IL139649A - Water-soluble azulis, broad-spectrum antifungals, their preparation process and pharmaceutical preparations containing them - Google Patents
Water-soluble azulis, broad-spectrum antifungals, their preparation process and pharmaceutical preparations containing themInfo
- Publication number
- IL139649A IL139649A IL13964999A IL13964999A IL139649A IL 139649 A IL139649 A IL 139649A IL 13964999 A IL13964999 A IL 13964999A IL 13964999 A IL13964999 A IL 13964999A IL 139649 A IL139649 A IL 139649A
- Authority
- IL
- Israel
- Prior art keywords
- phenyl
- amino
- alkyl
- triazol
- formula
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 43
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 10
- 230000008569 process Effects 0.000 title claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title description 39
- 229940121375 antifungal agent Drugs 0.000 title description 31
- 238000002360 preparation method Methods 0.000 title description 20
- 150000003851 azoles Chemical class 0.000 title description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 197
- -1 hydroxy, mercapto Chemical class 0.000 claims abstract description 172
- 150000001875 compounds Chemical class 0.000 claims abstract description 165
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 67
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 53
- 239000001257 hydrogen Substances 0.000 claims abstract description 53
- 125000003118 aryl group Chemical group 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 125000001424 substituent group Chemical group 0.000 claims abstract description 24
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 14
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 13
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 11
- 125000000815 N-oxide group Chemical group 0.000 claims abstract description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 10
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 10
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 9
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 9
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 7
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims abstract description 7
- DUAJIKVIRGATIW-UHFFFAOYSA-N trinitrogen(.) Chemical compound [N]=[N+]=[N-] DUAJIKVIRGATIW-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims abstract description 5
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 4
- 125000005110 aryl thio group Chemical group 0.000 claims abstract description 4
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims abstract description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 4
- 125000001786 isothiazolyl group Chemical group 0.000 claims abstract description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims abstract description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims abstract description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims abstract description 4
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims abstract description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims abstract description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims abstract description 4
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 4
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims abstract description 3
- 125000005877 1,4-benzodioxanyl group Chemical group 0.000 claims abstract description 3
- 125000005940 1,4-dioxanyl group Chemical group 0.000 claims abstract description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims abstract description 3
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims abstract description 3
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims abstract description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims abstract description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims abstract description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims abstract description 3
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims abstract description 3
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims abstract description 3
- 125000005879 dioxolanyl group Chemical group 0.000 claims abstract description 3
- 125000002541 furyl group Chemical group 0.000 claims abstract description 3
- 125000002632 imidazolidinyl group Chemical group 0.000 claims abstract description 3
