAPBYXVEH-UHFFFAOYSA-N 7-[1-(4-ethylsulfanylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C1=CC(SCC)=CC=C1OC(C)C1=CC=NC2=NC=NN12 JCGNIAAPBYXVEH-UHFFFAOYSA-N 0.000 claims description 2
- ZGJNYZAHWGQJCU-UHFFFAOYSA-N 7-[1-(4-methoxyphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C1=CC(OC)=CC=C1OC(C)C1=CC=NC2=NC=NN12 ZGJNYZAHWGQJCU-UHFFFAOYSA-N 0.000 claims description 2
- DAMUBRAZMMOTHY-UHFFFAOYSA-N 7-[1-(4-methylsulfanylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C1=CC(SC)=CC=C1OC(C)C1=CC=NC2=NC=NN12 DAMUBRAZMMOTHY-UHFFFAOYSA-N 0.000 claims description 2
- XOCCGFZIVGVNDL-UHFFFAOYSA-N 7-[1-(4-methylsulfinylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C=1C=NC2=NC=NN2C=1C(C)OC1=CC=C(S(C)=O)C=C1 XOCCGFZIVGVNDL-UHFFFAOYSA-N 0.000 claims description 2
- QOAYBGGYBZKPPA-UHFFFAOYSA-N 7-[1-(4-methylsulfonylphenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C=1C=NC2=NC=NN2C=1C(C)OC1=CC=C(S(C)(=O)=O)C=C1 QOAYBGGYBZKPPA-UHFFFAOYSA-N 0.000 claims description 2
- XAJABHCRHXABGJ-UHFFFAOYSA-N 7-[1-[4-(trifluoromethoxy)phenoxy]ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C=1C=NC2=NC=NN2C=1C(C)OC1=CC=C(OC(F)(F)F)C=C1 XAJABHCRHXABGJ-UHFFFAOYSA-N 0.000 claims description 2
- AOPCMPFQNOFJOG-UHFFFAOYSA-N 7-[1-[4-(trifluoromethyl)phenoxy]ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C=1C=NC2=NC=NN2C=1C(C)OC1=CC=C(C(F)(F)F)C=C1 AOPCMPFQNOFJOG-UHFFFAOYSA-N 0.000 claims description 2
- SCLBUULVTPJYGC-UHFFFAOYSA-N 7-[2-(4-chlorophenoxy)propan-2-yl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C=1C=NC2=NC=NN2C=1C(C)(C)OC1=CC=C(Cl)C=C1 SCLBUULVTPJYGC-UHFFFAOYSA-N 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
- 230000005764 inhibitory process Effects 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 6
- 125000001475 halogen functional group Chemical group 0.000 claims 5
- 229940031576 hydroxypropylbetadex (0.58-0.68 ms) Drugs 0.000 claims 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-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)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 WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims 2
- CWJSGPLPYFBOGX-UHFFFAOYSA-N 7-[1-(2,4-dichlorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C=1C=NC2=NC=NN2C=1C(C)OC1=CC=C(Cl)C=C1Cl CWJSGPLPYFBOGX-UHFFFAOYSA-N 0.000 claims 1
- VUJAOETYODJPOS-UHFFFAOYSA-N 7-[1-(4-fluorophenoxy)ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound C=1C=NC2=NC=NN2C=1C(C)OC1=CC=C(F)C=C1 VUJAOETYODJPOS-UHFFFAOYSA-N 0.000 claims 1
- 241001367053 Autographa gamma Species 0.000 claims 1
- 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 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- AFHQSQTUSWXNCL-UHFFFAOYSA-N pyrimidin-5-ol Chemical compound OC1=CN=CN=C1.OC1=CN=CN=C1 AFHQSQTUSWXNCL-UHFFFAOYSA-N 0.000 claims 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 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 15
- 210000003657 middle cerebral artery Anatomy 0.000 description 14
- 235000002639 sodium chloride Nutrition 0.000 description 14
- 230000006378 damage Effects 0.000 description 13
- 125000005843 halogen group Chemical group 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 230000003902 lesion Effects 0.000 description 7
- 239000006186 oral dosage form Substances 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- 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 5
- 241000700159 Rattus Species 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 229940097362 cyclodextrins Drugs 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 239000000843 powder 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
- 210000004556 brain Anatomy 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 230000000302 ischemic effect Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 239000005995 Aluminium silicate 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
- 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
- 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
- 235000012211 aluminium silicate Nutrition 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- 239000007894 caplet Substances 0.000 description 3
- 210000003710 cerebral cortex Anatomy 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 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
- 210000003205 muscle Anatomy 0.000 description 3
- 230000004112 neuroprotection Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011780 sodium chloride Substances 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
- 235000000346 sugar Nutrition 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 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
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-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
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920002907 Guar gum Polymers 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 235000019759 Maize starch Nutrition 0.000 description 2
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- 239000000047 product Substances 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- SZSKAHAHBFDQKN-UHFFFAOYSA-N pyrimidine-2-carboximidamide Chemical compound NC(=N)C1=NC=CC=N1 SZSKAHAHBFDQKN-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 238000007492 two-way ANOVA Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 210000000216 zygoma Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
A pharmaceutical composition comprising a) a 1,2,4-triazolo(1,5-a)pyrimidine derivative of formula (I) including pharmaceutically acceptable salts, 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.</SD OAB>
Description
CYCLODEXTRIN
The present invention relates to pharmaceutical compositions comprising a 1,2,4-triazolo[1,5-a]pyrimidine derivative and a cyclodextrin, and to their use in the treatment and/or prophylaxis of migraine, seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, head injuries and haemorrhage.
Cerebral ischaemia is a major cause of morbidity and mortality in the Western world, but drug therapy for this condition remains inadequate and prevention is still the most effective treatment (De Deyn, P.' P., De Reuck, J., Deberdt, W., Vlietinck, R., Orgogozo, J. M. (1997) Treatment of acute ischemic stroke with piracetam. Stroke, 28, 2347-2352.). Drugs which provide neuroprotection in stroke victims suffering progressing, rather than threatened ischaemic damage would have profound implications for the treatment of this disease.
Compounds of formula A
Rs R~
Rs N~N
~~-- R
~N
R N
The present invention relates to pharmaceutical compositions comprising a 1,2,4-triazolo[1,5-a]pyrimidine derivative and a cyclodextrin, and to their use in the treatment and/or prophylaxis of migraine, seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, head injuries and haemorrhage.
Cerebral ischaemia is a major cause of morbidity and mortality in the Western world, but drug therapy for this condition remains inadequate and prevention is still the most effective treatment (De Deyn, P.' P., De Reuck, J., Deberdt, W., Vlietinck, R., Orgogozo, J. M. (1997) Treatment of acute ischemic stroke with piracetam. Stroke, 28, 2347-2352.). Drugs which provide neuroprotection in stroke victims suffering progressing, rather than threatened ischaemic damage would have profound implications for the treatment of this disease.
Compounds of formula A
Rs R~
Rs N~N
~~-- R
~N
R N
in which:R~ represents H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C»alkyl, C»alkoxy or C~_salkanoyl;
R2 and R3 independently represent H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C~~alkyl, C~_salkoxy, C»alkanoyl, C~_salkylthio, C~_salkylsulphinyl, or C~~alkylsulphonyl ; R4 and independently represent H, C~_salkyl or R4 and R5 combined together with the carbon atom to which they are attached represent C3~cycloalkylidene (each alkyl or cycloalkylidene being optionally substituted with one or more of halo, cyano, hydroxy, amino or C~_6alkyl); and R6, R~ and R8 independently represent H, halo, hydroxy, mercapto, nitro, cyano or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino; and any nitrogen atom being optionally substituted with one or more C» alkyl): C~_6alkyl, C»alkanoyl, C~_salkoxy, C2_salkoxycarbonyl, carboxy, C~_fialkanoyioxy, C~_salkylthio, C~_salkylsulphinyl, C~_salkylsulphonyl, C~_salkyl-sulphonylamino, sulphamoyl, carbamoyl, C2 salkyl-carbamoyl or C~_salkanoylamino; processes for their preparation, and their use in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, head injuries and haemorrhage are described in W095/10521 (Knoll AG).
A
process for preparing these compounds is disclosed in W098/07724 (Knoll AG).
However, the compounds of formula A suffer from the disadvantages that they. are insoluble in water and have a short plasma half-life in humans after solid oral dosing. These findings would suggest that these compounds would be of limited use in the treatment of stroke. Surprisingly the present invention solves these problems and provides a potential method for the effective treatment of stroke.
