SK3192000A3 - Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase - Google Patents

Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase Download PDF

Info

Publication number: SK3192000A3
Authority: SK; Slovakia
Prior art keywords: isopropyl; carbonyl; rel; pyrrol; methanesulfonyl
Prior art date: 1997-09-09

Application number

SK319-2000A

Other languages

English (en)

Slovak (sk)

Inventor

Geoffrey Duke Edward Clarke

Michael Dennis Dowle

Harry Finch

Lee Andrew Harrison

Graham George Adam Inglis

Martin Redpath Johnson

Simon John Macdonald

Pritom Shah

Robin Andrew Smith

Original Assignee

Glaxo Group Ltd

Priority date (The priority date 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 date listed.)

1997-09-09

Filing date

1998-09-07

Publication date

2001-03-12

1997-09-09 Priority claimed from GBGB9719183.7A external-priority patent/GB9719183D0/en

1997-09-09 Priority claimed from GBGB9719189.4A external-priority patent/GB9719189D0/en

1997-09-10 Priority claimed from GBGB9719290.0A external-priority patent/GB9719290D0/en

1998-02-21 Priority claimed from GBGB9803611.4A external-priority patent/GB9803611D0/en

1998-09-07 Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd

2001-03-12 Publication of SK3192000A3 publication Critical patent/SK3192000A3/sk

Links

108010028275 Leukocyte Elastase Proteins 0.000 title description 6
102000016799 Leukocyte elastase Human genes 0.000 title description 6
239000003112 inhibitor Substances 0.000 title description 5
ACJSMQZKXAMMRA-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyrrol-5-one Chemical class N1C=CC2=NC(=O)C=C21 ACJSMQZKXAMMRA-UHFFFAOYSA-N 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 213
-1 4-phenyl-piperazin-1-ylmethyl Chemical group 0.000 claims description 90
239000002904 solvent Substances 0.000 claims description 84
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 83
239000000203 mixture Substances 0.000 claims description 70
238000006243 chemical reaction Methods 0.000 claims description 43
238000000034 method Methods 0.000 claims description 41
VIXWGKYSYIBATJ-UHFFFAOYSA-N pyrrol-2-one Chemical compound O=C1C=CC=N1 VIXWGKYSYIBATJ-UHFFFAOYSA-N 0.000 claims description 30
125000000217 alkyl group Chemical group 0.000 claims description 26
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
150000003839 salts Chemical class 0.000 claims description 24
238000002360 preparation method Methods 0.000 claims description 23
125000004432 carbon atom Chemical group C* 0.000 claims description 19
229910052757 nitrogen Inorganic materials 0.000 claims description 18
239000002253 acid Substances 0.000 claims description 13
229910052739 hydrogen Inorganic materials 0.000 claims description 12
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
239000000460 chlorine Substances 0.000 claims description 11
239000001257 hydrogen Substances 0.000 claims description 11
206010006451 bronchitis Diseases 0.000 claims description 10
239000008194 pharmaceutical composition Substances 0.000 claims description 10
239000012453 solvate Substances 0.000 claims description 10
229910052717 sulfur Inorganic materials 0.000 claims description 10
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
239000004480 active ingredient Substances 0.000 claims description 9
125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
229910052801 chlorine Inorganic materials 0.000 claims description 8
150000002148 esters Chemical class 0.000 claims description 8
229910052736 halogen Inorganic materials 0.000 claims description 8
125000005843 halogen group Chemical group 0.000 claims description 8
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
230000008569 process Effects 0.000 claims description 8
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
150000002367 halogens Chemical group 0.000 claims description 7
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
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 description 6
206010006458 Bronchitis chronic Diseases 0.000 claims description 6
229930040373 Paraformaldehyde Natural products 0.000 claims description 6
150000008064 anhydrides Chemical class 0.000 claims description 6
