SK132498A3 - Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase - Google Patents

Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase Download PDF

Info

Publication number: SK132498A3
Authority: SK; Slovakia
Prior art keywords: rel; pyrrol; methanesulfonyl; isopropyl; compound
Prior art date: 1996-03-28

Application number

SK1324-98A

Other languages

English (en)

Slovak (sk)

Inventor

Michael D Dowle

Harry Finch

Lee A Harrison

Graham G A Inglis

Martin R Johnson

Simon J F Macdonald

Pritom Shah

Robin A 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.)

1996-03-28

Filing date

1997-03-26

Publication date

1999-08-06

1996-03-28 Priority claimed from GBGB9606508.1A external-priority patent/GB9606508D0/en

1996-11-05 Priority claimed from GBGB9623001.6A external-priority patent/GB9623001D0/en

1997-03-26 Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd

1999-08-06 Publication of SK132498A3 publication Critical patent/SK132498A3/sk

Links

108010028275 Leukocyte Elastase Proteins 0.000 title description 4
102000016799 Leukocyte elastase Human genes 0.000 title description 4
239000003112 inhibitor Substances 0.000 title description 4
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 386
239000000203 mixture Substances 0.000 claims abstract description 105
238000000034 method Methods 0.000 claims abstract description 101
230000008569 process Effects 0.000 claims abstract description 19
206010006451 bronchitis Diseases 0.000 claims abstract description 12
206010006458 Bronchitis chronic Diseases 0.000 claims abstract description 9
208000007451 chronic bronchitis Diseases 0.000 claims abstract description 9
239000003814 drug Substances 0.000 claims abstract description 4
-1 (CH 2) m -NR 4 R 5 Chemical group 0.000 claims description 98
125000004432 carbon atom Chemical group C* 0.000 claims description 79
125000000217 alkyl group Chemical group 0.000 claims description 71
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 58
229910052757 nitrogen Inorganic materials 0.000 claims description 58
238000002360 preparation method Methods 0.000 claims description 43
150000003839 salts Chemical class 0.000 claims description 43
VIXWGKYSYIBATJ-UHFFFAOYSA-N pyrrol-2-one Chemical compound O=C1C=CC=N1 VIXWGKYSYIBATJ-UHFFFAOYSA-N 0.000 claims description 32
125000003342 alkenyl group Chemical group 0.000 claims description 31
125000003118 aryl group Chemical group 0.000 claims description 27
125000004433 nitrogen atom Chemical group N* 0.000 claims description 26
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 22
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 19
230000015572 biosynthetic process Effects 0.000 claims description 19
239000002253 acid Substances 0.000 claims description 18
229920006395 saturated elastomer Polymers 0.000 claims description 18
125000001424 substituent group Chemical group 0.000 claims description 18
239000001257 hydrogen Substances 0.000 claims description 17
229910052739 hydrogen Inorganic materials 0.000 claims description 17
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 16
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 16
125000006239 protecting group Chemical group 0.000 claims description 16
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
125000005907 alkyl ester group Chemical class 0.000 claims description 12
125000005843 halogen group Chemical group 0.000 claims description 12
125000001072 heteroaryl group Chemical group 0.000 claims description 12
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 11
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 11
239000008194 pharmaceutical composition Substances 0.000 claims description 11
229910052717 sulfur Inorganic materials 0.000 claims description 11
239000000126 substance Substances 0.000 claims description 10
PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 9
125000003545 alkoxy group Chemical group 0.000 claims description 9
229910052801 chlorine Inorganic materials 0.000 claims description 9
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
229910052736 halogen Inorganic materials 0.000 claims description 9
150000002367 halogens Chemical class 0.000 claims description 9
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
125000004414 alkyl thio group Chemical group 0.000 claims description 7
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 7
238000004519 manufacturing process Methods 0.000 claims description 7
230000002265 prevention Effects 0.000 claims description 7
239000012453 solvate Substances 0.000 claims description 7
239000011593 sulfur Substances 0.000 claims description 7
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
229910052794 bromium Inorganic materials 0.000 claims description 6
229910052799 carbon Inorganic materials 0.000 claims description 6
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 6
239000000460 chlorine Substances 0.000 claims description 6
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
239000004480 active ingredient Substances 0.000 claims description 5
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
238000010511 deprotection reaction Methods 0.000 claims description 5
150000002148 esters Chemical class 0.000 claims description 5
229910052760 oxygen Inorganic materials 0.000 claims description 5
238000006268 reductive amination reaction Methods 0.000 claims description 5
208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 claims description 4
125000005018 aryl alkenyl group Chemical group 0.000 claims description 4
XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 4
125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
125000004193 piperazinyl group Chemical group 0.000 claims description 4
125000001544 thienyl group Chemical group 0.000 claims description 4
CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 4
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 3
125000001309 chloro group Chemical group Cl* 0.000 claims description 3
239000003085 diluting agent Substances 0.000 claims description 3
125000002541 furyl group Chemical group 0.000 claims description 3
125000005842 heteroatom Chemical group 0.000 claims description 3
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
125000000168 pyrrolyl group Chemical group 0.000 claims description 3
238000005694 sulfonylation reaction Methods 0.000 claims description 3
125000003831 tetrazolyl group Chemical group 0.000 claims description 3
125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 3
SDGKUVSVPIIUCF-UHFFFAOYSA-N 2,6-dimethylpiperidine Chemical compound CC1CCCC(C)N1 SDGKUVSVPIIUCF-UHFFFAOYSA-N 0.000 claims description 2
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
125000003368 amide group Chemical group 0.000 claims description 2
METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims description 2
125000004494 ethyl ester group Chemical group 0.000 claims description 2
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
238000005932 reductive alkylation reaction Methods 0.000 claims description 2
125000006413 ring segment Chemical group 0.000 claims description 2
RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium group Chemical group [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 claims description 2
230000006103 sulfonylation Effects 0.000 claims description 2
125000004434 sulfur atom Chemical group 0.000 claims description 2
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 2
238000002560 therapeutic procedure Methods 0.000 claims description 2