The present invention provides a pharmaceutical composition comprising a) a compound of formula I
Rs R~
R
R4 C-Rs s I
N~N
~~--- R
~N
R N
z including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof in which:
R~ represents H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C~_salkyl, C~~alkoxy or C~_salkanoyl;
R2 and R3 independently represent H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C~~alkyl, C~_salkoxy, C»alkanoyl, C~_salkylthio, C~_salkylsulphinyl, or C~~alkylsulphonyl ; R4 and independently represent H, C~_salkyl or R4 and R5 combined together with the carbon atom to which they are attached represent C3~cycloalkylidene (each alkyl or cycloalkylidene being optionally substituted with one or more of halo, cyano, hydroxy, amino or C~_6alkyl); and R6, R~ and R8 independently represent H, halo, hydroxy, mercapto, nitro, cyano or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino; and any nitrogen atom being optionally substituted with one or more C» alkyl): C~_6alkyl, C»alkanoyl, C~_salkoxy, C2_salkoxycarbonyl, carboxy, C~_fialkanoyioxy, C~_salkylthio, C~_salkylsulphinyl, C~_salkylsulphonyl, C~_salkyl-sulphonylamino, sulphamoyl, carbamoyl, C2 salkyl-carbamoyl or C~_salkanoylamino; processes for their preparation, and their use in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, head injuries and haemorrhage are described in W095/10521 (Knoll AG).
A
process for preparing these compounds is disclosed in W098/07724 (Knoll AG).
However, the compounds of formula A suffer from the disadvantages that they. are insoluble in water and have a short plasma half-life in humans after solid oral dosing. These findings would suggest that these compounds would be of limited use in the treatment of stroke. Surprisingly the present invention solves these problems and provides a potential method for the effective treatment of stroke.
The present invention provides a pharmaceutical composition comprising a) a compound of formula I
Rs R~
R
R4 C-Rs s I
N~N
~~--- R
~N
R N
z including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof in which:
R~ represents H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C~_salkyl, C~~alkoxy or C~_salkanoyl;
R2 and R3 independently represent H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C~_salkyl, C~_salkoxy, C~_salkanoyl, C~_salkylthio, C~_6alkylsulphinyl, C~_salkylsulphonyl or hydroxy;
R4 and R5 independently represent H, C~_salkyl or R4 and R5 combined together with the carbon atom to which they are attached represent C3_6cycloalkylidene (each alkyl or cycloalkylidene being optionally substituted with one or more of halo, cyano, hydroxy, amino or C~_salkyl); and R6, R7 and R$ independently represent H, halo, hydroxy, mercapto, nitro, cyano or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino; and any nitrogen atom being optionally substituted with one or more C1_6 alkyl): C~_salkyl, C~_salkanoyl, C~_fialkoxy, CZ_salkoxycarbonyl, carboxy, C~_salkanoyloxy, C~_fialkylthio, C~_salkylsulphinyl, C~_salkylsulphonyl, C~_salkyl-sulphonylamino, sulphamoyl, carbamoyl, C2_6alkylcarbamoyl or C~_salkanoylamino;
and b) a cyclodextrin.
It will be understood that any group mentioned herein which contains a chain of three or more carbon atoms signifies a group in which the chain may be straight or branched. For example, an alkyl group may comprise propyl which includes n-propyl and isopropyl and butyl which includes n-butyl, sec-butyl, isobutyl and tert-butyl. The total number of carbon atoms is specified herein for certain substituents, for example C,_s signifies an alkyl group having from 1 to 6 carbon atoms. The term ' halo' as used herein signifies fluoro, chloro, bromo and iodo. The term 'optionally substituted' as used herein, unless immediately followed by a list of substituent groups, means optionally substituted with one or more group or groups selected from halo, cyano, hydroxy and amino. When the phenyl ring substituents R6, R~ and Re are other than H, the substituent may replace any H attached to a carbon atom in the ring and may be located at any such position of the ring, ie up to three of positions 2, 3, 4 andlor 5.
Suitably the composition is a mixture of the compound of formula I and a cyclodextrin. Preferably the composition comprises a complex of the compound of formula I and the cyclodextrin. Suitably the ratio of the compound of formula I to the cyclodextrin in the complex is in the range from 0.1-1 to 1-0.1.
Suitably the complex may be prepared by forming a mixture of the compound of formula I or a pharmaceutically acceptable salt thereof and the cyclodextrin and water at a temperature in the range of 10-100°C to form a suspension or a solution and to then remove the water by a technique such as spray granulation, spray drying, drum drying or freeze drying. Spray drying is preferred as this may produce a free-flowing granular solid. Fluid bed spray drying is particularly preferred.
A mixture of the compound of formula I with a cyclodextrin or the complex of the compound of formula I with a cyclodextrin may be formulated into any of the well-known solid pharmaceutical formulations, for example tablets, capsules, granules, powders, etc. The compositions may be formulated with an effervescent couple, a buffer system, sweetners, flavourings, colours, etc. and diluents are carriers such as water soluble saccharides, such as dextrose, lactose or sucrose.
In therapeutic use, the compositions of the present invention may be formulated into pharmaceutical compositions for oral, rectal or parenteral administration. Thus the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration. The compositions may be formulated in a manner known to those skilled in the art, to give a controlled release, for example rapid release or sustained release, of the active compound. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The compositions may contain from about 0.1 % to about 99% by weight of active compound and are generally prepared in unit dosage form. Preferably the unit dosage of active ingredient is from about 1 mg to about 1000 mg, more preferably from about 1 mg to about 500 mg. The excipients used in the preparation of these compositions are the excipients known in the pharmacist's art.
Preferably the compositions of the invention are administered orally in the known pharmaceutical forms for such administration. Dosage forms suitable for oral administration may comprise tablets, pills, capsules, caplets, multiparticulates including: granules, beads, pellets and micro-encapsulated particles; powders, elixirs, syrups, suspensions and solutions.
Solid oral dosage forms, for example tablets, may be prepared by mixing the 5 pharmaceutical composition of the present invention with one or more of the following ingredients or mixtures thereof:
inert diluents, for example calcium carbonate, calcium sulphate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactose, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc and tribasic calcium phosphate;
disintegrating agents, for example alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate, starch including maize starch and agar;
lubricating agents, for example calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc and zinc stearate;
binders, for example acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, magnesium aluminium silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, starch including maize starch, zein, sugars (such as sucrose, molasses and lactose), and natural and synthetic gums (such as extract of Irish moss, polyethylene glycol, waxes, microcrystalline cellulose and polyvinylpyrrolidone);
colouring agents, for example conventional pharmaceutically acceptable dyes;
sweetening and flavouring agents;
preservatives;
R4 and R5 independently represent H, C~_salkyl or R4 and R5 combined together with the carbon atom to which they are attached represent C3_6cycloalkylidene (each alkyl or cycloalkylidene being optionally substituted with one or more of halo, cyano, hydroxy, amino or C~_salkyl); and R6, R7 and R$ independently represent H, halo, hydroxy, mercapto, nitro, cyano or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino; and any nitrogen atom being optionally substituted with one or more C1_6 alkyl): C~_salkyl, C~_salkanoyl, C~_fialkoxy, CZ_salkoxycarbonyl, carboxy, C~_salkanoyloxy, C~_fialkylthio, C~_salkylsulphinyl, C~_salkylsulphonyl, C~_salkyl-sulphonylamino, sulphamoyl, carbamoyl, C2_6alkylcarbamoyl or C~_salkanoylamino;
and b) a cyclodextrin.
It will be understood that any group mentioned herein which contains a chain of three or more carbon atoms signifies a group in which the chain may be straight or branched. For example, an alkyl group may comprise propyl which includes n-propyl and isopropyl and butyl which includes n-butyl, sec-butyl, isobutyl and tert-butyl. The total number of carbon atoms is specified herein for certain substituents, for example C,_s signifies an alkyl group having from 1 to 6 carbon atoms. The term ' halo' as used herein signifies fluoro, chloro, bromo and iodo. The term 'optionally substituted' as used herein, unless immediately followed by a list of substituent groups, means optionally substituted with one or more group or groups selected from halo, cyano, hydroxy and amino. When the phenyl ring substituents R6, R~ and Re are other than H, the substituent may replace any H attached to a carbon atom in the ring and may be located at any such position of the ring, ie up to three of positions 2, 3, 4 andlor 5.
Suitably the composition is a mixture of the compound of formula I and a cyclodextrin. Preferably the composition comprises a complex of the compound of formula I and the cyclodextrin. Suitably the ratio of the compound of formula I to the cyclodextrin in the complex is in the range from 0.1-1 to 1-0.1.
Suitably the complex may be prepared by forming a mixture of the compound of formula I or a pharmaceutically acceptable salt thereof and the cyclodextrin and water at a temperature in the range of 10-100°C to form a suspension or a solution and to then remove the water by a technique such as spray granulation, spray drying, drum drying or freeze drying. Spray drying is preferred as this may produce a free-flowing granular solid. Fluid bed spray drying is particularly preferred.
A mixture of the compound of formula I with a cyclodextrin or the complex of the compound of formula I with a cyclodextrin may be formulated into any of the well-known solid pharmaceutical formulations, for example tablets, capsules, granules, powders, etc. The compositions may be formulated with an effervescent couple, a buffer system, sweetners, flavourings, colours, etc. and diluents are carriers such as water soluble saccharides, such as dextrose, lactose or sucrose.
In therapeutic use, the compositions of the present invention may be formulated into pharmaceutical compositions for oral, rectal or parenteral administration. Thus the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration. The compositions may be formulated in a manner known to those skilled in the art, to give a controlled release, for example rapid release or sustained release, of the active compound. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The compositions may contain from about 0.1 % to about 99% by weight of active compound and are generally prepared in unit dosage form. Preferably the unit dosage of active ingredient is from about 1 mg to about 1000 mg, more preferably from about 1 mg to about 500 mg. The excipients used in the preparation of these compositions are the excipients known in the pharmacist's art.
