ES2432058T3 - Ciclopentanos sustituidos que tienen actividad de prostaglandina - Google Patents
Ciclopentanos sustituidos que tienen actividad de prostaglandina Download PDFInfo
- Publication number
- ES2432058T3 ES2432058T3 ES08848280T ES08848280T ES2432058T3 ES 2432058 T3 ES2432058 T3 ES 2432058T3 ES 08848280 T ES08848280 T ES 08848280T ES 08848280 T ES08848280 T ES 08848280T ES 2432058 T3 ES2432058 T3 ES 2432058T3
- Authority
- ES
- Spain
- Prior art keywords
- hydroxy
- cyclopentyl
- thiophene
- chloro
- propyl
- 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.)
- Active
Links
- 150000003180 prostaglandins Chemical class 0.000 title description 6
- 150000001940 cyclopentanes Chemical class 0.000 title description 3
- 230000000694 effects Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims description 17
- 208000010412 Glaucoma Diseases 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- UEFCCMGZVPNKFG-BRSBDYLESA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-2-heptyl-3-hydroxycyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound CCCCCCC[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 UEFCCMGZVPNKFG-BRSBDYLESA-N 0.000 claims description 3
- GQOMGAMVIAXXDU-BRSBDYLESA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-2-hept-1-enyl-3-hydroxycyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound CCCCCC=C[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 GQOMGAMVIAXXDU-BRSBDYLESA-N 0.000 claims description 2
- MNRCJCDBASMYFZ-QBPKDAKJSA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-2-hexyl-3-hydroxycyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound CCCCCC[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 MNRCJCDBASMYFZ-QBPKDAKJSA-N 0.000 claims description 2
- BFMIXIZGHNEHAY-BRSBDYLESA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-3-hydroxy-2-(7-hydroxyhept-1-enyl)cyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound OCCCCCC=C[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 BFMIXIZGHNEHAY-BRSBDYLESA-N 0.000 claims description 2
- HNXYEYUUZZSFBR-BRSBDYLESA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-3-hydroxy-2-(7-hydroxyheptyl)cyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound OCCCCCCC[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 HNXYEYUUZZSFBR-BRSBDYLESA-N 0.000 claims description 2
- YBXGWWJKUQBHMV-UAFMIMERSA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-3-hydroxy-2-non-1-enylcyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound CCCCCCCC=C[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 YBXGWWJKUQBHMV-UAFMIMERSA-N 0.000 claims description 2
- VOSAZQWIEFWQDH-UAFMIMERSA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-3-hydroxy-2-nonylcyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound CCCCCCCCC[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 VOSAZQWIEFWQDH-UAFMIMERSA-N 0.000 claims description 2
- YQEIMGWXMUBJFG-NCXUSEDFSA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-3-hydroxy-2-oct-7-enylcyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound C=CCCCCCC[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 YQEIMGWXMUBJFG-NCXUSEDFSA-N 0.000 claims description 2
- WFAKLIBGIZQNAN-NCXUSEDFSA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-3-hydroxy-2-octylcyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound CCCCCCCC[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 WFAKLIBGIZQNAN-NCXUSEDFSA-N 0.000 claims description 2
- PLMYBWCKKMBKMA-KLHDSHLOSA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-3-hydroxy-2-pentylcyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound CCCCC[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 PLMYBWCKKMBKMA-KLHDSHLOSA-N 0.000 claims description 2
- ODNPRAJSASAODF-XRXFAXGQSA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-2-dec-1-enyl-3-hydroxycyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound CCCCCCCCC=C[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 ODNPRAJSASAODF-XRXFAXGQSA-N 0.000 claims 1
- JLMAVYSIVKNKDO-NCXUSEDFSA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-3-hydroxy-2-(8-hydroxyoct-1-enyl)cyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound OCCCCCCC=C[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 JLMAVYSIVKNKDO-NCXUSEDFSA-N 0.000 claims 1