- 125000002636 imidazolinyl group Chemical group 0.000 claims abstract description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims abstract description 3
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims abstract description 3
- 125000001041 indolyl group Chemical group 0.000 claims abstract description 3
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims abstract description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims abstract description 3
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 3
- 125000000160 oxazolidinyl group Chemical group 0.000 claims abstract description 3
- 125000002265 phtalazinyl group Chemical group 0.000 claims abstract description 3
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims abstract description 3
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims abstract description 3
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims abstract description 3
- 125000002755 pyrazolinyl group Chemical group 0.000 claims abstract description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims abstract description 3
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims abstract description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims abstract description 3
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims abstract description 3
- 125000001984 thiazolidinyl group Chemical group 0.000 claims abstract description 3
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims abstract description 3
- 125000004306 triazinyl group Chemical group 0.000 claims abstract description 3
- 125000001425 triazolyl group Chemical group 0.000 claims abstract description 3
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 11
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims abstract 2
- 125000001166 thiolanyl group Chemical group 0.000 claims abstract 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 56
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 12
- 206010017533 Fungal infection Diseases 0.000 claims description 10
- 208000031888 Mycoses Diseases 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 238000010511 deprotection reaction Methods 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000012442 inert solvent Substances 0.000 claims description 5
- 150000003335 secondary amines Chemical class 0.000 claims description 5
- 125000005002 aryl methyl group Chemical group 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 230000009466 transformation Effects 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 3
- 239000012458 free base Substances 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000000844 transformation Methods 0.000 claims description 2
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical group C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 claims 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 abstract description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract description 5
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 abstract description 3
- 125000000850 2H-chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 abstract description 2
- 125000001422 pyrrolinyl group Chemical group 0.000 abstract description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- 239000000203 mixture Substances 0.000 description 156
- 239000000543 intermediate Substances 0.000 description 108
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 105
- 239000002904 solvent Substances 0.000 description 95
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 51
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- 239000002244 precipitate Substances 0.000 description 46
- 239000003480 eluent Substances 0.000 description 41
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
- 239000003054 catalyst Substances 0.000 description 35
- 229960004592 isopropanol Drugs 0.000 description 35
- 239000000741 silica gel Substances 0.000 description 34
- 229910002027 silica gel Inorganic materials 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- 150000003254 radicals Chemical class 0.000 description 33
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 29
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 25
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 108010037444 diisopropylglutathione ester Proteins 0.000 description 23
- 229920000858 Cyclodextrin Polymers 0.000 description 22
- 238000004440 column chromatography Methods 0.000 description 21
- 239000000706 filtrate Substances 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 18