Preferably the compositions of the invention are administered orally in the known pharmaceutical forms for such administration. Dosage forms suitable for oral administration may comprise tablets, pills, capsules, caplets, multiparticulates including: granules, beads, pellets and micro-encapsulated particles; powders, elixirs, syrups, suspensions and solutions.
Solid oral dosage forms, for example tablets, may be prepared by mixing the 5 pharmaceutical composition of the present invention with one or more of the following ingredients or mixtures thereof:
inert diluents, for example calcium carbonate, calcium sulphate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactose, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc and tribasic calcium phosphate;
disintegrating agents, for example alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate, starch including maize starch and agar;
lubricating agents, for example calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc and zinc stearate;
binders, for example acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, magnesium aluminium silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, starch including maize starch, zein, sugars (such as sucrose, molasses and lactose), and natural and synthetic gums (such as extract of Irish moss, polyethylene glycol, waxes, microcrystalline cellulose and polyvinylpyrrolidone);
colouring agents, for example conventional pharmaceutically acceptable dyes;
sweetening and flavouring agents;
preservatives;
one or more pharmaceutically acceptable couple or couples (such as those comprising an acid and a carbonate or bicarbonate salt), which effervesces to aid dissolution when the solid dosage form is added to water; and other optional ingredients known in the art to permit production of oral dosage forms by known methods such as tabletting.
Solid oral dosage forms may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Film coated, solid oral dosage forms comprising compositions of the invention may be advantageous, depending on the nature of the active compound.
Various materials, for example shellac and/or sugar, may be present as coatings, or to otherwise modify the physical form of the oral dosage form. For example tablets or pills may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate and/or hydroxy propyl methylcellulose phthalate.
Capsules or caplets (for example hard or soft gelatin capsules) comprising the composition of the present invention (with or without added excipients such as a fatty oil), may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner. The contents of the capsule or caplet may be formulated using known methods to give sustained release of the active compound.
A particularly preferred oral liquid dosage form is a pharmaceutical formulation which is an aqueous solution comprising a therapeutically effective amount of a compound of formula I including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof as defined above and an amount of cyclodextrin which is sufficient to cause the dissolution of the compound of formula I. Preferably the cyclodextrin is a (3-cyclodextrin.
Liquid oral dosage forms may also comprise one or more sweetening agent, flavouring agent, preservatives and mixtures thereof.
The compositions of the present invention may be formulated into granules or powders with or without additional excipients. The granules or powders may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example water) before ingestion. The granules or powders may contain disintegrants (for example a pharmaceutically acceptable effervescent couple formed from an acid and a carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium.
Preferably each of the above oral dosage forms may contain from about 1 mg to about 500 mg (for example 10 mg, 50 mg, 100 mg, 200 mg, 400 mg or 500 mg) of the active compound.
Compositions of the invention may be administered rectally in the known pharmaceutical forms for such administration, for example, suppositories with hard fat, semi-synthetic glyceride, cocoa butter or polyethylene glycol bases.
Compositions of the invention may also be administered parenterally, for example by intravenous injection, in the known pharmaceutical forms for such administration, for example sterile solutions in a suitable solvent.
The compositions of the invention may also be administered by continuous infusion either from an external source (for example by intravenous infusion) or from a source of the compound placed within the body. Internal sources include implanted reservoirs containing the compound to be infused which is continuously released (for example by osmosis) or implants. The amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.
A particularly preferred embodiment of the invention for parenteral administration, especially intravenous injection, is a pharmaceutical formulation which is an aqueous solution comprising a therapeutically effective amount of a compound of formula I including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof as defined above and an amount of cyclodextrin which is sufficient to cause the dissolution of the compound of formula I.
Solid oral dosage forms may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Film coated, solid oral dosage forms comprising compositions of the invention may be advantageous, depending on the nature of the active compound.
Various materials, for example shellac and/or sugar, may be present as coatings, or to otherwise modify the physical form of the oral dosage form. For example tablets or pills may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate and/or hydroxy propyl methylcellulose phthalate.
Capsules or caplets (for example hard or soft gelatin capsules) comprising the composition of the present invention (with or without added excipients such as a fatty oil), may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner. The contents of the capsule or caplet may be formulated using known methods to give sustained release of the active compound.
A particularly preferred oral liquid dosage form is a pharmaceutical formulation which is an aqueous solution comprising a therapeutically effective amount of a compound of formula I including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof as defined above and an amount of cyclodextrin which is sufficient to cause the dissolution of the compound of formula I. Preferably the cyclodextrin is a (3-cyclodextrin.
Liquid oral dosage forms may also comprise one or more sweetening agent, flavouring agent, preservatives and mixtures thereof.
The compositions of the present invention may be formulated into granules or powders with or without additional excipients. The granules or powders may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example water) before ingestion. The granules or powders may contain disintegrants (for example a pharmaceutically acceptable effervescent couple formed from an acid and a carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium.
Preferably each of the above oral dosage forms may contain from about 1 mg to about 500 mg (for example 10 mg, 50 mg, 100 mg, 200 mg, 400 mg or 500 mg) of the active compound.
Compositions of the invention may be administered rectally in the known pharmaceutical forms for such administration, for example, suppositories with hard fat, semi-synthetic glyceride, cocoa butter or polyethylene glycol bases.
Compositions of the invention may also be administered parenterally, for example by intravenous injection, in the known pharmaceutical forms for such administration, for example sterile solutions in a suitable solvent.
The compositions of the invention may also be administered by continuous infusion either from an external source (for example by intravenous infusion) or from a source of the compound placed within the body. Internal sources include implanted reservoirs containing the compound to be infused which is continuously released (for example by osmosis) or implants. The amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.
A particularly preferred embodiment of the invention for parenteral administration, especially intravenous injection, is a pharmaceutical formulation which is an aqueous solution comprising a therapeutically effective amount of a compound of formula I including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof as defined above and an amount of cyclodextrin which is sufficient to cause the dissolution of the compound of formula I.
In some compositions it may be beneficial to use the active compound in the form of particles of very small size, for example as obtained by fluid energy milling.
In the above compositions the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
The compositions of the present invention are indicated for use as neuroprotective agents to protect against conditions such as stroke, and for the treatment of seizures and neurological disorders such as epilepsy. The therapeutic activity of the compositions has been demonstrated by means of various in vivo pharmacological tests in standard laboratory animals.
Accordingly, a further aspect of the present invention provides a method of treating seizures and/or neurological disorders such as epilepsy and/or a method of neuroprotection to protect against conditions such as stroke, in animals including human beings, which comprises the administration to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition containing a therapeutically effective amount of the active compound of a compound of formula I
and a cyclodextrin. Thus the compositions of the present invention are useful for the inhibition of seizures and/or neurological disorders such as epilepsy and/or as neuroprotective agents to protect against conditions such as stroke, in animals including human beings. The compositions of the present invention are also useful in the treatment and prevention of migraine.
Whilst the precise amount of the active compound administered in the treatments outlined above will depend on a number of factors, for example the severity of the condition, the age and past medical history of the patient, and always lies within the sound discretion of the administering pharmacist, physician or veterinary a suitable daily dose of the active compound for administration to human beings, is generally from about 1 mg to about 5000 mg, more usually from about 5 mg to about 1000 mg, given in a single dose or in divided doses at one or more times during the day. Oral administration or intravenous infusion is preferred.
In the above compositions the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
The compositions of the present invention are indicated for use as neuroprotective agents to protect against conditions such as stroke, and for the treatment of seizures and neurological disorders such as epilepsy. The therapeutic activity of the compositions has been demonstrated by means of various in vivo pharmacological tests in standard laboratory animals.
Accordingly, a further aspect of the present invention provides a method of treating seizures and/or neurological disorders such as epilepsy and/or a method of neuroprotection to protect against conditions such as stroke, in animals including human beings, which comprises the administration to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition containing a therapeutically effective amount of the active compound of a compound of formula I
and a cyclodextrin. Thus the compositions of the present invention are useful for the inhibition of seizures and/or neurological disorders such as epilepsy and/or as neuroprotective agents to protect against conditions such as stroke, in animals including human beings. The compositions of the present invention are also useful in the treatment and prevention of migraine.
Whilst the precise amount of the active compound administered in the treatments outlined above will depend on a number of factors, for example the severity of the condition, the age and past medical history of the patient, and always lies within the sound discretion of the administering pharmacist, physician or veterinary a suitable daily dose of the active compound for administration to human beings, is generally from about 1 mg to about 5000 mg, more usually from about 5 mg to about 1000 mg, given in a single dose or in divided doses at one or more times during the day. Oral administration or intravenous infusion is preferred.
The compositions of the present invention may be used in adjunctive therapy with one or more other compound or compounds having activity in the treatment of seizures and/or neurological disorders such as epilepsy and/or as neuroprotective agents to protect against conditions such as stroke, and in the treatment and prevention of migraine in animals including human beings. It will be appreciated that the term therapy as used herein includes prophylactic use of the active compound and pharmaceutical ~ composition or compositions comprising a therapeutically effective amount of the active compound, for example to prevent the onset of neurological disorders such as epileptic seizures, or as neuroprotective agents to protect against conditions such as stroke, in animals including human beings.