KAKQVSNHTBLJCH-UHFFFAOYSA-N trifluoromethanesulfonimidic acid Chemical compound NS(=O)(=O)C(F)(F)F KAKQVSNHTBLJCH-UHFFFAOYSA-N 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 5
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 5
125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 2
DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 2
125000000719 pyrrolidinyl group Chemical group 0.000 claims 2
AYKBFCREVQLSOZ-UHFFFAOYSA-N 4-propyl-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrol-5-one Chemical compound C1CNC2CC(=O)N(CCC)C21 AYKBFCREVQLSOZ-UHFFFAOYSA-N 0.000 claims 1
125000004648 C2-C8 alkenyl group Chemical group 0.000 claims 1
159000000007 calcium salts Chemical class 0.000 claims 1
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 claims 1
SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 claims 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 660
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 489
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 345
239000000243 solution Substances 0.000 description 282
239000000543 intermediate Substances 0.000 description 271
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 258
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 196
238000001819 mass spectrum Methods 0.000 description 185
238000004809 thin layer chromatography Methods 0.000 description 184
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 166
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 146
239000011541 reaction mixture Substances 0.000 description 133
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 130
239000007787 solid Substances 0.000 description 112
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 110
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 97
239000000377 silicon dioxide Substances 0.000 description 92
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239000002904 solvent Substances 0.000 description 91
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238000006243 chemical reaction Methods 0.000 description 88
235000019441 ethanol Nutrition 0.000 description 87
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 85
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 78
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 72
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 69
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 56
239000007858 starting material Substances 0.000 description 56
229910052943 magnesium sulfate Inorganic materials 0.000 description 55
235000019341 magnesium sulphate Nutrition 0.000 description 55
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 54
239000000284 extract Substances 0.000 description 52
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 52
229910021529 ammonia Inorganic materials 0.000 description 45
238000003818 flash chromatography Methods 0.000 description 41
239000000047 product Substances 0.000 description 38
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 36
239000003921 oil Substances 0.000 description 35
235000019198 oils Nutrition 0.000 description 35
235000017557 sodium bicarbonate Nutrition 0.000 description 34
229910000030 sodium bicarbonate Inorganic materials 0.000 description 34
229910052938 sodium sulfate Inorganic materials 0.000 description 33
235000011152 sodium sulphate Nutrition 0.000 description 33
239000002585 base Substances 0.000 description 30
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 29
229910000041 hydrogen chloride Inorganic materials 0.000 description 29
239000012299 nitrogen atmosphere Substances 0.000 description 27
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 26
239000000843 powder Substances 0.000 description 26
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 23
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 22
238000003756 stirring Methods 0.000 description 22
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 21
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 20
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
238000001914 filtration Methods 0.000 description 19
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
239000000725 suspension Substances 0.000 description 17
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 15
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 15
102000016387 Pancreatic elastase Human genes 0.000 description 15
108010067372 Pancreatic elastase Proteins 0.000 description 15
239000006260 foam Substances 0.000 description 15
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 14
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
239000000706 filtrate Substances 0.000 description 13
238000003786 synthesis reaction Methods 0.000 description 13
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 12
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
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238000010521 absorption reaction Methods 0.000 description 12
WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 12
201000010099 disease Diseases 0.000 description 12
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
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VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
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238000004587 chromatography analysis Methods 0.000 description 10
239000012458 free base Substances 0.000 description 10
230000005484 gravity Effects 0.000 description 10
210000004072 lung Anatomy 0.000 description 10
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239000003054 catalyst Substances 0.000 description 9
238000004296 chiral HPLC Methods 0.000 description 9
239000012230 colorless oil Substances 0.000 description 9
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QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
244000166102 Eucalyptus leucoxylon Species 0.000 description 8
235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 8
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230000000694 effects Effects 0.000 description 8
239000003480 eluent Substances 0.000 description 8
CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 description 8
239000010502 orange oil Substances 0.000 description 8
NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 8
238000000746 purification Methods 0.000 description 8
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 8
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
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239000012298 atmosphere Substances 0.000 description 7
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230000014759 maintenance of location Effects 0.000 description 7
239000011347 resin Substances 0.000 description 7
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239000011780 sodium chloride Substances 0.000 description 7
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229910015900 BF3 Inorganic materials 0.000 description 6
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
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FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
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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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
- 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
- A61P35/00—Antineoplastic agents
- 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
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- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D207/14—Nitrogen atoms not forming part of a nitro radical