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
208000007451 chronic bronchitis Diseases 0.000 claims description 6
239000012458 free base Substances 0.000 claims description 6
229920002866 paraformaldehyde Polymers 0.000 claims description 6
125000003386 piperidinyl group Chemical group 0.000 claims description 6
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
239000003814 drug Substances 0.000 claims description 5
125000002757 morpholinyl group Chemical group 0.000 claims description 5
229910052760 oxygen Inorganic materials 0.000 claims description 5
125000004193 piperazinyl group Chemical group 0.000 claims description 5
125000003373 pyrazinyl group Chemical group 0.000 claims description 5
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
230000002378 acidificating effect Effects 0.000 claims description 4
125000003118 aryl group Chemical group 0.000 claims description 4
125000005842 heteroatom Chemical group 0.000 claims description 4
125000002950 monocyclic group Chemical group 0.000 claims description 4
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
125000004434 sulfur atom Chemical group 0.000 claims description 4
125000000335 thiazolyl group Chemical group 0.000 claims description 4
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
125000002619 bicyclic group Chemical group 0.000 claims description 3
150000002431 hydrogen Chemical class 0.000 claims description 3
125000000842 isoxazolyl group Chemical group 0.000 claims description 3
238000004519 manufacturing process Methods 0.000 claims description 3
125000003226 pyrazolyl group Chemical group 0.000 claims description 3
125000001424 substituent group Chemical group 0.000 claims description 3
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 2
125000003342 alkenyl group Chemical group 0.000 claims description 2
208000006673 asthma Diseases 0.000 claims description 2
125000002785 azepinyl group Chemical group 0.000 claims description 2
125000002393 azetidinyl group Chemical group 0.000 claims description 2
150000001733 carboxylic acid esters Chemical class 0.000 claims description 2
239000007795 chemical reaction product Substances 0.000 claims description 2
125000001309 chloro group Chemical group Cl* 0.000 claims description 2
125000002971 oxazolyl group Chemical group 0.000 claims description 2
230000001590 oxidative effect Effects 0.000 claims description 2
DSILUGCORMLHPA-UHFFFAOYSA-N 2,3,3a,4,6,6a-hexahydro-1h-pyrrolo[3,2-b]pyrrol-5-one Chemical compound N1CCC2NC(=O)CC21 DSILUGCORMLHPA-UHFFFAOYSA-N 0.000 claims 10
239000003208 petroleum Substances 0.000 claims 3
MEDXAFZZWXHGBT-HYVNUMGLSA-N (3ar,6s,6as)-4-methylsulfonyl-6-propan-2-yl-1-[2-(pyrrolidin-1-ylmethyl)-1,3-oxazole-4-carbonyl]-3,3a,6,6a-tetrahydro-2h-pyrrolo[3,2-b]pyrrol-5-one Chemical compound C([C@@H]1[C@@H]2[C@@H](C(N1S(C)(=O)=O)=O)C(C)C)CN2C(=O)C(N=1)=COC=1CN1CCCC1 MEDXAFZZWXHGBT-HYVNUMGLSA-N 0.000 claims 1
HUXNOGURDDFLLU-UHFFFAOYSA-N 1-(1h-pyrrol-2-ylmethyl)piperidine Chemical compound C=1C=CNC=1CN1CCCCC1 HUXNOGURDDFLLU-UHFFFAOYSA-N 0.000 claims 1
239000013067 intermediate product Substances 0.000 claims 1
208000027866 inflammatory disease Diseases 0.000 abstract description 2
210000002345 respiratory system Anatomy 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 446
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 239
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 172
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 166
239000000543 intermediate Substances 0.000 description 155
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 148
239000000243 solution Substances 0.000 description 147
239000007787 solid Substances 0.000 description 132
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
238000004809 thin layer chromatography Methods 0.000 description 82
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 68
239000011541 reaction mixture Substances 0.000 description 65
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
235000019441 ethanol Nutrition 0.000 description 59
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 58
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 50
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 46