The active compound and/or a pharmaceutical composition or compositions comprising a therapeutically effective amount of the active compound may be used to provide a local and/or systemic therapeutic effect.
A still further aspect of the present invention provides use of the compositions of the present invention in the preparation of a medicament for the treatment of seizures and/or neurological disorders such as epilepsy and/or for neuroprotection to protect against conditions such as stroke and/or the treatment and prevention of stroke, in animals including human beings.
Specific compounds of formula I are:-7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo(1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo(1,5-a]pyrimidine;
7-[1-(4-bromophenoxy)ethyl]-1,2,4-triazolo(1,5-a]pyrimidine;
7-[1-(4-cyanophenoxy)ethyl]-1,2,4-triazolo[1, 5-a]pyrimidine;
7-[1-(4-trifluoromethylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-methoxyphenoxy)ethyl]-1,2,4-triazolo(1, 5-a]pyrimidine;
7-[1-(4-trifluoromethoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-acetylphenoxy)ethyl]-1,2,4-triazolo(1, 5-a]pyrimidine;
7-{1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-methylsulphinylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-methylsulphonylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
5 7-{1-[4-(ethylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(3-chlorophenoxy)ethyl]-1,2,4-triazolo[1, 5-a]pyrimidine;
7-(1-(2,4-difluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(2,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1; 5-a]pyrimidine;
7-[1-(3,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(2-chloro-4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)ethyl]-2-methyl-1,2,4-triazolo[1,5-a]pyrimidine;
7-(4-chlorophenoxymethyl)-1,2,4-triazolo[1,5-a]pyrimidine;
7-(1-(4-chlorophenoxy)-1-methylethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)propyl]-1,2,4-triazolo[1,5-a]pyrimidine; and 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of their stereoisomers; and pharmaceutically acceptable salts thereof.
Specific examples of the stereoisomers of compounds of formula I are:-(+)-7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
(-)-7-[1-(4-fluorophenoxy)ethyl]-1, 2,4-triazolo(1, 5-a]pyrimidine (+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
(-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
(+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol; and (-)-7-[ 1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol;
and pharmaceutically acceptable salts thereof.
Preferred compound of formula I are 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo(1,5-a]-pyrimidin-5-of including the racemates, enantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof. More preferred compounds of formula I
are (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and (S)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and pharmaceutically acceptable salts thereof. A most preferred compound of formula I is (R)-7-[1-(4-chloro-phenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and pharmaceutically acceptable salts thereof. The free base of (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine has a negative optical rotation.
The compounds of formula I may be prepared as described in W095/10521 (Knoll AG) and W098/07724 (Knoll AG).
Suitably the cyclodextrin is selected from an a-cyclodextrin, (3-cyclodextrin or a y-cyclodextrin. Suitable (3-cyclodextrins include (3-cyclodextrin, methyl-R-cyclodextrin, 2-hydroxyethyl-~i-cyclodextrin, 2-hydroxypropyl-[3-cyclodextrin, 3-hydroxypropyl-(3-cyclodextrin, 2,3-dihydroxypropyl-(3-cyclodextrin, trimethyl-(3-cyclodextrin, 6-O-a-D-glucosyl-[3-cyclodextrin, 6-O-a-D-maltosyl-[i-cyclodextrin, dimaltosyl-~-cyclodextrin, diglucosyl-[3-cyclodextrin, maltotriosyl-~i-cyclodextrin, carboxymethyl-(3-cyclodextrin, carboxyethyl-(3-cyclodextrin, heptakis-(2,6-di-O-methyl)- (3-cyclodextrin, heptakis-(2,3,6-tri-O-methyl)- (3-cyclodextrin, (3-cyclodextrin sulphobutyl ether (described in US 5,376,645 and US 5,134,127). Suitable y-cyclodextrins include 2-hydroxypropyl-y-cyclodextrin. Preferably the cyclodextrin is a (3-cyclodextrin. More preferably the cyclodextrin is methyl-(3-cyclodextrin or 2-hydroxypropyl-(3-cyclodextrin. Most preferably the cyclodextrin is 2-hydroxypropyl-(3-cyclodextrin.
A preferred embodiment of the present invention is a pharmaceutical composition in the form of an aqueous solution comprising a) a therapeutically effective amount of a compound of formula I as defined above and b) a (3-cyclodextrin.
Surprisingly a composition comprising a compound of formula I, and in particular (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine, and 2-hydroxypropyl-(3-cyclodextrin is particularly advantageous as a result of increased solubility and reduced adverse toxicity compared to compositions containing other cyclodextrins. Such compositions provide aqueous solutions which may be administered by intravenous injection or by continuous infusion to patients suffering from stroke. Such compositions may provide a major advance in the treatment of stroke where rapid treatment is essential. These compositions may be considered to be a particular selection from the possible combinations of the compounds of formula I with cyclodextrins with unexpected advantageous properties not shared by the other possible combinations.
A more preferred embodiment of the present invention is a pharmaceutical composition in the form of an aqueous solution comprising a) a therapeutically effective amount of a compound of formula I as defined above and b) 2-hydroxypropyl-[i-cyclodextrin.
A most preferred embodiment of the present invention is a pharmaceutical composition in the form of an aqueous solution comprising a) a therapeutically effective amount of a compound of formula I as defined above at a concentration in the range of 0.1-30% w/v and b) 2-hydroxypropyl-[3-cyclodextrin at a concentration in range of 5-75% w/v. It will be understood that the remainder of the composition is normally water to 100% but that additional pharmaceutically acceptable additives, for example preservatives, anti-oxidants, anti-microbials, flavourings etc. may also be present at levels known to those skilled in the art. Preferably the compound of formula I is present at a concentration in the range of 1-30% w/v, for example 10-20% w/v and 12-18% w/v, more preferably at a concentration in the range of 0.5-5% w/v and most preferably at a concentration in the range of 1-3% w/v.
Preferably the concentration of 2-hydroxypropyl-(3-cyclodextrin is in the range of 20-50% w/v and more preferably is in the range of 30-40% w/v.
An especially preferred embodiment of the present invention is a pharmaceutical composition in the form of an aqueous solution comprising:
a) (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine at a concen-tration in the range of 0.1-30% w/v and b) 2-hydroxypropyl-(3-cyclodextrin at a concentration in range of 5-75% w/v.
Preferably the concentration of (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo(1,5-a]pyrimidine is in the range of 1-30% w/v, for example 10-20% w/v and most preferably is in the range of 12-18% w/v, more preferably at a concentration in the range of 0.5-5% w/v and most preferably at a concentration in the range of 1-3% w/v.
Preferably the concentration of 2-hydroxypropyl-[i-cyclodextrin is in the range 20-50% w/v and more preferably is in the range 30-40% w/v.
1~0 The efficacy of the compositions of the present invention was demonstrated by the following study.
METHODS
i) Middle Cerebral Artery (MCA) occlusion Male Sprague-Dawley rats (300 - 350g) were anaesthetised with halothane in oxygen (1000 ml/min). Anaesthesia was induced with 5% (v/v) halothane and maintained using a face mask at a concentration of 2.25 - 2.5%. Body temperature of the animals was maintained at 37 t 0.5°C throughout the procedure using a thermostatically-controlled heated operating blanket. A scalp incision was made at the mid-point between the right eye and right ear. The temporalis muscle was separated in the plane of its fibre bundles and retracted to expose the zygoma and squamosal bones. Muscle and connective tissue was scraped from the bone to locate the drill point. Using microsurgical techniques, a craniotomy was made using a No. 5 round-head dental burr, rostral to the fusion point of the two cranial bones.
The skull was cooled by regular swabbing with sterile saline to avoid causing thermal injury to the cerebral cortex. The dura mater and pia-arachnoid membranes were incised with a 25 g hypodermic needle bent at the tip to form a hook and were gently pulled from the surface of the cortex with fine forceps. The exposed middle cerebral artery was electrocauterised using bipolar diathermy (GU Manufacturing Company, London) below the rhinal fissure and at a second point below the bifurcation of the artery into parietal and frontal cortical branches. Animals which haemorrhaged on occlusion of the MCA were discarded from the study. The MCA was severed at both points with a pair of micro-scissors to ensure separation of the vessel. Care was taken to avoid causing non-specific damage to the surface of the cerebral cortex.
Finally, the temporalis muscle and overlying skin were placed back into position and sutured. Following operation, animals were placed in cages on absorbent paper and allowed to regain consciousness under gentle warming from a red, 60 W light bulb.
After recovery, animals were grouped together (n = 4 - 6) in cages. The duration of the operation was 15 - 20 min and animals regained consciousness within another - 15 min after arterial occlusion.