- 235000019441 ethanol Nutrition 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 125000005843 halogen group Chemical group 0.000 description 11
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
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- 239000000126 substance Substances 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 229930192474 thiophene Natural products 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 8
- 230000000843 anti-fungal effect Effects 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 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 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 150000001721 carbon Chemical group 0.000 description 7
- 150000004862 dioxolanes Chemical group 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 230000002538 fungal effect Effects 0.000 description 7
- 230000037361 pathway Effects 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 229920003169 water-soluble polymer Polymers 0.000 description 7
- MWRBNPKJOOWZPW-GPADLTIESA-N 1,2-di-[(9E)-octadecenoyl]-sn-glycero-3-phosphoethanolamine Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C\CCCCCCCC MWRBNPKJOOWZPW-GPADLTIESA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- 230000010933 acylation Effects 0.000 description 6
- 238000005917 acylation reaction Methods 0.000 description 6
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- 150000003141 primary amines Chemical class 0.000 description 6
- 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 description 6
- 239000011734 sodium Substances 0.000 description 6
- 230000009885 systemic effect Effects 0.000 description 6
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 5
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
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- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 4
- IRBAWVGZNJIROV-SFHVURJKSA-N 9-(2-cyclopropylethynyl)-2-[[(2s)-1,4-dioxan-2-yl]methoxy]-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one Chemical compound C1=C2C3=CC=C(C#CC4CC4)C=C3CCN2C(=O)N=C1OC[C@@H]1COCCO1 IRBAWVGZNJIROV-SFHVURJKSA-N 0.000 description 4
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- 230000005526 G1 to G0 transition Effects 0.000 description 4
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- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- WMZZTYIRJLUTIN-UHFFFAOYSA-N n-(1,4-dioxaspiro[4.5]decan-8-ylamino)formamide Chemical compound C1CC(NNC=O)CCC21OCCO2 WMZZTYIRJLUTIN-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- WWJFFVUVFNBJTN-UHFFFAOYSA-N neopolyoxin C Natural products C=1C=C(O)C=NC=1C(O)C(C)C(N)C(=O)NC(C(O)=O)C(C(C1O)O)OC1N1C=CC(=O)NC1=O WWJFFVUVFNBJTN-UHFFFAOYSA-N 0.000 description 1
- WWJFFVUVFNBJTN-VHDFTHOZSA-N nikkomycin Z Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@H]2O)O)[C@H](NC(=O)[C@@H](N)[C@H](C)[C@H](O)C=2N=CC(O)=CC=2)C(O)=O)C=CC(=O)NC1=O WWJFFVUVFNBJTN-VHDFTHOZSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- VJZNUICECYWOFV-UHFFFAOYSA-N o-phenyl carbamothioate Chemical compound NC(=S)OC1=CC=CC=C1 VJZNUICECYWOFV-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000001451 organic peroxides Chemical class 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 108010058641 papulacandins Proteins 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000004965 peroxy acids Chemical group 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- NTGBUUXKGAZMSE-UHFFFAOYSA-N phenyl n-[4-[4-(4-methoxyphenyl)piperazin-1-yl]phenyl]carbamate Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C=CC(NC(=O)OC=3C=CC=CC=3)=CC=2)CC1 NTGBUUXKGAZMSE-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229960001407 sodium bicarbonate Drugs 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229940001593 sodium carbonate Drugs 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000004544 spot-on Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 description 1
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Natural products NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000004879 turbidimetry Methods 0.000 description 1
- OXUXQTLJGMPEAY-UHFFFAOYSA-N urea trihydrochloride Chemical compound Cl.Cl.Cl.NC(N)=O OXUXQTLJGMPEAY-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/12—Oxygen or sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP98201588A EP0957101A1 (en) | 1998-05-14 | 1998-05-14 | Water soluble azoles as broad-spectrum antifungals |