239000000843 powder Substances 0.000 description 43
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
239000000047 product Substances 0.000 description 38
229910021529 ammonia Inorganic materials 0.000 description 34
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 31
238000004949 mass spectrometry Methods 0.000 description 28
239000000377 silicon dioxide Substances 0.000 description 28
238000003756 stirring Methods 0.000 description 28
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 26
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 26
229910000041 hydrogen chloride Inorganic materials 0.000 description 26
229910052943 magnesium sulfate Inorganic materials 0.000 description 25
235000019341 magnesium sulphate Nutrition 0.000 description 25
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
239000002585 base Substances 0.000 description 21
238000003818 flash chromatography Methods 0.000 description 21
239000000284 extract Substances 0.000 description 20
239000000725 suspension Substances 0.000 description 20
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
125000006239 protecting group Chemical group 0.000 description 19
238000010992 reflux Methods 0.000 description 19
235000017557 sodium bicarbonate Nutrition 0.000 description 19
229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
239000003921 oil Substances 0.000 description 18
235000019198 oils Nutrition 0.000 description 18
102000016387 Pancreatic elastase Human genes 0.000 description 17
108010067372 Pancreatic elastase Proteins 0.000 description 17
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 16
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 16
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
229910052938 sodium sulfate Inorganic materials 0.000 description 16
235000011152 sodium sulphate Nutrition 0.000 description 16
239000007858 starting material Substances 0.000 description 16
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
239000000126 substance Substances 0.000 description 15
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
201000010099 disease Diseases 0.000 description 13
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FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 12
238000001819 mass spectrum Methods 0.000 description 12
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 11
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 11
229910000027 potassium carbonate Inorganic materials 0.000 description 11
235000011181 potassium carbonates Nutrition 0.000 description 11
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 10
230000000694 effects Effects 0.000 description 10
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210000001519 tissue Anatomy 0.000 description 9
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CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
0 CN(CCC1*)C1=O Chemical compound CN(CCC1*)C1=O 0.000 description 7
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230000004968 inflammatory condition Effects 0.000 description 7
210000004072 lung Anatomy 0.000 description 7
210000000440 neutrophil Anatomy 0.000 description 7
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
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GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 description 1
239000004137 magnesium phosphate Substances 0.000 description 1
229960002261 magnesium phosphate Drugs 0.000 description 1
229910000157 magnesium phosphate Inorganic materials 0.000 description 1
235000010994 magnesium phosphates Nutrition 0.000 description 1
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BGFZBYKHHGUPSG-UHFFFAOYSA-N methyl 2,4-diaminobutanoate;dihydrochloride Chemical compound Cl.Cl.COC(=O)C(N)CCN BGFZBYKHHGUPSG-UHFFFAOYSA-N 0.000 description 1
NXXLIQGNOSXXHB-UHFFFAOYSA-N methyl 2-(bromomethyl)-1,3-oxazole-4-carboxylate Chemical compound COC(=O)C1=COC(CBr)=N1 NXXLIQGNOSXXHB-UHFFFAOYSA-N 0.000 description 1
HLKQXQWARLHUBP-UHFFFAOYSA-N methyl 2-(piperidin-1-ylmethyl)-1,3-oxazole-4-carboxylate Chemical compound COC(=O)C1=COC(CN2CCCCC2)=N1 HLKQXQWARLHUBP-UHFFFAOYSA-N 0.000 description 1