10 ii) Drug preparation Two different cyclodextrin solutions (Research Biochemicals Inc.) were initially used for solubilisation of (-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine (hereinafter referred to as the test compound); 2-hydroxypropyl-[3-cyclodextrin and methyl-(3-cyclodextrin. The test compound was added to each cyclodextrin solution (35% w/v in water) and sonicated for 5 - 10 minutes in a sonicating water bath, avoiding warming of the solution. The compound was soluble to approximate concentrations of 15 mg/ml in the 2-hydroxypropyl-[3-cyclodextrin solution (that is from 0.1 to 15 mg/ml) and 40 mg/ml in methyl-[3-cyclodextrin. 2-Hydroxypropyl-[3-cyclodextrin was selected for the study as animals were unable to tolerate intraperitoneal injection of methyl-[i-cyclodextrin.
iii) Treatment of animals Two groups of animals were used; MCA occlusion plus test compound (n=11) and MCA occlusion plus vehicle (n=12). Animals were weighed immediately before MCA occlusion and after 6 days of recovery. The test compound was dissolved to a concentration of 15 mg/ml in 35% w/v 2-hydroxypropyl-(3-cyclodextrin in sterile saline by placing in a sonicating water bath. The pH of the vehicle and drug solutions was adjusted to 7.4 and they were stored at 4°C for the duration of the experiment. Sixty minutes after coagulation and severance of the MCA, the animals were injected intraperitoneally with 35 mg/kg of test compound or equivalent volume of vehicle.
The animals were dosed thereafter at 20 mg/kg at 12 hourly intervals for 36 hours.
iv) Histopathological assessment of ischaemic damage After 6 days of recovery, animals were anaesthetised with Sagatal (85 mg/kg 5 intraperitoneally; Rhone Merieux) and perfused traps-cardially with cold (4°C) phosphate-buffered saline (Oxoid) for 3 min, followed by cold 4% formaldehyde in phosphate-buffered saline (pH 7.4) for 15 min. The brains were removed and immersion-fixed for at least 48 hours at 4°C .
10 The brains were sectioned in the coronal plane at 250 Nm intervals and 30 pm thickness using a vibratome (General Scientific, Series 1000) and were stained with 0.2% toluidine blue. The extent of ischaemic damage was assessed in 13 planes at 500Nm intervals from +2.7 mm to -3.3 mm relative to bregma.
Slides were placed onto a slide illuminator (Carl Zeiss; 17.5x magnification) and areas of 15 damage were delineated onto stereotaxic brain maps. Lesion areas were measured using a SeeScan image analyser and lesion volumes calculated using computational analysis (GraphPad Prism). All sections were recoded and lesion sizes were measured by an operator unaware of treatment procedures.
v) Statistical analysis of data Histological damage assessment and changes in rat weights were analysed using two-way ANOVA. All data are quoted as mean t standard error of the mean.
RESULTS
Animals did not show gross neurological deficits, such as seizures or hemiparesis due to MCA occlusion and those treated with the test compound showed only mild sedation, particularly in the first 5 - 6 hours after the initial dosing.
Two rats out of a total of 25 were killed shortly after their recovery from the anaesthetic because of haemorrhaging due to incomplete sealing of the MCA by the electrocoagulator. None of the animals treated with either vehicle or the test compound died.
i) Histopathological damage after MCA occlusion Ischaemic injury in toluidine blue-stained brain sections was manifest as areas of pallor with sharply demarcated margins between healthy and damaged tissue. Damage from MCA occlusion was present mainly in the parietal, insular, frontal and forelimb cortical regions. Damage was also found in the outer region of the caudate-putamen. This was caused by secondary damage produced by compression, due to the presence of oedema in the cortex and corpus callosum.
This may be concluded as there is no arterial supply to the caudate-putamen distal to the occlusion site.
When assessed 6 days after the ischaemic insult, treatment of rats with test compound (60 min post-MCAO; 35 mg/kg ip + 20 mglkg x 3) resulted in a 40%
reduction of lesion volume when compared with animals given vehicle alone. The lesion volumes were 72.0 t 7.9 mm3 for vehicle treated rats and 43.6 ~ 4.9 mm3 for test compound-treated animals.
In a comparative study rats were treated with a suspension of the test compound (15 min post-MCAO; 50 mg/kg x 3) by oral gavage. The test compound provided a 31 % reduction of lesion volume (56.9 ~ 6.1 mm3) when compared with vehicle-treated controls (82.6 ~ 6.47 mm3).
These results demonstrate that the compositions of the present invention are advantageous over previously known compositions. In particular, solutions of the compounds of formula I are advantageous as they are more efficacious than suspensions, i.e. greater reduction in lesion volume, with lower doses and administered at a later time-point after MCA occlusion. Solution formulations according to the present invention are also likely to overcome the short half-life of the compounds of formula I in humans. Additionally such solution formulations can be administered by continuous intravenous infusion which is particularly beneficial in the treatment of stroke.
The invention is illustrated by the following Example which is given by way of example only. The final product of each of this Examples was characterised by the following procedures: gas-liquid chromatography; high performance liquid chromatography; elemental analysis; nuclear magnetic resonance spectroscopy and infrared spectroscopy.
Other compounds of the present invention are prepared as described in W095/10521 (Knoll AG) and W098/07724 (Knoll AG) which are incorporated herein by reference. Cyclodextrins are commercially available or may be prepared by methods disclosed in Chemical Reviews (1998) 98,1474-2076 and references cited therein.
Example 1 1 a) A mixture of 2-(4-chlorophenoxy)propionic acid (30.0 g) in toluene (300 ml) was added to a solution of thionyl chloride (22.0 ml) and dimethylformamide (2 ml) in toluene (150 ml) at 60-70°C with stirring. The mixture was stirred for 18 hours at 70-80°C and then evaporated under reduced pressure to give the acid chloride. A solution of Meldrum's acid (23.5 g) in dichloromethane (90 ml) was cooled to 0-5°C under nitrogen and pyridine (33 ml) was added at 0-5°C. To this mixture was added a solution of the acid chloride prepared above in dichloromethane (90 ml) dropwise keeping the temperature below 5°C. The mixture was stirred for 1 hour at 0-5°C and then at ambient temperature for 18 hours. The mixture was diluted with dichloromethane (150 ml) and washed with 2M hydrochloric acid and then with saturated sodium bicarbonate solution and then water. The bicarbonate washes were acidified with 5M hydrochloric acid and extracted into dichloromethane.
These dichloromethane extracts were combined with the original dichloromethane solution and dried and evaporated to give the crude intermediate Meldrum's acid derivative. This derivative was boiled under reflux with methanol (400 ml) for 6 hours and then left to stand at ambient temperature for 66 hours with methanolic hydrogen chloride solution (10 ml).
The mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated off, washed with saturated sodium bicarbonate solution, brine and then dried and evaporated under reduced pressure to give an oil which was distilled under high vacuum. The distillate was purified by flash column chromatography on silica using petroleum ether, b.p. 60-80°C I ethyl acetate 20:1 as the mobile phase to give methyl 4-(4-chlorophenoxy)-3-oxopentanoate as an oil.
b) Guanidine hydrochloride (1.87 g) was added with stirring to a solution of sodium (0.41 g) in ethanol (15 ml). The mixture was stirred for 15 minutes and then to this mixture was added a solution of methyl 4-(4-chlorophenoxy)-3-oxopentanoate (5.0 g) in ethanol (15 ml). The mixture was stirred and boiled under reflux for 16 hours. The mixture was cooled and then evaporated to dryness under reduced pressure to give a solid.
The solid was triturated with water (10 ml) containing glacial acetic acid (2 ml) and dichloromethane (20 ml) for 1 hour and then filtered. The residue obtained was washed with water (20 ml) and then with dichloromethane to give 2-amino-4-[1-(4-chlorophenoxy)ethyl-6-hydroxypyrimidine, m.p. 125°C.
c) A mixture of 2-amino-4-[1-(4-chlorophenoxy)ethyl-6-hydroxypyrimidine (0.5 g), dimethylformamide dimethyl acetal (0.5 ml) and toluene (5 ml) was stirred and boiled under reflux for 8 hours. The mixture was evaporated for 8 hours. The mixture was allowed to stand at ambient temperature for 24 hours and then evaporated to dryness under reduced pressure to give a solid which was triturated with ether and filtered to give the amidine as a solid.
d) Sodium hydride (62 mg of a 60% dispersion in mineral oil from which the mineral oil had been removed by washing with petrol) was dissolved in methanol (10 ml) and hydroxylamine hydrochloride (0.12 g) was added.
The mixture was stirred for 5 minutes and then added to the amidinopyrimidine (0.5 g) obtained in c). The mixture was stirred at ambient temperature for 72 hours and then evaporated to dryness under reduced pressure to give a residue which was washed with water and dried to give the formamidoxine.
e) The product from d) (5.0 g) and polyphosphoric acid (100 g) were stirred and heated on a steam bath for 4 hours. The mixture was allowed to cool to ambient temperature and then ice (100 g) and ethyl acetate (100 ml) were added. A solution of potassium carbonate (110 g) in water (total volume 100 ml) was added dropwise over 15 minutes to neutralise the mixture. The mixture was separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were dried and evaporated to give a solid which was purified by flash column chromatography on silica using dichloromethane / methanol (75:3) as the mobile phase to give 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol, m.p. 190°C.
Example 2 (-)-7-[1-(4-Chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine was prepared as described in W095/10521.