- QJKBBTPYPVOIKG-NCXUSEDFSA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-3-hydroxy-2-(8-hydroxyoctyl)cyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound OCCCCCCCC[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 QJKBBTPYPVOIKG-NCXUSEDFSA-N 0.000 claims 1
- FUDHERGUBLWRPR-KLHDSHLOSA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-3-hydroxy-2-pent-1-enylcyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound CCCC=C[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 FUDHERGUBLWRPR-KLHDSHLOSA-N 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 52
- 239000000243 solution Substances 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000000203 mixture Substances 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- 238000003818 flash chromatography Methods 0.000 description 20
- 239000000741 silica gel Substances 0.000 description 20
- 229910002027 silica gel Inorganic materials 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- 238000000746 purification Methods 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- 229910052799 carbon Inorganic materials 0.000 description 14
- 239000007832 Na2SO4 Substances 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 10
- 101710129069 Serine/threonine-protein phosphatase 5 Proteins 0.000 description 8
- 101710199542 Serine/threonine-protein phosphatase T Proteins 0.000 description 8
- 229920000470 poly(p-phenylene terephthalate) polymer Polymers 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 150000001721 carbon Chemical group 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- -1 hydride ion Chemical class 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 210000002159 anterior chamber Anatomy 0.000 description 4
- 230000004410 intraocular pressure Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 229910010084 LiAlH4 Inorganic materials 0.000 description 3
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 210000001742 aqueous humor Anatomy 0.000 description 3
- 239000013626 chemical specie Substances 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 3
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 3
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 2
- PJOMSIZYJPPCCO-WMDDLZNTSA-N 2-[(1r,2r,3r,5s)-5-methylsulfonyloxy-2-octyl-3-(oxan-2-yloxy)cyclopentyl]ethyl methanesulfonate Chemical compound C1[C@H](OS(C)(=O)=O)[C@H](CCOS(C)(=O)=O)[C@@H](CCCCCCCC)[C@@H]1OC1OCCCC1 PJOMSIZYJPPCCO-WMDDLZNTSA-N 0.000 description 2
- KFHGHVRQPZAHFB-IDIOOTERSA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-3-hydroxy-2-[(e,3r)-3-hydroxyoct-1-enyl]cyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound CCCCC[C@@H](O)\C=C\[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 KFHGHVRQPZAHFB-IDIOOTERSA-N 0.000 description 2
- MMXRRNUXCHUHOE-UHFFFAOYSA-N 7-bromoheptan-1-ol Chemical compound OCCCCCCCBr MMXRRNUXCHUHOE-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 208000002177 Cataract Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 238000007239 Wittig reaction Methods 0.000 description 2
- 201000001326 acute closed-angle glaucoma Diseases 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000002723 alicyclic group Chemical group 0.000 description 2
- 229960000711 alprostadil Drugs 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000001934 delay Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002066 eicosanoids Chemical class 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 208000030533 eye disease Diseases 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 201000006366 primary open angle glaucoma Diseases 0.000 description 2
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 2
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 2
- WGJJROVFWIXTPA-OALUTQOASA-N prostanoic acid Chemical class CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC(O)=O WGJJROVFWIXTPA-OALUTQOASA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 2