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General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
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Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
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Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Urology & Nephrology (AREA)
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Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Pain & Pain Management (AREA)
Rheumatology (AREA)
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Pyrrole Compounds (AREA)

SK1324-98A 1996-03-28 1997-03-26 Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase SK132498A3 (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
GBGB9606508.1A GB9606508D0 (en)	1996-03-28	1996-03-28	Chemical componds
GBGB9623001.6A GB9623001D0 (en)	1996-11-05	1996-11-05	Chemical compounds
PCT/EP1997/001530 WO1997036903A1 (en)	1996-03-28	1997-03-26	Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase

Publications (1)

Publication Number	Publication Date
SK132498A3 true SK132498A3 (en)	1999-08-06

Family

ID=26309008

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
SK1324-98A SK132498A3 (en)	1996-03-28	1997-03-26	Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase

Country Status (30)

Country	Link
US (3)	US5994344A (cs)
EP (1)	EP0891362B1 (cs)
JP (1)	JP4118337B2 (cs)
KR (1)	KR20000005039A (cs)
CN (1)	CN1067075C (cs)
AP (1)	AP823A (cs)
AR (1)	AR006401A1 (cs)
AT (1)	ATE261969T1 (cs)
AU (1)	AU726649B2 (cs)
BR (1)	BR9708449A (cs)
CA (1)	CA2250209A1 (cs)
CO (1)	CO4790152A1 (cs)
CZ (1)	CZ309798A3 (cs)
DE (1)	DE69728139T2 (cs)
DK (1)	DK0891362T3 (cs)
EA (1)	EA001437B1 (cs)
EE (1)	EE9800335A (cs)
ES (1)	ES2217404T3 (cs)
HU (1)	HUP9900567A3 (cs)
IL (1)	IL125859A0 (cs)
IS (1)	IS4837A (cs)
NO (1)	NO984470L (cs)
NZ (1)	NZ331490A (cs)
PE (1)	PE55298A1 (cs)
PL (1)	PL329153A1 (cs)
PT (1)	PT891362E (cs)
SK (1)	SK132498A3 (cs)
TR (1)	TR199801935T2 (cs)
WO (1)	WO1997036903A1 (cs)
YU (1)	YU41198A (cs)