HPRCDTCZLUPVTP-UHFFFAOYSA-N methyl 2-(pyrrolidin-1-ylmethyl)-1,3-oxazole-4-carboxylate Chemical compound COC(=O)C1=COC(CN2CCCC2)=N1 HPRCDTCZLUPVTP-UHFFFAOYSA-N 0.000 description 1
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RGYWBCLGCBPHBP-UHFFFAOYSA-N methyl 2-[(cyclopropylmethylamino)methyl]-1,3-oxazole-4-carboxylate hydrochloride Chemical compound Cl.COC(=O)C1=COC(CNCC2CC2)=N1 RGYWBCLGCBPHBP-UHFFFAOYSA-N 0.000 description 1
FWTQVMVXUWMQHM-UHFFFAOYSA-N methyl 2-[(dibutylamino)methyl]-1,3-oxazole-4-carboxylate Chemical compound CCCCN(CCCC)CC1=NC(C(=O)OC)=CO1 FWTQVMVXUWMQHM-UHFFFAOYSA-N 0.000 description 1
VOSCNOGVWUXDMU-UHFFFAOYSA-N methyl 2-[(dicyclohexylamino)methyl]-1,3-oxazole-4-carboxylate Chemical compound COC(=O)C1=COC(CN(C2CCCCC2)C2CCCCC2)=N1 VOSCNOGVWUXDMU-UHFFFAOYSA-N 0.000 description 1
OIGRHUBIDWZLHR-UHFFFAOYSA-N methyl 5-(bromomethyl)pyrazine-2-carboxylate Chemical compound COC(=O)C1=CN=C(CBr)C=N1 OIGRHUBIDWZLHR-UHFFFAOYSA-N 0.000 description 1
IRQSKJQDKUAART-UHFFFAOYSA-N methyl 6-(bromomethyl)pyridine-3-carboxylate Chemical compound COC(=O)C1=CC=C(CBr)N=C1 IRQSKJQDKUAART-UHFFFAOYSA-N 0.000 description 1
229920000609 methyl cellulose Polymers 0.000 description 1
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HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
210000002200 mouth mucosa Anatomy 0.000 description 1
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230000003843 mucus production Effects 0.000 description 1
239000003149 muscarinic antagonist Substances 0.000 description 1
208000025113 myeloid leukemia Diseases 0.000 description 1
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FGNGTWFJQFTFGN-UHFFFAOYSA-N n,n,n',n'-tetramethylethane-1,2-diamine Chemical compound CN(C)CCN(C)C.CN(C)CCN(C)C FGNGTWFJQFTFGN-UHFFFAOYSA-N 0.000 description 1
PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
239000012299 nitrogen atmosphere Substances 0.000 description 1
239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
239000002687 nonaqueous vehicle Substances 0.000 description 1
230000000269 nucleophilic effect Effects 0.000 description 1
GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
201000008482 osteoarthritis Diseases 0.000 description 1
239000001301 oxygen Substances 0.000 description 1
239000012188 paraffin wax Substances 0.000 description 1
238000007911 parenteral administration Methods 0.000 description 1
239000000312 peanut oil Substances 0.000 description 1
239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
150000004965 peroxy acids Chemical class 0.000 description 1
239000008177 pharmaceutical agent Substances 0.000 description 1
230000003285 pharmacodynamic effect Effects 0.000 description 1
239000012071 phase Substances 0.000 description 1
YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
125000005544 phthalimido group Chemical group 0.000 description 1
239000002798 polar solvent Substances 0.000 description 1
229940068917 polyethylene glycols Drugs 0.000 description 1
239000001267 polyvinylpyrrolidone Substances 0.000 description 1
229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
229920001592 potato starch Polymers 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
230000002335 preservative effect Effects 0.000 description 1
230000002265 prevention Effects 0.000 description 1
239000003380 propellant Substances 0.000 description 1
239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
210000002307 prostate Anatomy 0.000 description 1
208000023958 prostate neoplasm Diseases 0.000 description 1
230000001681 protective effect Effects 0.000 description 1
102000004169 proteins and genes Human genes 0.000 description 1
108090000623 proteins and genes Proteins 0.000 description 1
239000003586 protic polar solvent Substances 0.000 description 1
230000002685 pulmonary effect Effects 0.000 description 1
NIPZZXUFJPQHNH-UHFFFAOYSA-M pyrazine-2-carboxylate Chemical compound [O-]C(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-M 0.000 description 1
125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 description 1
125000004497 pyrazol-5-yl group Chemical group N1N=CC=C1* 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
DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Natural products OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 1