Solubility Determinations Example 1 Example 2 Water < 33 p.g/ml 125-170 p.g/ml 35% w/v methyl-(3-cyclodextrin2 mg/ml 40 mg/ml in water 35% w/v 2-hydroxypropyl-(3-cyclodextrin1 mg/ml 15 mglml in water 35% w/v 2-hydroxypropyl-y-cyclodextrin< 62 p.g/ml 6 mg/ml in water
The active compound and/or a pharmaceutical composition or compositions comprising a therapeutically effective amount of the active compound may be used to provide a local and/or systemic therapeutic effect.
A still further aspect of the present invention provides use of the compositions of the present invention in the preparation of a medicament for the treatment of seizures and/or neurological disorders such as epilepsy and/or for neuroprotection to protect against conditions such as stroke and/or the treatment and prevention of stroke, in animals including human beings.
Specific compounds of formula I are:-7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo(1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo(1,5-a]pyrimidine;
7-[1-(4-bromophenoxy)ethyl]-1,2,4-triazolo(1,5-a]pyrimidine;
7-[1-(4-cyanophenoxy)ethyl]-1,2,4-triazolo[1, 5-a]pyrimidine;
7-[1-(4-trifluoromethylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-methoxyphenoxy)ethyl]-1,2,4-triazolo(1, 5-a]pyrimidine;
7-[1-(4-trifluoromethoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-acetylphenoxy)ethyl]-1,2,4-triazolo(1, 5-a]pyrimidine;
7-{1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-methylsulphinylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-methylsulphonylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
5 7-{1-[4-(ethylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(3-chlorophenoxy)ethyl]-1,2,4-triazolo[1, 5-a]pyrimidine;
7-(1-(2,4-difluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(2,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1; 5-a]pyrimidine;
7-[1-(3,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(2-chloro-4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)ethyl]-2-methyl-1,2,4-triazolo[1,5-a]pyrimidine;
7-(4-chlorophenoxymethyl)-1,2,4-triazolo[1,5-a]pyrimidine;
7-(1-(4-chlorophenoxy)-1-methylethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)propyl]-1,2,4-triazolo[1,5-a]pyrimidine; and 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of their stereoisomers; and pharmaceutically acceptable salts thereof.
Specific examples of the stereoisomers of compounds of formula I are:-(+)-7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
(-)-7-[1-(4-fluorophenoxy)ethyl]-1, 2,4-triazolo(1, 5-a]pyrimidine (+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
(-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
(+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol; and (-)-7-[ 1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol;
and pharmaceutically acceptable salts thereof.
Preferred compound of formula I are 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo(1,5-a]-pyrimidin-5-of including the racemates, enantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof. More preferred compounds of formula I
are (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and (S)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and pharmaceutically acceptable salts thereof. A most preferred compound of formula I is (R)-7-[1-(4-chloro-phenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and pharmaceutically acceptable salts thereof. The free base of (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine has a negative optical rotation.
The compounds of formula I may be prepared as described in W095/10521 (Knoll AG) and W098/07724 (Knoll AG).
Suitably the cyclodextrin is selected from an a-cyclodextrin, (3-cyclodextrin or a y-cyclodextrin. Suitable (3-cyclodextrins include (3-cyclodextrin, methyl-R-cyclodextrin, 2-hydroxyethyl-~i-cyclodextrin, 2-hydroxypropyl-[3-cyclodextrin, 3-hydroxypropyl-(3-cyclodextrin, 2,3-dihydroxypropyl-(3-cyclodextrin, trimethyl-(3-cyclodextrin, 6-O-a-D-glucosyl-[3-cyclodextrin, 6-O-a-D-maltosyl-[i-cyclodextrin, dimaltosyl-~-cyclodextrin, diglucosyl-[3-cyclodextrin, maltotriosyl-~i-cyclodextrin, carboxymethyl-(3-cyclodextrin, carboxyethyl-(3-cyclodextrin, heptakis-(2,6-di-O-methyl)- (3-cyclodextrin, heptakis-(2,3,6-tri-O-methyl)- (3-cyclodextrin, (3-cyclodextrin sulphobutyl ether (described in US 5,376,645 and US 5,134,127). Suitable y-cyclodextrins include 2-hydroxypropyl-y-cyclodextrin. Preferably the cyclodextrin is a (3-cyclodextrin. More preferably the cyclodextrin is methyl-(3-cyclodextrin or 2-hydroxypropyl-(3-cyclodextrin. Most preferably the cyclodextrin is 2-hydroxypropyl-(3-cyclodextrin.
A preferred embodiment of the present invention is a pharmaceutical composition in the form of an aqueous solution comprising a) a therapeutically effective amount of a compound of formula I as defined above and b) a (3-cyclodextrin.
Surprisingly a composition comprising a compound of formula I, and in particular (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine, and 2-hydroxypropyl-(3-cyclodextrin is particularly advantageous as a result of increased solubility and reduced adverse toxicity compared to compositions containing other cyclodextrins. Such compositions provide aqueous solutions which may be administered by intravenous injection or by continuous infusion to patients suffering from stroke. Such compositions may provide a major advance in the treatment of stroke where rapid treatment is essential. These compositions may be considered to be a particular selection from the possible combinations of the compounds of formula I with cyclodextrins with unexpected advantageous properties not shared by the other possible combinations.
A more preferred embodiment of the present invention is a pharmaceutical composition in the form of an aqueous solution comprising a) a therapeutically effective amount of a compound of formula I as defined above and b) 2-hydroxypropyl-[i-cyclodextrin.
A most preferred embodiment of the present invention is a pharmaceutical composition in the form of an aqueous solution comprising a) a therapeutically effective amount of a compound of formula I as defined above at a concentration in the range of 0.1-30% w/v and b) 2-hydroxypropyl-[3-cyclodextrin at a concentration in range of 5-75% w/v. It will be understood that the remainder of the composition is normally water to 100% but that additional pharmaceutically acceptable additives, for example preservatives, anti-oxidants, anti-microbials, flavourings etc. may also be present at levels known to those skilled in the art. Preferably the compound of formula I is present at a concentration in the range of 1-30% w/v, for example 10-20% w/v and 12-18% w/v, more preferably at a concentration in the range of 0.5-5% w/v and most preferably at a concentration in the range of 1-3% w/v.
Preferably the concentration of 2-hydroxypropyl-(3-cyclodextrin is in the range of 20-50% w/v and more preferably is in the range of 30-40% w/v.
An especially preferred embodiment of the present invention is a pharmaceutical composition in the form of an aqueous solution comprising:
a) (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine at a concen-tration in the range of 0.1-30% w/v and b) 2-hydroxypropyl-(3-cyclodextrin at a concentration in range of 5-75% w/v.
Preferably the concentration of (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo(1,5-a]pyrimidine is in the range of 1-30% w/v, for example 10-20% w/v and most preferably is in the range of 12-18% w/v, more preferably at a concentration in the range of 0.5-5% w/v and most preferably at a concentration in the range of 1-3% w/v.
Preferably the concentration of 2-hydroxypropyl-[i-cyclodextrin is in the range 20-50% w/v and more preferably is in the range 30-40% w/v.
1~0 The efficacy of the compositions of the present invention was demonstrated by the following study.
METHODS
i) Middle Cerebral Artery (MCA) occlusion Male Sprague-Dawley rats (300 - 350g) were anaesthetised with halothane in oxygen (1000 ml/min). Anaesthesia was induced with 5% (v/v) halothane and maintained using a face mask at a concentration of 2.25 - 2.5%. Body temperature of the animals was maintained at 37 t 0.5°C throughout the procedure using a thermostatically-controlled heated operating blanket. A scalp incision was made at the mid-point between the right eye and right ear. The temporalis muscle was separated in the plane of its fibre bundles and retracted to expose the zygoma and squamosal bones. Muscle and connective tissue was scraped from the bone to locate the drill point. Using microsurgical techniques, a craniotomy was made using a No. 5 round-head dental burr, rostral to the fusion point of the two cranial bones.
The skull was cooled by regular swabbing with sterile saline to avoid causing thermal injury to the cerebral cortex. The dura mater and pia-arachnoid membranes were incised with a 25 g hypodermic needle bent at the tip to form a hook and were gently pulled from the surface of the cortex with fine forceps. The exposed middle cerebral artery was electrocauterised using bipolar diathermy (GU Manufacturing Company, London) below the rhinal fissure and at a second point below the bifurcation of the artery into parietal and frontal cortical branches. Animals which haemorrhaged on occlusion of the MCA were discarded from the study. The MCA was severed at both points with a pair of micro-scissors to ensure separation of the vessel. Care was taken to avoid causing non-specific damage to the surface of the cerebral cortex.
Finally, the temporalis muscle and overlying skin were placed back into position and sutured. Following operation, animals were placed in cages on absorbent paper and allowed to regain consciousness under gentle warming from a red, 60 W light bulb.
After recovery, animals were grouped together (n = 4 - 6) in cages. The duration of the operation was 15 - 20 min and animals regained consciousness within another - 15 min after arterial occlusion.