- VHGJKGGMDSRIHD-QUIYGKKVSA-N (1s,2r,3r,4r)-2-(2-hydroxyethyl)-3-octyl-4-(oxan-2-yloxy)cyclopentan-1-ol Chemical compound C1[C@H](O)[C@H](CCO)[C@@H](CCCCCCCC)[C@@H]1OC1OCCCC1 VHGJKGGMDSRIHD-QUIYGKKVSA-N 0.000 description 1
- MVTSQCYUWSYGAP-DZJUANEXSA-N (3ar,4r,5r,6as)-4-octyl-5-(oxan-2-yloxy)-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-2-one Chemical compound O([C@H]1[C@@H]([C@H]2CC(=O)O[C@H]2C1)CCCCCCCC)C1CCCCO1 MVTSQCYUWSYGAP-DZJUANEXSA-N 0.000 description 1
- IMARPNDXMKVPAR-AKHDSKFASA-N (3ar,4r,5r,6as)-5-[tert-butyl(dimethyl)silyl]oxy-4-oct-1-enyl-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-2-one Chemical compound O1C(=O)C[C@@H]2[C@@H](C=CCCCCCC)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]21 IMARPNDXMKVPAR-AKHDSKFASA-N 0.000 description 1
- CYIXFXFEPORWIT-SYQHCUMBSA-N (3ar,4r,5r,6as)-5-hydroxy-4-octyl-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-2-one Chemical compound O1C(=O)C[C@@H]2[C@@H](CCCCCCCC)[C@H](O)C[C@@H]21 CYIXFXFEPORWIT-SYQHCUMBSA-N 0.000 description 1
- YDXQPTHHAPCTPP-AATRIKPKSA-N (E)-3-Octen-1-ol Chemical compound CCCC\C=C\CCO YDXQPTHHAPCTPP-AATRIKPKSA-N 0.000 description 1
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 1
- UWLHSHAHTBJTBA-UHFFFAOYSA-N 1-iodooctane Chemical compound CCCCCCCCI UWLHSHAHTBJTBA-UHFFFAOYSA-N 0.000 description 1
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 1
- IJYBSQFJCPBQEG-UHFFFAOYSA-N 2-(7-bromoheptoxy)oxane Chemical compound BrCCCCCCCOC1CCCCO1 IJYBSQFJCPBQEG-UHFFFAOYSA-N 0.000 description 1
- JBKRKGDOZNJDDZ-XRXFAXGQSA-N 2-hydroxyethyl 5-[3-[(1r,2r,3r,5r)-5-chloro-3-hydroxy-2-octylcyclopentyl]propyl]thiophene-2-carboxylate Chemical compound CCCCCCCC[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(=O)OCCO)S1 JBKRKGDOZNJDDZ-XRXFAXGQSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- YDXQPTHHAPCTPP-UHFFFAOYSA-N 3-Octen-1-ol Natural products CCCCC=CCCO YDXQPTHHAPCTPP-UHFFFAOYSA-N 0.000 description 1
- KGEXFWRLWGNGCC-XRXFAXGQSA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-2-decyl-3-hydroxycyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound CCCCCCCCCC[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 KGEXFWRLWGNGCC-XRXFAXGQSA-N 0.000 description 1
- LDHTWNOWEPVCSP-IIAWZERTSA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-3-hydroxy-2-[(e)-oct-3-enyl]cyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound CCCC\C=C\CC[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(O)=O)S1 LDHTWNOWEPVCSP-IIAWZERTSA-N 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
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- 206010012565 Developmental glaucoma Diseases 0.000 description 1
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- 206010020565 Hyperaemia Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010037520 Pupillary block Diseases 0.000 description 1
- CLCQNBJFWQERSS-WISYIIOYSA-N TBS-Corey Lactone Aldehyde Chemical compound O1C(=O)C[C@@H]2[C@@H](C=O)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]21 CLCQNBJFWQERSS-WISYIIOYSA-N 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 102000015005 beta-adrenergic receptor activity proteins Human genes 0.000 description 1
- 108040006818 beta-adrenergic receptor activity proteins Proteins 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 201000005667 central retinal vein occlusion Diseases 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 201000005682 chronic closed-angle glaucoma Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- CNHISCQPKKGDPO-UHFFFAOYSA-N ethyl 2-bromo-1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)C1=CSC(Br)=N1 CNHISCQPKKGDPO-UHFFFAOYSA-N 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- RFNJHLCSNWZALO-UHFFFAOYSA-N heptylphosphanium;bromide Chemical compound [Br-].CCCCCCC[PH3+] RFNJHLCSNWZALO-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- QPVXVFYOBPUMQX-OQPYTZTLSA-N methyl 5-[3-[(1r,2r,3r,5r)-5-chloro-2-heptyl-3-(oxan-2-yloxy)cyclopentyl]propyl]thiophene-2-carboxylate Chemical compound C([C@H]1[C@H](Cl)C[C@H]([C@@H]1CCCCCCC)OC1OCCCC1)CCC1=CC=C(C(=O)OC)S1 QPVXVFYOBPUMQX-OQPYTZTLSA-N 0.000 description 1