125000000168 pyrrolyl group Chemical group 0.000 description 1
229940107700 pyruvic acid Drugs 0.000 description 1
150000003254 radicals Chemical class 0.000 description 1
239000000376 reactant Substances 0.000 description 1
230000008707 rearrangement Effects 0.000 description 1
230000009467 reduction Effects 0.000 description 1
230000010410 reperfusion Effects 0.000 description 1
230000029058 respiratory gaseous exchange Effects 0.000 description 1
230000004044 response Effects 0.000 description 1
206010039073 rheumatoid arthritis Diseases 0.000 description 1
230000007017 scission Effects 0.000 description 1
238000000926 separation method Methods 0.000 description 1
230000036303 septic shock Effects 0.000 description 1
208000013223 septicemia Diseases 0.000 description 1
125000005353 silylalkyl group Chemical group 0.000 description 1
229940023144 sodium glycolate Drugs 0.000 description 1
235000019333 sodium laurylsulphate Nutrition 0.000 description 1
229940079832 sodium starch glycolate Drugs 0.000 description 1
239000008109 sodium starch glycolate Substances 0.000 description 1
229920003109 sodium starch glycolate Polymers 0.000 description 1
235000010265 sodium sulphite Nutrition 0.000 description 1
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
239000012265 solid product Substances 0.000 description 1
238000000527 sonication Methods 0.000 description 1
239000004334 sorbic acid Substances 0.000 description 1
235000010199 sorbic acid Nutrition 0.000 description 1
229940075582 sorbic acid Drugs 0.000 description 1
239000001593 sorbitan monooleate Substances 0.000 description 1
235000011069 sorbitan monooleate Nutrition 0.000 description 1
229940035049 sorbitan monooleate Drugs 0.000 description 1
229960002920 sorbitol Drugs 0.000 description 1
239000007921 spray Substances 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
239000008174 sterile solution Substances 0.000 description 1
239000012258 stirred mixture Substances 0.000 description 1
239000011550 stock solution Substances 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
239000000758 substrate Substances 0.000 description 1
235000000346 sugar Nutrition 0.000 description 1
QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 description 1
230000006103 sulfonylation Effects 0.000 description 1
239000000829 suppository Substances 0.000 description 1
239000002511 suppository base Substances 0.000 description 1
239000003765 sweetening agent Substances 0.000 description 1
229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
229960000278 theophylline Drugs 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
230000008719 thickening Effects 0.000 description 1
125000001544 thienyl group Chemical group 0.000 description 1
230000000451 tissue damage Effects 0.000 description 1
231100000827 tissue damage Toxicity 0.000 description 1
208000037816 tissue injury Diseases 0.000 description 1
230000000699 topical effect Effects 0.000 description 1
235000010487 tragacanth Nutrition 0.000 description 1
239000000196 tragacanth Substances 0.000 description 1
229940116362 tragacanth Drugs 0.000 description 1
CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
229940029284 trichlorofluoromethane Drugs 0.000 description 1
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
239000002753 trypsin inhibitor Substances 0.000 description 1
WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
229910052721 tungsten Inorganic materials 0.000 description 1
239000010937 tungsten Substances 0.000 description 1
238000002604 ultrasonography Methods 0.000 description 1
230000008728 vascular permeability Effects 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
238000005303 weighing Methods 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1
230000029663 wound healing Effects 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Public Health (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Pulmonology (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Pain & Pain Management (AREA)
Rheumatology (AREA)
Dermatology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Hydrogenated Pyridines (AREA)