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GB9719189D0 (en) *	1997-09-09	1997-11-12	Glaxo Group Ltd	New therapeutic method
GB9719172D0 (en) *	1997-09-09	1997-11-12	Glaxo Group Ltd	Compounds
PE107899A1 (es) *	1997-09-09	1999-11-17	Glaxo Group Ltd	Derivados de pirrolopirrolona como inhibidores de elastasa leucocitaria
GB9719187D0 (en) *	1997-09-09	1997-11-12	Glaxo Group Ltd	Compounds
GB9821199D0 (en) *	1998-09-30	1998-11-25	Glaxo Group Ltd	Chemical compounds
GB9905418D0 (en) *	1999-03-09	1999-05-05	Glaxo Group Ltd	Process
WO2004081015A1 (en) *	2003-03-10	2004-09-23	Hetero Drugs Limited	Amorphous clopidogrel hydrogen sulfate
RU2366655C2 (ru)	2003-03-14	2009-09-10	Оно Фармасьютикал Ко., Лтд.	Азотсодержащие гетероциклические производные и лекарственные средства, содержащие их в качестве активного ингредиента
US8530509B2 (en)	2003-06-20	2013-09-10	Siga Technologies, Inc.	Compounds, compositions and methods for treatment and prevention of orthopoxvirus infections and associated diseases
US7692037B2 (en) *	2004-09-02	2010-04-06	Eastman Chemical Company	Optimized liquid-phase oxidation
GB2418427A (en)	2004-09-02	2006-03-29	Univ Cambridge Tech	Ligands for G-protein coupled receptors
US8143404B2 (en)	2004-09-13	2012-03-27	Ono Pharmaceutical Co., Ltd	Nitrogenous heterocylic derivative and medicine containing the same as an active ingredient
GB0512238D0 (en) *	2005-06-15	2005-07-27	Univ Cambridge Tech	Anti-inflammatory agents
CA2644368A1 (en)	2006-03-10	2007-09-20	Ono Pharmaceutical Co., Ltd.	Nitrogenated heterocyclic derivative, and pharmaceutical agent comprising the derivative as active ingredient
CN104758281A (zh) *	2007-04-23	2015-07-08	西佳技术公司	用于治疗和预防正痘病毒感染和相关疾病的化合物、组合物和方法
NZ585298A (en)	2007-11-16	2012-08-31	Rigel Pharmaceuticals Inc	Carboxamide, sulfonamide and amine compounds for metabolic disorders
EP2231666B1 (en)	2007-12-12	2015-07-29	Rigel Pharmaceuticals, Inc.	Carboxamide, sulfonamide and amine compounds for metabolic disorders
BRPI0911681B8 (pt)	2008-04-23	2021-05-25	Rigel Pharmaceuticals Inc	composto, composição farmacêutica, e, método para ativar a via de proteína quinase ativada por 5'-amp em uma célula in vitro
EP2935274B1 (en) *	2012-12-18	2018-10-03	Chiesi Farmaceutici S.p.A.	3-oxo-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine derivatives for the treatmetn of respiratory diseases
JP7672641B2 (ja)	2019-09-17	2025-05-08	メレオバイオファーマ４リミテッド	移植片拒絶反応、閉塞性細気管支炎症候群、及び移植片対宿主病の治療に使用するためのアルベレスタット
IL297211B2 (en)	2020-04-16	2025-12-01	Mereo Biopharma 4 Ltd	Methods involving neutrophil elastase inhibitor alvelestat for treating respiratory disease mediated by alpha-1 antitrypsin deficiency
KR20240090272A (ko)	2021-10-20	2024-06-21	메레오 바이오파마 4 리미티드	섬유화 치료에 사용하기 위한 호중구 엘라스테이스 억제제