- VHKFTAIVLYETHZ-NCXUSEDFSA-N methyl 5-[3-[(1r,2r,3r,5r)-5-chloro-2-heptyl-3-hydroxycyclopentyl]propyl]thiophene-2-carboxylate Chemical compound CCCCCCC[C@H]1[C@H](O)C[C@@H](Cl)[C@@H]1CCCC1=CC=C(C(=O)OC)S1 VHKFTAIVLYETHZ-NCXUSEDFSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- COCAUCFPFHUGAA-MGNBDDOMSA-N n-[3-[(1s,7s)-5-amino-4-thia-6-azabicyclo[5.1.0]oct-5-en-7-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide Chemical compound C=1C=C(F)C([C@@]23N=C(SCC[C@@H]2C3)N)=CC=1NC(=O)C1=CC=C(Cl)C=N1 COCAUCFPFHUGAA-MGNBDDOMSA-N 0.000 description 1
- OBLXVLWZBMAMHE-UHFFFAOYSA-M octyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCCCCCC)C1=CC=CC=C1 OBLXVLWZBMAMHE-UHFFFAOYSA-M 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- PXGPLTODNUVGFL-UHFFFAOYSA-N prostaglandin F2alpha Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CC=CCCCC(O)=O PXGPLTODNUVGFL-UHFFFAOYSA-N 0.000 description 1
- PXGPLTODNUVGFL-JZFBHDEDSA-N prostaglandin F2beta Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@@H](O)[C@@H]1C\C=C/CCCC(O)=O PXGPLTODNUVGFL-JZFBHDEDSA-N 0.000 description 1
- 230000010344 pupil dilation Effects 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 208000004644 retinal vein occlusion Diseases 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- IWPOSDLLFZKGOW-AATRIKPKSA-N trans-beta-octenoic acid Chemical compound CCCC\C=C\CC(O)=O IWPOSDLLFZKGOW-AATRIKPKSA-N 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D333/40—Thiophene-2-carboxylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Ophthalmology & Optometry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US98684907P | 2007-11-09 | 2007-11-09 | |
| US986849P | 2007-11-09 | ||
| US265062 | 2008-11-05 | ||
| US12/265,062 US9006464B2 (en) | 2007-11-09 | 2008-11-05 | Substituted cyclopentanes having prostaglandin activity |
| PCT/US2008/082469 WO2009061811A1 (en) | 2007-11-09 | 2008-11-05 | Substituted cyclopentanes having prostaglanding activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2432058T3 true ES2432058T3 (es) | 2013-11-29 |
Family
ID=40524829
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES08848280T Active ES2432058T3 (es) | 2007-11-09 | 2008-11-05 | Ciclopentanos sustituidos que tienen actividad de prostaglandina |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US9006464B2 (enExample) |
| EP (1) | EP2217581B1 (enExample) |
| JP (1) | JP2011503089A (enExample) |
| KR (1) | KR20100101097A (enExample) |
| CN (2) | CN101952261B (enExample) |
| AR (1) | AR069228A1 (enExample) |
| AU (1) | AU2008324793B2 (enExample) |
| BR (1) | BRPI0818902A2 (enExample) |
| CA (1) | CA2705150C (enExample) |
| CL (1) | CL2008003332A1 (enExample) |
| CO (1) | CO6280480A2 (enExample) |
| DK (1) | DK2217581T3 (enExample) |
| ES (1) | ES2432058T3 (enExample) |
| IL (1) | IL205604A (enExample) |
| MX (1) | MX2010005105A (enExample) |
| NZ (1) | NZ585517A (enExample) |
| RU (1) | RU2481339C2 (enExample) |
| TW (1) | TWI411438B (enExample) |
| UA (1) | UA99840C2 (enExample) |
| WO (1) | WO2009061811A1 (enExample) |
| ZA (1) | ZA201003304B (enExample) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8673341B2 (en) * | 2004-04-30 | 2014-03-18 | Allergan, Inc. | Intraocular pressure reduction with intracameral bimatoprost implants |
| US9498457B2 (en) | 2004-04-30 | 2016-11-22 | Allergan, Inc. | Hypotensive prostamide-containing biodegradable intraocular implants and related implants |
| US7799336B2 (en) | 2004-04-30 | 2010-09-21 | Allergan, Inc. | Hypotensive lipid-containing biodegradable intraocular implants and related methods |
| US7993634B2 (en) | 2004-04-30 | 2011-08-09 | Allergan, Inc. | Oil-in-oil emulsified polymeric implants containing a hypotensive lipid and related methods |
| US8722097B2 (en) | 2004-04-30 | 2014-05-13 | Allergan, Inc. | Oil-in-water method for making polymeric implants containing a hypotensive lipid |
| US20100247606A1 (en) * | 2009-03-25 | 2010-09-30 | Allergan, Inc. | Intraocular sustained release drug delivery systems and methods for treating ocular conditions |
| EP3991734B1 (en) | 2019-06-28 | 2024-11-27 | Gurus BioPharm Inc. | Agent for the treatment of alopecia and promoting hair growth |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7012A (en) * | 1850-01-15 | Improvement in mowing-machines | ||