SK319-2000A 1997-09-09 1998-09-07 Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase SK3192000A3 (en)

Applications Claiming Priority (5)

Application Number	Priority Date	Filing Date	Title
GBGB9719183.7A GB9719183D0 (en)	1997-09-09	1997-09-09	Compounds
GBGB9719189.4A GB9719189D0 (en)	1997-09-09	1997-09-09	New therapeutic method
GBGB9719290.0A GB9719290D0 (en)	1997-09-10	1997-09-10	Compounds
GBGB9803611.4A GB9803611D0 (en)	1998-02-21	1998-02-21	Compounds
PCT/EP1998/005609 WO1999012933A2 (en)	1997-09-09	1998-09-07	Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase

Publications (1)

Publication Number	Publication Date
SK3192000A3 true SK3192000A3 (en)	2001-03-12

Family

ID=27451698

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
SK319-2000A SK3192000A3 (en)	1997-09-09	1998-09-07	Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase

Country Status (24)

Country	Link
EP (1)	EP1003748A2 (xx)
JP (1)	JP2001515904A (xx)
KR (1)	KR20010023766A (xx)
CN (1)	CN1278820A (xx)
AP (1)	AP2000001761A0 (xx)
AR (1)	AR017072A1 (xx)
AU (1)	AU9741298A (xx)
BR (1)	BR9812062A (xx)
CA (1)	CA2303176A1 (xx)
CO (1)	CO4970719A1 (xx)
EA (1)	EA200000204A1 (xx)
EE (1)	EE200000138A (xx)
HU (1)	HUP0004644A3 (xx)
ID (1)	ID24452A (xx)
IL (1)	IL134791A0 (xx)
IS (1)	IS5391A (xx)
MA (1)	MA26543A1 (xx)
NO (1)	NO20001198L (xx)
NZ (1)	NZ503130A (xx)
PE (1)	PE107899A1 (xx)
PL (1)	PL339176A1 (xx)
SK (1)	SK3192000A3 (xx)
TR (1)	TR200000907T2 (xx)
WO (1)	WO1999012933A2 (xx)

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* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
GB9905418D0 (en) *	1999-03-09	1999-05-05	Glaxo Group Ltd	Process
MXPA06011410A (es)	2004-03-31	2007-04-20	Johnson & Johnson	Compuestos heterociclicos sin imidazol como moduladores de receptor de histamina h3.
DE102004024772A1 (de) *	2004-05-17	2005-12-22	Grünenthal GmbH	Substituierte 5-Aminomethyl-1H-pyrrol-2-carbonsäureamide
TWI355380B (en) *	2004-05-27	2012-01-01	Nihon Nohyaku Co Ltd	Substituted pyrazinecarboxanilide derivatives or s
JP4853759B2 (ja) *	2004-05-27	2012-01-11	日本農薬株式会社	置換ピラジンカルボン酸アニリド誘導体又はその塩類、その中間体及び農園芸用薬剤並びにその使用方法
GB2418427A (en)	2004-09-02	2006-03-29	Univ Cambridge Tech	Ligands for G-protein coupled receptors
AP2007003979A0 (en)	2004-11-23	2007-06-30	Warner Lambert Co	7-(2h-pyrazol-3-yl)-3,5-dihyroxy-heptanoic acid derivatives as hmg co-a reductase inhibitors for thetreatment of lipidemia
US8198288B2 (en)	2006-05-04	2012-06-12	Pulmagen Therapeutics (Inflammation) Limited	Tetrahydropyrrolopyrimidinediones and their use in therapy
SI2024367T1 (sl)	2006-05-04	2011-04-29	Pulmagen Therapeutics Inflammation Ltd	Tetrahidropirolopirimidinedioni in njihova uporaba kot äśloveĺ ki neutrofil elastazni inhibitorji
GB2452696B (en)	2007-08-02	2009-09-23	Cambridge Entpr Ltd	3-(2',2'-dimethylpropanoylamino)-tetrahydropyridin-2-one and its use in pharmaceutical compositions
US7662967B2 (en)	2007-08-02	2010-02-16	Cambridge Enterprise Limited	Anti-inflammatory compounds and compositions
WO2009060206A1 (en) *	2007-11-07	2009-05-14	Argenta Discovery Limited	3,4,6,7-tetrahydro-1h-pyrrolo[3,4-d]pyrimidine-2,5-diones and their therapeutic use
US20110212181A1 (en) *	2010-02-26	2011-09-01	The University Of Hong Kong	Compositions and methods for treating chronic respiratory inflammation
CA3154761A1 (en)	2019-09-17	2021-03-25	Mereo Biopharma 4 Limited	Alvelestat for use in the treatment of graft rejection, bronchiolitis obliterans syndrome and graft versus host disease
SI4106757T1 (sl)	2020-04-16	2023-11-30	Mereo Biopharma 4 Limited	Postopki, ki vključujejo zaviralec nevtrofilne elastaze alvelestat, za zdravljenje bolezni dihal, ki jo sproži pomanjkanje antitripsina alfa-1
WO2023067103A1 (en)	2021-10-20	2023-04-27	Mereo Biopharma 4 Limited	Neutrophil elastase inhibitors for use in the treatment of fibrosis