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US2932650A (en) *	1957-11-19	1960-04-12	Arthur C Cope	2-6-diazabicyclo (3. 3. 0) octanes
US4997950A (en) *	1989-04-20	1991-03-05	Richard Finbar Murphy	Novel C-terminal gastrin antagonists
GB9211783D0 (en) *	1992-06-04	1992-07-15	Ici Plc	Amide derivatives
GB9402680D0 (en) *	1994-02-11	1994-04-06	Zeneca Ltd	Pyrrolidine derivatives
US5610296A (en) *	1994-12-05	1997-03-11	G. D. Searle & Co.	Process for the preparation of amidino phenyl pyrrolidine beta-alanine urea analogs

1997
- 1997-03-26 CA CA002250209A patent/CA2250209A1/en not_active Abandoned
- 1997-03-26 AT AT97915439T patent/ATE261969T1/de not_active IP Right Cessation
- 1997-03-26 EP EP97915439A patent/EP0891362B1/en not_active Expired - Lifetime
- 1997-03-26 IL IL12585997A patent/IL125859A0/xx unknown
- 1997-03-26 TR TR1998/01935T patent/TR199801935T2/xx unknown
- 1997-03-26 CZ CZ983097A patent/CZ309798A3/cs unknown
- 1997-03-26 WO PCT/EP1997/001530 patent/WO1997036903A1/en not_active Ceased
- 1997-03-26 EE EE9800335A patent/EE9800335A/xx unknown
- 1997-03-26 AR ARP970101212A patent/AR006401A1/es not_active Application Discontinuation
- 1997-03-26 SK SK1324-98A patent/SK132498A3/sk unknown
- 1997-03-26 ES ES97915439T patent/ES2217404T3/es not_active Expired - Lifetime
- 1997-03-26 CN CN97194959A patent/CN1067075C/zh not_active Expired - Lifetime
- 1997-03-26 US US09/155,323 patent/US5994344A/en not_active Expired - Fee Related
- 1997-03-26 HU HU9900567A patent/HUP9900567A3/hu unknown
- 1997-03-26 AP APAP/P/1998/001351A patent/AP823A/en active
- 1997-03-26 EA EA199800773A patent/EA001437B1/ru not_active IP Right Cessation
- 1997-03-26 PL PL97329153A patent/PL329153A1/xx unknown
- 1997-03-26 AU AU22917/97A patent/AU726649B2/en not_active Ceased
- 1997-03-26 BR BR9708449A patent/BR9708449A/pt unknown
- 1997-03-26 PT PT97915439T patent/PT891362E/pt unknown
- 1997-03-26 PE PE1997000244A patent/PE55298A1/es not_active Application Discontinuation
- 1997-03-26 JP JP53490797A patent/JP4118337B2/ja not_active Expired - Fee Related
- 1997-03-26 KR KR1019980707664A patent/KR20000005039A/ko not_active Withdrawn
- 1997-03-26 DK DK97915439T patent/DK0891362T3/da active
- 1997-03-26 DE DE69728139T patent/DE69728139T2/de not_active Expired - Fee Related
- 1997-03-26 NZ NZ331490A patent/NZ331490A/en unknown
- 1997-03-31 CO CO97015902A patent/CO4790152A1/es unknown
1998
- 1998-08-28 IS IS4837A patent/IS4837A/is unknown
- 1998-09-23 YU YU41198A patent/YU41198A/sh unknown
- 1998-09-25 NO NO984470A patent/NO984470L/no not_active Application Discontinuation
1999
- 1999-10-15 US US09/418,644 patent/US6057457A/en not_active Expired - Fee Related
2000
- 2000-03-03 US US09/517,963 patent/US6215002B1/en not_active Expired - Fee Related