10 ii) Drug preparation Two different cyclodextrin solutions (Research Biochemicals Inc.) were initially used for solubilisation of (-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine (hereinafter referred to as the test compound); 2-hydroxypropyl-[3-cyclodextrin and methyl-(3-cyclodextrin. The test compound was added to each cyclodextrin solution (35% w/v in water) and sonicated for 5 - 10 minutes in a sonicating water bath, avoiding warming of the solution. The compound was soluble to approximate concentrations of 15 mg/ml in the 2-hydroxypropyl-[3-cyclodextrin solution (that is from 0.1 to 15 mg/ml) and 40 mg/ml in methyl-[3-cyclodextrin. 2-Hydroxypropyl-[3-cyclodextrin was selected for the study as animals were unable to tolerate intraperitoneal injection of methyl-[i-cyclodextrin.
iii) Treatment of animals Two groups of animals were used; MCA occlusion plus test compound (n=11) and MCA occlusion plus vehicle (n=12). Animals were weighed immediately before MCA occlusion and after 6 days of recovery. The test compound was dissolved to a concentration of 15 mg/ml in 35% w/v 2-hydroxypropyl-(3-cyclodextrin in sterile saline by placing in a sonicating water bath. The pH of the vehicle and drug solutions was adjusted to 7.4 and they were stored at 4°C for the duration of the experiment. Sixty minutes after coagulation and severance of the MCA, the animals were injected intraperitoneally with 35 mg/kg of test compound or equivalent volume of vehicle.
The animals were dosed thereafter at 20 mg/kg at 12 hourly intervals for 36 hours.
iv) Histopathological assessment of ischaemic damage After 6 days of recovery, animals were anaesthetised with Sagatal (85 mg/kg 5 intraperitoneally; Rhone Merieux) and perfused traps-cardially with cold (4°C) phosphate-buffered saline (Oxoid) for 3 min, followed by cold 4% formaldehyde in phosphate-buffered saline (pH 7.4) for 15 min. The brains were removed and immersion-fixed for at least 48 hours at 4°C .
10 The brains were sectioned in the coronal plane at 250 Nm intervals and 30 pm thickness using a vibratome (General Scientific, Series 1000) and were stained with 0.2% toluidine blue. The extent of ischaemic damage was assessed in 13 planes at 500Nm intervals from +2.7 mm to -3.3 mm relative to bregma.
Slides were placed onto a slide illuminator (Carl Zeiss; 17.5x magnification) and areas of 15 damage were delineated onto stereotaxic brain maps. Lesion areas were measured using a SeeScan image analyser and lesion volumes calculated using computational analysis (GraphPad Prism). All sections were recoded and lesion sizes were measured by an operator unaware of treatment procedures.
v) Statistical analysis of data Histological damage assessment and changes in rat weights were analysed using two-way ANOVA. All data are quoted as mean t standard error of the mean.
RESULTS
Animals did not show gross neurological deficits, such as seizures or hemiparesis due to MCA occlusion and those treated with the test compound showed only mild sedation, particularly in the first 5 - 6 hours after the initial dosing.
Two rats out of a total of 25 were killed shortly after their recovery from the anaesthetic because of haemorrhaging due to incomplete sealing of the MCA by the electrocoagulator. None of the animals treated with either vehicle or the test compound died.
i) Histopathological damage after MCA occlusion Ischaemic injury in toluidine blue-stained brain sections was manifest as areas of pallor with sharply demarcated margins between healthy and damaged tissue. Damage from MCA occlusion was present mainly in the parietal, insular, frontal and forelimb cortical regions. Damage was also found in the outer region of the caudate-putamen. This was caused by secondary damage produced by compression, due to the presence of oedema in the cortex and corpus callosum.
This may be concluded as there is no arterial supply to the caudate-putamen distal to the occlusion site.
When assessed 6 days after the ischaemic insult, treatment of rats with test compound (60 min post-MCAO; 35 mg/kg ip + 20 mglkg x 3) resulted in a 40%
reduction of lesion volume when compared with animals given vehicle alone. The lesion volumes were 72.0 t 7.9 mm3 for vehicle treated rats and 43.6 ~ 4.9 mm3 for test compound-treated animals.
In a comparative study rats were treated with a suspension of the test compound (15 min post-MCAO; 50 mg/kg x 3) by oral gavage. The test compound provided a 31 % reduction of lesion volume (56.9 ~ 6.1 mm3) when compared with vehicle-treated controls (82.6 ~ 6.47 mm3).
These results demonstrate that the compositions of the present invention are advantageous over previously known compositions. In particular, solutions of the compounds of formula I are advantageous as they are more efficacious than suspensions, i.e. greater reduction in lesion volume, with lower doses and administered at a later time-point after MCA occlusion. Solution formulations according to the present invention are also likely to overcome the short half-life of the compounds of formula I in humans. Additionally such solution formulations can be administered by continuous intravenous infusion which is particularly beneficial in the treatment of stroke.
The invention is illustrated by the following Example which is given by way of example only. The final product of each of this Examples was characterised by the following procedures: gas-liquid chromatography; high performance liquid chromatography; elemental analysis; nuclear magnetic resonance spectroscopy and infrared spectroscopy.
Other compounds of the present invention are prepared as described in W095/10521 (Knoll AG) and W098/07724 (Knoll AG) which are incorporated herein by reference. Cyclodextrins are commercially available or may be prepared by methods disclosed in Chemical Reviews (1998) 98,1474-2076 and references cited therein.
Example 1 1 a) A mixture of 2-(4-chlorophenoxy)propionic acid (30.0 g) in toluene (300 ml) was added to a solution of thionyl chloride (22.0 ml) and dimethylformamide (2 ml) in toluene (150 ml) at 60-70°C with stirring. The mixture was stirred for 18 hours at 70-80°C and then evaporated under reduced pressure to give the acid chloride. A solution of Meldrum's acid (23.5 g) in dichloromethane (90 ml) was cooled to 0-5°C under nitrogen and pyridine (33 ml) was added at 0-5°C. To this mixture was added a solution of the acid chloride prepared above in dichloromethane (90 ml) dropwise keeping the temperature below 5°C. The mixture was stirred for 1 hour at 0-5°C and then at ambient temperature for 18 hours. The mixture was diluted with dichloromethane (150 ml) and washed with 2M hydrochloric acid and then with saturated sodium bicarbonate solution and then water. The bicarbonate washes were acidified with 5M hydrochloric acid and extracted into dichloromethane.
These dichloromethane extracts were combined with the original dichloromethane solution and dried and evaporated to give the crude intermediate Meldrum's acid derivative. This derivative was boiled under reflux with methanol (400 ml) for 6 hours and then left to stand at ambient temperature for 66 hours with methanolic hydrogen chloride solution (10 ml).
The mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated off, washed with saturated sodium bicarbonate solution, brine and then dried and evaporated under reduced pressure to give an oil which was distilled under high vacuum. The distillate was purified by flash column chromatography on silica using petroleum ether, b.p. 60-80°C I ethyl acetate 20:1 as the mobile phase to give methyl 4-(4-chlorophenoxy)-3-oxopentanoate as an oil.
b) Guanidine hydrochloride (1.87 g) was added with stirring to a solution of sodium (0.41 g) in ethanol (15 ml). The mixture was stirred for 15 minutes and then to this mixture was added a solution of methyl 4-(4-chlorophenoxy)-3-oxopentanoate (5.0 g) in ethanol (15 ml). The mixture was stirred and boiled under reflux for 16 hours. The mixture was cooled and then evaporated to dryness under reduced pressure to give a solid.
The solid was triturated with water (10 ml) containing glacial acetic acid (2 ml) and dichloromethane (20 ml) for 1 hour and then filtered. The residue obtained was washed with water (20 ml) and then with dichloromethane to give 2-amino-4-[1-(4-chlorophenoxy)ethyl-6-hydroxypyrimidine, m.p. 125°C.
c) A mixture of 2-amino-4-[1-(4-chlorophenoxy)ethyl-6-hydroxypyrimidine (0.5 g), dimethylformamide dimethyl acetal (0.5 ml) and toluene (5 ml) was stirred and boiled under reflux for 8 hours. The mixture was evaporated for 8 hours. The mixture was allowed to stand at ambient temperature for 24 hours and then evaporated to dryness under reduced pressure to give a solid which was triturated with ether and filtered to give the amidine as a solid.
d) Sodium hydride (62 mg of a 60% dispersion in mineral oil from which the mineral oil had been removed by washing with petrol) was dissolved in methanol (10 ml) and hydroxylamine hydrochloride (0.12 g) was added.
The mixture was stirred for 5 minutes and then added to the amidinopyrimidine (0.5 g) obtained in c). The mixture was stirred at ambient temperature for 72 hours and then evaporated to dryness under reduced pressure to give a residue which was washed with water and dried to give the formamidoxine.
e) The product from d) (5.0 g) and polyphosphoric acid (100 g) were stirred and heated on a steam bath for 4 hours. The mixture was allowed to cool to ambient temperature and then ice (100 g) and ethyl acetate (100 ml) were added. A solution of potassium carbonate (110 g) in water (total volume 100 ml) was added dropwise over 15 minutes to neutralise the mixture. The mixture was separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were dried and evaporated to give a solid which was purified by flash column chromatography on silica using dichloromethane / methanol (75:3) as the mobile phase to give 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol, m.p. 190°C.
Example 2 (-)-7-[1-(4-Chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine was prepared as described in W095/10521.