| IE37602B1 (en) * | 1971-05-11 | 1977-08-31 | Ici Ltd | Cyclopentane derivatives |
| JPS5623984B2 (enExample) * | 1973-04-19 | 1981-06-03 | ||
| US4065472A (en) * | 1975-09-29 | 1977-12-27 | Pfizer Inc. | 5-(2-Carboxythiophen-5-yl)-16-aryloxy-α-tetranor-ω-tetranorprostaglandins |
| GB1563201A (en) * | 1975-11-05 | 1980-03-19 | Shell Int Research | Preparation of herbicidally acitve alanine derivatives |
| US5698598A (en) * | 1995-08-04 | 1997-12-16 | Allergan | EP2 -receptor agonists as agents for lowering intraocular pressure |
| US5877211A (en) * | 1997-11-21 | 1999-03-02 | Allergan | EP2 receptor agonists as neuroprotective agents for the eye |
| US6545045B1 (en) * | 1998-12-24 | 2003-04-08 | Alcon Manufacturing, Ltd. | Prostaglandin E agonists for treatment of glaucoma |
| US7091231B2 (en) * | 2004-12-10 | 2006-08-15 | Allergan, Inc. | 12-Aryl prostaglandin analogs |
| US7585895B2 (en) * | 2005-12-06 | 2009-09-08 | Allergan, Inc. | Therapeutic substituted cyclopentanes |
| US7427685B2 (en) * | 2005-12-06 | 2008-09-23 | Allergan, Inc. | Therapeutic substituted cyclopentanes |
| US7439372B2 (en) * | 2006-05-03 | 2008-10-21 | Allergan, Inc. | Therapeutic compounds |
| WO2008094958A1 (en) | 2007-02-01 | 2008-08-07 | Allergan, Inc. | Thiophene derivatives useful as medicaments for treating ocular hypertension |
-
2008
- 2008-11-05 CN CN2008801227890A patent/CN101952261B/zh not_active Expired - Fee Related
- 2008-11-05 AU AU2008324793A patent/AU2008324793B2/en not_active Ceased
- 2008-11-05 JP JP2010533210A patent/JP2011503089A/ja not_active Ceased
- 2008-11-05 MX MX2010005105A patent/MX2010005105A/es active IP Right Grant
- 2008-11-05 WO PCT/US2008/082469 patent/WO2009061811A1/en not_active Ceased
- 2008-11-05 RU RU2010122681/04A patent/RU2481339C2/ru not_active IP Right Cessation
- 2008-11-05 UA UAA201007073A patent/UA99840C2/ru unknown
- 2008-11-05 CN CN2012104400409A patent/CN102977048A/zh active Pending
- 2008-11-05 DK DK08848280T patent/DK2217581T3/da active
- 2008-11-05 ES ES08848280T patent/ES2432058T3/es active Active
- 2008-11-05 BR BRPI0818902 patent/BRPI0818902A2/pt not_active IP Right Cessation
- 2008-11-05 NZ NZ58551708A patent/NZ585517A/xx not_active IP Right Cessation
- 2008-11-05 US US12/265,062 patent/US9006464B2/en active Active
- 2008-11-05 KR KR1020107012599A patent/KR20100101097A/ko not_active Ceased
- 2008-11-05 CA CA2705150A patent/CA2705150C/en not_active Expired - Fee Related
- 2008-11-05 EP EP20080848280 patent/EP2217581B1/en not_active Not-in-force
- 2008-11-07 AR ARP080104883 patent/AR069228A1/es not_active Application Discontinuation
- 2008-11-07 TW TW97143230A patent/TWI411438B/zh not_active IP Right Cessation
- 2008-11-07 CL CL2008003332A patent/CL2008003332A1/es unknown
-
2010
- 2010-05-06 IL IL205604A patent/IL205604A/en not_active IP Right Cessation
- 2010-05-11 ZA ZA2010/03304A patent/ZA201003304B/en unknown
- 2010-06-02 CO CO10066597A patent/CO6280480A2/es active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| DK2217581T3 (da) | 2013-10-21 |
| ZA201003304B (en) | 2014-03-26 |
| EP2217581B1 (en) | 2013-07-31 |
| RU2481339C2 (ru) | 2013-05-10 |
| CN101952261B (zh) | 2013-06-12 |
| TWI411438B (zh) | 2013-10-11 |
| WO2009061811A1 (en) | 2009-05-14 |
| CL2008003332A1 (es) | 2011-08-12 |
| AR069228A1 (es) | 2010-01-06 |
| CA2705150A1 (en) | 2009-05-14 |
| EP2217581A1 (en) | 2010-08-18 |
| CA2705150C (en) | 2016-06-14 |
| IL205604A (en) | 2014-06-30 |
| IL205604A0 (en) | 2010-11-30 |
| US9006464B2 (en) | 2015-04-14 |
| US20090124676A1 (en) | 2009-05-14 |
| CO6280480A2 (es) | 2011-05-20 |
| UA99840C2 (ru) | 2012-10-10 |
| KR20100101097A (ko) | 2010-09-16 |
| WO2009061811A8 (en) | 2009-07-02 |
| JP2011503089A (ja) | 2011-01-27 |
| AU2008324793B2 (en) | 2013-12-05 |
| TW200934500A (en) | 2009-08-16 |
| NZ585517A (en) | 2012-08-31 |
| CN102977048A (zh) | 2013-03-20 |
| BRPI0818902A2 (pt) | 2015-05-12 |
| CN101952261A (zh) | 2011-01-19 |
| MX2010005105A (es) | 2010-05-27 |
| RU2010122681A (ru) | 2011-12-20 |
| AU2008324793A1 (en) | 2009-05-14 |
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