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
GB9211783D0 (en) *	1992-06-04	1992-07-15	Ici Plc	Amide derivatives
GB9402680D0 (en) *	1994-02-11	1994-04-06	Zeneca Ltd	Pyrrolidine derivatives
NZ331490A (en) *	1996-03-28	2000-06-23	Glaxo Group Ltd	Pyrrolopyrrolone derivatives for the treatment or prophylaxis of inflammatory disease such as chronic bronchitis, obstructive pulmonary disease and asthma

1998
- 1998-09-04 PE PE1998000828A patent/PE107899A1/es not_active Application Discontinuation
- 1998-09-07 AP APAP/P/2000/001761A patent/AP2000001761A0/en unknown
- 1998-09-07 TR TR2000/00907T patent/TR200000907T2/xx unknown
- 1998-09-07 EA EA200000204A patent/EA200000204A1/ru unknown
- 1998-09-07 CA CA002303176A patent/CA2303176A1/en not_active Abandoned
- 1998-09-07 HU HU0004644A patent/HUP0004644A3/hu unknown
- 1998-09-07 WO PCT/EP1998/005609 patent/WO1999012933A2/en not_active Ceased
- 1998-09-07 SK SK319-2000A patent/SK3192000A3/sk unknown
- 1998-09-07 MA MA25243A patent/MA26543A1/fr unknown
- 1998-09-07 ID IDW20000445A patent/ID24452A/id unknown
- 1998-09-07 IL IL13479198A patent/IL134791A0/xx unknown
- 1998-09-07 EP EP98951348A patent/EP1003748A2/en not_active Withdrawn
- 1998-09-07 AU AU97412/98A patent/AU9741298A/en not_active Abandoned
- 1998-09-07 EE EEP200000138A patent/EE200000138A/xx unknown
- 1998-09-07 BR BR9812062-0A patent/BR9812062A/pt not_active Application Discontinuation
- 1998-09-07 PL PL98339176A patent/PL339176A1/xx not_active Application Discontinuation
- 1998-09-07 NZ NZ503130A patent/NZ503130A/en unknown
- 1998-09-07 JP JP2000510740A patent/JP2001515904A/ja active Pending
- 1998-09-07 KR KR1020007002422A patent/KR20010023766A/ko not_active Withdrawn
- 1998-09-07 CN CN98810954A patent/CN1278820A/zh active Pending
- 1998-09-07 AR ARP980104458A patent/AR017072A1/es unknown
- 1998-09-08 CO CO98051488A patent/CO4970719A1/es unknown
2000
- 2000-02-29 IS IS5391A patent/IS5391A/is unknown
- 2000-03-08 NO NO20001198A patent/NO20001198L/no not_active Application Discontinuation

Also Published As

Publication number	Publication date
EA200000204A1 (ru)	2000-10-30
CN1278820A (zh)	2001-01-03
JP2001515904A (ja)	2001-09-25
EE200000138A (et)	2001-02-15
AR017072A1 (es)	2001-08-22
AP2000001761A0 (en)	2000-03-31
IS5391A (is)	2000-02-29
KR20010023766A (ko)	2001-03-26
HUP0004644A3 (en)	2002-01-28
PL339176A1 (en)	2000-12-04
CA2303176A1 (en)	1999-03-18
NZ503130A (en)	2001-08-31
WO1999012933A2 (en)	1999-03-18
EP1003748A2 (en)	2000-05-31
NO20001198L (no)	2000-05-08
MA26543A1 (fr)	2004-12-20
PE107899A1 (es)	1999-11-17
WO1999012933A3 (en)	1999-05-27
AU9741298A (en)	1999-03-29
HUP0004644A2 (hu)	2001-09-28
NO20001198D0 (no)	2000-03-08
ID24452A (id)	2000-07-20
BR9812062A (pt)	2000-09-26
IL134791A0 (en)	2001-04-30
TR200000907T2 (tr)	2000-11-21
CO4970719A1 (es)	2000-11-07

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