Also Published As

Publication number	Publication date
NZ331490A (en)	2000-06-23
JP4118337B2 (ja)	2008-07-16
HUP9900567A2 (hu)	1999-06-28
DK0891362T3 (da)	2004-07-12
DE69728139T2 (de)	2004-10-21
US5994344A (en)	1999-11-30
WO1997036903A1 (en)	1997-10-09
PT891362E (pt)	2004-08-31
CN1067075C (zh)	2001-06-13
KR20000005039A (ko)	2000-01-25
CO4790152A1 (es)	1999-05-31
ATE261969T1 (de)	2004-04-15
TR199801935T2 (xx)	1999-03-22
EA199800773A1 (ru)	1999-06-24
BR9708449A (pt)	1999-08-03
NO984470L (no)	1998-11-25
DE69728139D1 (de)	2004-04-22
CZ309798A3 (cs)	1999-02-17
EP0891362A1 (en)	1999-01-20
JP2000507950A (ja)	2000-06-27
IS4837A (is)	1998-08-28
PE55298A1 (es)	1998-09-19
AU2291797A (en)	1997-10-22
AU726649B2 (en)	2000-11-16
CA2250209A1 (en)	1997-10-09
NO984470D0 (no)	1998-09-25
US6215002B1 (en)	2001-04-10
YU41198A (sh)	1999-09-27
AR006401A1 (es)	1999-08-25
EA001437B1 (ru)	2001-02-26
ES2217404T3 (es)	2004-11-01
AP823A (en)	2000-04-25
AP9801351A0 (en)	1998-09-30
PL329153A1 (en)	1999-03-15
EP0891362B1 (en)	2004-03-17
HUP9900567A3 (en)	2001-02-28
CN1219935A (zh)	1999-06-16
IL125859A0 (en)	1999-04-11
US6057457A (en)	2000-05-02
EE9800335A (et)	1999-04-15

Publication	Publication Date	Title
SK132498A3 (en)	1999-08-06	Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase
US5374648A (en)	1994-12-20	Indole derivatives and pharmaceutical use thereof
DE69411317T2 (de)	1999-02-18	Indoloylguanidinderivate als Inhibitoren des Natrium-Protonen Austauschs
US20030232832A1 (en)	2003-12-18	Pyrrolotriazinone compounds and their use to teat diseases
US20030153507A1 (en)	2003-08-14	HIV protease inhibitors, compositions containing the same, their pharmaceutical uses and materials for their synthesis
JP4607457B2 (ja)	2011-01-05	ピロロピリミジンＡ２ｂ選択的アンタゴニスト化合物、それらの合成、及び使用
CA2501947A1 (en)	2004-04-22	Azaindole derivatives as inhibitors of p38 kinase
US5977136A (en)	1999-11-02	Tetrahydroquinolines as NMDA antagonists
IE58788B1 (en)	1993-11-17	Ethylenediamine monoamide derivatives
RU2162470C2 (ru)	2001-01-27	2,7-замещенные производные октагидропирроло[1,2-а]пиразина, способ лечения, фармацевтическая композиция, промежуточные соединения
US5962448A (en)	1999-10-05	Pyrroloazepine derivatives
US5210208A (en)	1993-05-11	Disubstituted aryl compounds exhibiting selective leukotriene b4 antagonist activity
EP0436157B1 (en)	1995-08-23	Quinazoline derivatives and their preparation
EP0557526A1 (en)	1993-09-01	Pyrroloazepine compound
SK3242000A3 (en)	2001-03-12	Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase
JPWO1997000258A1 (ja)	1998-08-25	三環性ベンゾアゼピン化合物
US6310064B1 (en)	2001-10-30	Aralkyl diazabicycloalkane derivatives for CNS disorders
EP0008950A2 (en)	1980-03-19	Pyrimido(1,6-a)indole derivatives and intermediates therefor, processes for their preparation, pharmaceutical compositions containing the derivatives and their use
JP2001515905A (ja)	2001-09-25	ピロロピロロン誘導体
CZ2000878A3 (cs)	2000-08-16	Pyrrolopyrrolonové deriváty
HK1107984A1 (en)	2008-04-25	Pyrrolopyridine-2-carboxylic acid amide derivative useful as inhibitor of glycogen phosphorylase
HK1107984B (en)	2008-11-14	Pyrrolopyridine-2-carboxylic acid amide derivative useful as inhibitor of glycogen phosphorylase