| PCT/EP1999/003243 WO1999058530A1 (en) | 1998-05-14 | 1999-05-06 | Water soluble azoles as broad-spectrum antifungals |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL139649A0 IL139649A0 (en) | 2002-02-10 |
| IL139649A true IL139649A (en) | 2004-09-27 |
Family
ID=8233724
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL13964999A IL139649A (en) | 1998-05-14 | 1999-05-06 | Water-soluble azulis, broad-spectrum antifungals, their preparation process and pharmaceutical preparations containing them |
| IL13964799A IL139647A0 (en) | 1998-05-14 | 1999-05-06 | Water soluble azoles as broad-spectrum antifungals |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL13964799A IL139647A0 (en) | 1998-05-14 | 1999-05-06 | Water soluble azoles as broad-spectrum antifungals |
Country Status (31)
| Country | Link |
|---|---|
| US (2) | US6384030B1 (cs) |
| EP (3) | EP0957101A1 (cs) |
| JP (2) | JP2002514645A (cs) |
| KR (2) | KR100575147B1 (cs) |
| CN (2) | CN1135229C (cs) |
| AR (2) | AR016482A1 (cs) |
| AT (2) | ATE221884T1 (cs) |
| AU (2) | AU751135B2 (cs) |
| BG (2) | BG64388B1 (cs) |
| BR (2) | BR9910448A (cs) |
| CA (2) | CA2331187C (cs) |
| CO (1) | CO5021227A1 (cs) |
| CZ (2) | CZ299481B6 (cs) |
| DE (2) | DE69907171T2 (cs) |
| DK (1) | DK1077976T3 (cs) |
| EE (2) | EE04346B1 (cs) |
| ES (2) | ES2198915T3 (cs) |
| HR (2) | HRP20000741B1 (cs) |
| HU (2) | HUP0103536A3 (cs) |
| IL (2) | IL139649A (cs) |
| MY (2) | MY122147A (cs) |
| NO (2) | NO319760B1 (cs) |
| NZ (2) | NZ507966A (cs) |
| PL (2) | PL194085B1 (cs) |
| PT (1) | PT1077976E (cs) |
| SI (1) | SI1077976T1 (cs) |
| SK (2) | SK286156B6 (cs) |
| TR (2) | TR200003323T2 (cs) |
| TW (2) | TWI259835B (cs) |
| WO (2) | WO1999058529A1 (cs) |
| ZA (2) | ZA200007173B (cs) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0957101A1 (en) * | 1998-05-14 | 1999-11-17 | Janssen Pharmaceutica N.V. | Water soluble azoles as broad-spectrum antifungals |
| CA2402345A1 (en) * | 2000-03-07 | 2001-09-13 | Sudershan K. Arora | Azole compounds as therapeutic agents for fungal infections |
| EP1413301A1 (fr) * | 2002-10-24 | 2004-04-28 | Bayer CropScience SA | Médicaments antifongiques à base de dérivés d'arylamidine |
| ITMI20032020A1 (it) | 2003-10-17 | 2005-04-18 | Italfarmaco Spa | Nuovi agenti antifungini azolici con diminuita interazione con i citocromi metabolici |
| AR052342A1 (es) * | 2004-12-21 | 2007-03-14 | Janssen Pharmaceutica Nv | Derivados sustituidos de triazolona,tetrazolona e imidazolona con actividad selectiva antagonista de alfa2c-adenoreceptores |
| BR112012029227B1 (pt) * | 2010-05-19 | 2020-01-07 | Sandoz Ag | Processo para a preparação de um composto quiral, composto quiral e uso de um composto |
| US11028078B2 (en) * | 2011-09-07 | 2021-06-08 | The Johns Hopkins University | Itraconazole analogs and use thereof |
| US9346791B2 (en) | 2011-09-07 | 2016-05-24 | The Johns Hopkins University | Itraconazole analogs and use thereof |
| ES2991873T3 (es) * | 2013-06-07 | 2024-12-05 | Scripps Research Inst | Análogos del itraconazol como inhibidores de fibrosis |
| HUE048685T2 (hu) | 2014-12-05 | 2020-07-28 | Pulmocide Ltd | Antimikotikus vegyület |
| US10336735B2 (en) | 2014-12-10 | 2019-07-02 | The Scripps Research Institute | Small molecule inhibitors of fibrosis |
| DK3298006T3 (da) * | 2015-05-21 | 2020-03-30 | Pulmocide Ltd | Antifungal 4-(4-(4-(((3r,5r)-5-((1h-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorphenyl)tetrahydrofuran-3-yl)methoxy)-3-methylphenyl)piperazin-1-yl)-n-(2-hydroxycyclohexyl)benzamid eller et farmaceutisk acceptabelt salt deraf |
| CN105237392B (zh) * | 2015-11-24 | 2017-12-12 | 辽宁渤大化工有限公司 | 芳烷基水杨酸及其衍生物的制备方法 |
| WO2019040363A1 (en) * | 2017-08-20 | 2019-02-28 | University Of Connecticut | AZOLE-TYPE COMPOUND ANALOGUES AND METHODS OF USE |
| CN111138421A (zh) * | 2019-12-26 | 2020-05-12 | 上海英诺富成生物科技有限公司 | 抗真菌水溶性化合物及其制备方法与应用 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4218458A (en) * | 1978-06-23 | 1980-08-19 | Janssen Pharmaceutica, N.V. | Heterocyclic derivatives of (4-aryloxy-methyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles |
| NZ249494A (en) * | 1992-03-18 | 1996-04-26 | Janssen Pharmaceutica Nv | Itraconazole and saperconazole stereoisomers; pharmaceutical compositions |
| CZ294823B6 (cs) * | 1993-12-21 | 2005-03-16 | Schering Corporation | Fungicidní tetrahydrofurany |
| SI0741737T1 (en) * | 1994-01-24 | 2000-02-29 | Janssen Pharmaceutica N.V. | Watersoluble azole antifungals |