Solubility Determinations Example 1 Example 2 Water < 33 p.g/ml 125-170 p.g/ml 35% w/v methyl-(3-cyclodextrin2 mg/ml 40 mg/ml in water 35% w/v 2-hydroxypropyl-(3-cyclodextrin1 mg/ml 15 mglml in water 35% w/v 2-hydroxypropyl-y-cyclodextrin< 62 p.g/ml 6 mg/ml in water
Claims (18)
1. A pharmaceutical composition comprising a) a compound of formula I
including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof in which:
R1 represents H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C1-6alkyl, C1-6alkoxy or C1-6alkanoyl;
R2 and R3 independently represent H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C1-6alkyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkylthio, C1-6alkylsulphinyl, C1-6alkylsulphonyl or hydroxy;
R4 and R5 independently represent H, C1-6alkyl or R4 and R5 combined together with the carbon atom to which they are attached represent C3-6cycloalkylidene (each alkyl or cycloalkylidene being optionally substituted with one or more of halo, cyano, hydroxy, amino or C1-6alkyl); and R6, R7 and R8 independently represent H, halo, hydroxy, mercapto, nitro, cyano or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino; and any nitrogen atom being optionally substituted with one or more C1-6 alkyl): C1-6alkyl, C1-6alkanoyl, C1-6alkoxy, C2-6alkoxycarbonyl, carboxy, C1-6alkanoyloxy, C1-6alkylthio, C1-6alkylsulphinyl, C1-6alkylsulphonyl, C1-6alkyl-sulphonylamino, sulphamoyl, carbamoyl, C2-6alkylcarbamoyl or C1-6alkanoylamino;
and b) a cyclodextrin.
including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof in which:
R1 represents H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C1-6alkyl, C1-6alkoxy or C1-6alkanoyl;
R2 and R3 independently represent H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C1-6alkyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkylthio, C1-6alkylsulphinyl, C1-6alkylsulphonyl or hydroxy;
R4 and R5 independently represent H, C1-6alkyl or R4 and R5 combined together with the carbon atom to which they are attached represent C3-6cycloalkylidene (each alkyl or cycloalkylidene being optionally substituted with one or more of halo, cyano, hydroxy, amino or C1-6alkyl); and R6, R7 and R8 independently represent H, halo, hydroxy, mercapto, nitro, cyano or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino; and any nitrogen atom being optionally substituted with one or more C1-6 alkyl): C1-6alkyl, C1-6alkanoyl, C1-6alkoxy, C2-6alkoxycarbonyl, carboxy, C1-6alkanoyloxy, C1-6alkylthio, C1-6alkylsulphinyl, C1-6alkylsulphonyl, C1-6alkyl-sulphonylamino, sulphamoyl, carbamoyl, C2-6alkylcarbamoyl or C1-6alkanoylamino;
and b) a cyclodextrin.
2. A composition according to claim 1 in which the composition is a mixture of the compound of formula I and a cyclodextrin.
3. A composition according to claim 1 in which the composition comprises a complex of the compound of formula I and the cyclodextrin.
4. A composition according to any previous claim wherein the compound of formula I is selected from:
7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo(1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo(1,5-a]pyrimidine;
7-[1-(4-bromophenoxy)ethyl]-1,2,4-triazolo(1,5-a]pyrimidine;
7-[1-(4-cyanophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-trifluoromethylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-methoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-trifluoromethoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-acetylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-{1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-methylsulphinylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-methylsulphonylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-{1-[4-(ethylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(3-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(2,4-difluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(2,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(3,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(2-chloro-4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)ethyl]-2-methyl-1,2,4-triazolo[1,5-a]pyrimidine;
7-(4-chlorophenoxymethyl)-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)-1-methylethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)propyl]-1,2,4-triazolo[1,5-a]pyrimidine; and 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of their stereoisomers; and pharmaceutically acceptable salts thereof.
7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo(1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo(1,5-a]pyrimidine;
7-[1-(4-bromophenoxy)ethyl]-1,2,4-triazolo(1,5-a]pyrimidine;
7-[1-(4-cyanophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-trifluoromethylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-methoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-trifluoromethoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-acetylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-{1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-methylsulphinylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-methylsulphonylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-{1-[4-(ethylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(3-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(2,4-difluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(2,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(3,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(2-chloro-4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)ethyl]-2-methyl-1,2,4-triazolo[1,5-a]pyrimidine;
7-(4-chlorophenoxymethyl)-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)-1-methylethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)propyl]-1,2,4-triazolo[1,5-a]pyrimidine; and 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of their stereoisomers; and pharmaceutically acceptable salts thereof.
5. A composition according to any previous claim in which the compound of formula I is selected from:
(+)-7-[1-(4-fluorophenoxy)ethyl]-1,2;4-triazolo[1,5-a]pyrimidine;
(-)-7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo(1,5-a]pyrimidine (+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
(-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
(+)-7-(1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol; and (-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol;
and pharmaceutically acceptable salts thereof.
(+)-7-[1-(4-fluorophenoxy)ethyl]-1,2;4-triazolo[1,5-a]pyrimidine;
(-)-7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo(1,5-a]pyrimidine (+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
(-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
(+)-7-(1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol; and (-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol;
and pharmaceutically acceptable salts thereof.
6. A composition according to any previous claim in which the compound of formula I is (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine.
7. A composition according to claim 1 in the form of an aqueous solution comprising a) a therapeutically effective amount of a compound of formula I as defined in any one of claims 1 to 6 and b) a cyclodextrin.
8. A composition according to any previous claim in which the cyclodextrin is selected from an .alpha.-cyclodextrin, a .beta.-cyclodextrin or a .gamma.-cyclodextrin.
9. A composition according to any previous claim in which the cyclodextrin is a .beta.-cyclodextrin.
10. A composition according to claim 9 in which the cyclodextrin is methyl-.beta.-cyclodextrin or 2-hydroxypropyl-.beta.-cyclodextrin.
11. A composition according to claim 9 in which the cyclodextrin is 2-hydroxypropyl-.beta.-cyclodextrin.
12. A composition according to claim 1 in the form of an aqueous solution comprising a) a therapeutically effective amount of a compound of formula I as defined in any one of claims 1 to 6 at a concentration in the range of 0.1-30%
w/v and b) 2-hydroxypropyl-.beta.-cyclodextrin at a concentration in range of 5-75% w/v.
w/v and b) 2-hydroxypropyl-.beta.-cyclodextrin at a concentration in range of 5-75% w/v.
13. A composition according to claim 12 wherein the compound of formula I is present at a concentration in the range of 1-3% w/v.
14. A composition according to either claim 12 or claim 13 wherein the concentration of 2-hydroxypropyl-.beta.-cyclodextrin is in the range of 30-40%
w/v.
w/v.
15. A composition according to any previous claim for oral use.
16. A composition according to any one of claims 12 to 14 for use in intravenous infusion.
17. The use of a composition according to any previous claim for the inhibition of 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.
18. The use of a composition according to any previous claim in the treatment and prevention of migraine.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9906126.9A GB9906126D0 (en) | 1999-03-18 | 1999-03-18 | Pharmaceutical formulations |
GB9906126.9 | 1999-03-18 | ||
PCT/EP2000/001940 WO2000056336A2 (en) | 1999-03-18 | 2000-03-06 | Pharmaceutical compositions comprising a pyrimidine derivative and cyclodextrin |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2367040A1 true CA2367040A1 (en) | 2000-09-28 |
Family
ID=10849799
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002367040A Abandoned CA2367040A1 (en) | 1999-03-18 | 2000-03-06 | Pharmaceutical compositions comprising a pyrimidine derivative and cyclodextrin |
Country Status (8)
Country | Link |
---|---|
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) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
WO2019180681A1 (en) | 2018-03-23 | 2019-09-26 | Bast Fibre Technologies Inc. | Nonwoven fabic comprised of crimped bast fibers |
CA3138307A1 (en) | 2019-05-13 | 2020-11-19 | Ecolab Usa Inc. | 1,2,4-triazolo[1,5-a] pyrimidine derivative as copper corrosion inhibitor |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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
-
2000
- 2000-03-06 AU AU32867/00A patent/AU3286700A/en not_active Abandoned
- 2000-03-06 MX MXPA01009384A patent/MXPA01009384A/en unknown
- 2000-03-06 CA CA002367040A patent/CA2367040A1/en not_active Abandoned
- 2000-03-06 EP EP00910780A patent/EP1161243A2/en not_active Withdrawn
- 2000-03-06 WO PCT/EP2000/001940 patent/WO2000056336A2/en not_active Application Discontinuation
- 2000-03-06 JP JP2000606241A patent/JP2002539261A/en not_active Withdrawn
- 2000-03-06 CN CN00807523A patent/CN1350456A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
GB9906126D0 (en) | 1999-05-12 |
WO2000056336A3 (en) | 2000-11-16 |
JP2002539261A (en) | 2002-11-19 |
EP1161243A2 (en) | 2001-12-12 |
WO2000056336A2 (en) | 2000-09-28 |
AU3286700A (en) | 2000-10-09 |
MXPA01009384A (en) | 2004-03-19 |
CN1350456A (en) | 2002-05-22 |
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