| FI98688C (fi) * | 1994-07-20 | 1997-07-25 | Nokia Telecommunications Oy | Menetelmä lyhytsanomalähetyksen käynnistämiseksi solukkoradiojärjestelmässä, solukkoradiojärjestelmä sekä solukkoradiojärjestelmän tilaajarekisteri |
| TW357146B (en) * | 1995-06-02 | 1999-05-01 | Schering Corp | Tetrahydrofuran antifungals |
| EP0837859B1 (en) * | 1995-06-19 | 2003-08-13 | Schering Corporation | Tetrahydrofuran antifungals |
| NZ334477A (en) | 1997-02-11 | 2001-05-25 | Janssen Pharmaceutica Nv | Amino acid ester containing azole antifungals |
| EP0957101A1 (en) * | 1998-05-14 | 1999-11-17 | Janssen Pharmaceutica N.V. | Water soluble azoles as broad-spectrum antifungals |
-
1998
- 1998-05-14 EP EP98201588A patent/EP0957101A1/en not_active Withdrawn
-
1999
- 1999-05-06 WO PCT/EP1999/003242 patent/WO1999058529A1/en active IP Right Grant
- 1999-05-06 BR BR9910448-2A patent/BR9910448A/pt not_active Application Discontinuation
- 1999-05-06 NZ NZ507966A patent/NZ507966A/xx not_active IP Right Cessation
- 1999-05-06 EP EP99926304A patent/EP1077976B1/en not_active Expired - Lifetime
- 1999-05-06 BR BR9911057-1A patent/BR9911057A/pt not_active Application Discontinuation
- 1999-05-06 IL IL13964999A patent/IL139649A/en not_active IP Right Cessation
- 1999-05-06 EE EEP200000651A patent/EE04346B1/xx not_active IP Right Cessation
- 1999-05-06 AT AT99926304T patent/ATE221884T1/de active
- 1999-05-06 JP JP2000548333A patent/JP2002514645A/ja active Pending
- 1999-05-06 KR KR1020007011624A patent/KR100575147B1/ko not_active Expired - Fee Related
- 1999-05-06 SK SK1681-2000A patent/SK286156B6/sk not_active IP Right Cessation
- 1999-05-06 CZ CZ20004108A patent/CZ299481B6/cs not_active IP Right Cessation
- 1999-05-06 WO PCT/EP1999/003243 patent/WO1999058530A1/en active IP Right Grant
- 1999-05-06 CN CNB998060690A patent/CN1135229C/zh not_active Expired - Fee Related
- 1999-05-06 HR HR20000741A patent/HRP20000741B1/xx not_active IP Right Cessation
- 1999-05-06 ES ES99924942T patent/ES2198915T3/es not_active Expired - Lifetime
- 1999-05-06 CA CA002331187A patent/CA2331187C/en not_active Expired - Fee Related
- 1999-05-06 PL PL99344047A patent/PL194085B1/pl unknown
- 1999-05-06 PT PT99926304T patent/PT1077976E/pt unknown
- 1999-05-06 IL IL13964799A patent/IL139647A0/xx not_active IP Right Cessation
- 1999-05-06 US US09/700,251 patent/US6384030B1/en not_active Expired - Lifetime
- 1999-05-06 US US09/700,166 patent/US6448244B1/en not_active Expired - Lifetime
- 1999-05-06 HU HU0103536A patent/HUP0103536A3/hu unknown
- 1999-05-06 AU AU41417/99A patent/AU751135B2/en not_active Ceased
- 1999-05-06 CA CA002331141A patent/CA2331141C/en not_active Expired - Fee Related
- 1999-05-06 TR TR2000/03323T patent/TR200003323T2/xx unknown
- 1999-05-06 SK SK1682-2000A patent/SK285763B6/sk not_active IP Right Cessation
- 1999-05-06 AU AU43615/99A patent/AU758876B2/en not_active Ceased
- 1999-05-06 DK DK99926304T patent/DK1077976T3/da active
- 1999-05-06 HU HU0102031A patent/HUP0102031A3/hu unknown
- 1999-05-06 HR HR20000740A patent/HRP20000740B1/xx not_active IP Right Cessation
- 1999-05-06 ES ES99926304T patent/ES2182531T3/es not_active Expired - Lifetime
- 1999-05-06 KR KR1020007009640A patent/KR100593395B1/ko not_active Expired - Fee Related
- 1999-05-06 AT AT99924942T patent/ATE238296T1/de not_active IP Right Cessation
- 1999-05-06 DE DE69907171T patent/DE69907171T2/de not_active Expired - Lifetime
- 1999-05-06 PL PL99344037A patent/PL194086B1/pl unknown
- 1999-05-06 JP JP2000548334A patent/JP2002514646A/ja active Pending
- 1999-05-06 SI SI9930131T patent/SI1077976T1/xx unknown
- 1999-05-06 CZ CZ20004109A patent/CZ298702B6/cs not_active IP Right Cessation
- 1999-05-06 EP EP99924942A patent/EP1077975B1/en not_active Expired - Lifetime
- 1999-05-06 CN CNB998059560A patent/CN1137118C/zh not_active Expired - Fee Related
- 1999-05-06 NZ NZ507965A patent/NZ507965A/en not_active IP Right Cessation
- 1999-05-06 TR TR2000/03322T patent/TR200003322T2/xx unknown
- 1999-05-06 DE DE69902461T patent/DE69902461T2/de not_active Expired - Lifetime
- 1999-05-06 EE EEP200000657A patent/EE04311B1/xx not_active IP Right Cessation
- 1999-05-10 TW TW088107505A patent/TWI259835B/zh not_active IP Right Cessation
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- 1999-05-13 AR ARP990102276A patent/AR016482A1/es active IP Right Grant
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2000
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