CA2278217A1 - Phosphodiesterase 4-inhibiting diazepinoindolones - Google Patents
Phosphodiesterase 4-inhibiting diazepinoindolones Download PDFInfo
- Publication number
- CA2278217A1 CA2278217A1 CA002278217A CA2278217A CA2278217A1 CA 2278217 A1 CA2278217 A1 CA 2278217A1 CA 002278217 A CA002278217 A CA 002278217A CA 2278217 A CA2278217 A CA 2278217A CA 2278217 A1 CA2278217 A1 CA 2278217A1
- Authority
- CA
- Canada
- Prior art keywords
- oxo
- methyl
- diazepino
- indol
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- ZWOMUDQWODQGQH-UHFFFAOYSA-N 1H-pyrrolo[2,3-g][1,2]benzodiazepin-2-one Chemical class C1=CC2=NN=CC=CC2=C2C1=CC(=O)N2 ZWOMUDQWODQGQH-UHFFFAOYSA-N 0.000 title claims description 15
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 title abstract 2
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 title abstract 2
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 title abstract 2
- 230000002401 inhibitory effect Effects 0.000 title description 6
- 238000000034 method Methods 0.000 claims abstract description 136
- 150000001875 compounds Chemical class 0.000 claims abstract description 122
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 10
- 208000006673 asthma Diseases 0.000 claims abstract description 9
- 206010065687 Bone loss Diseases 0.000 claims abstract description 5
- 206010012438 Dermatitis atopic Diseases 0.000 claims abstract description 5
- 206010040070 Septic Shock Diseases 0.000 claims abstract description 5
- 201000008937 atopic dermatitis Diseases 0.000 claims abstract description 5
- 231100000753 hepatic injury Toxicity 0.000 claims abstract description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 5
- 230000036303 septic shock Effects 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 206010067125 Liver injury Diseases 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 132
- 230000008569 process Effects 0.000 claims description 119
- 239000000203 mixture Substances 0.000 claims description 102
- 239000000543 intermediate Substances 0.000 claims description 78
- KCKIKSJECTZLJA-UHFFFAOYSA-N indol-4-one Chemical compound O=C1C=CC=C2N=CC=C12 KCKIKSJECTZLJA-UHFFFAOYSA-N 0.000 claims description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- 239000002253 acid Substances 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- -1 -(CH2)n-OR3 Chemical class 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 36
- 150000002431 hydrogen Chemical class 0.000 claims description 29
- 150000002148 esters Chemical class 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 21
- 150000001412 amines Chemical class 0.000 claims description 19
- 239000002609 medium Substances 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 16
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 claims description 10
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims description 10
- 150000001408 amides Chemical class 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 10
- RTDDGJVVKVRATF-UHFFFAOYSA-N 1,10-diazatricyclo[6.4.1.04,13]trideca-2,4(13),5,7,9-pentaen-12-one Chemical group O=C1CN=Cc2cccc3ccn1c23 RTDDGJVVKVRATF-UHFFFAOYSA-N 0.000 claims description 9
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 150000002466 imines Chemical class 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 6
- NWCMLDFYUXRUPL-UHFFFAOYSA-N 2-methyl-3-(9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydroquinazoline-7-carboxylic acid Chemical compound CC1=CC=2CCC=C(C(N(C=3)N4C(C5=CC=C(C=C5N=C4C)C(O)=O)=O)=O)C=2N1C=3C1=CC=CC=C1 NWCMLDFYUXRUPL-UHFFFAOYSA-N 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 208000011231 Crohn disease Diseases 0.000 claims description 5
- 230000006181 N-acylation Effects 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000004220 glutamic acid Substances 0.000 claims description 5
- IVKNUIVDQMARCO-UHFFFAOYSA-N oxazin-4-one Chemical compound O=C1C=CON=C1 IVKNUIVDQMARCO-UHFFFAOYSA-N 0.000 claims description 5
- AJGTXMYFYOYFFV-UHFFFAOYSA-N 2-methyl-3-(6-methyl-12-oxo-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-11-yl)-4-oxoquinazoline-5-carboxylic acid Chemical compound C=1C(C)=CC=2CCN(C(C(N=3)N4C(C5=C(C(O)=O)C=CC=C5N=C4C)=O)=O)C=2C=1C=3C1=CC=CC=C1 AJGTXMYFYOYFFV-UHFFFAOYSA-N 0.000 claims description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 4
- 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 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000004472 Lysine Substances 0.000 claims description 4
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 4
- 239000003377 acid catalyst Substances 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 206010019663 Hepatic failure Diseases 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- 230000002862 amidating effect Effects 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 150000004982 aromatic amines Chemical class 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 3
- 230000001900 immune effect Effects 0.000 claims description 3
- 231100000835 liver failure Toxicity 0.000 claims description 3
- 208000007903 liver failure Diseases 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 229910052987 metal hydride Inorganic materials 0.000 claims description 3
- 150000004681 metal hydrides Chemical class 0.000 claims description 3
- 208000005368 osteomalacia Diseases 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 239000000651 prodrug Substances 0.000 claims description 3
- 229940002612 prodrug Drugs 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 150000003335 secondary amines Chemical class 0.000 claims description 3
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 3
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 3
- GCQYMZYZLNYUSY-VWLOTQADSA-N (11S)-11-(5-fluoro-2-methyl-4-oxoquinazolin-3-yl)-6-methyl-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-12-one Chemical compound C=1C(C)=CC=2CCN(C([C@@H](N=3)N4C(C5=C(F)C=CC=C5N=C4C)=O)=O)C=2C=1C=3C1=CC=CC=C1 GCQYMZYZLNYUSY-VWLOTQADSA-N 0.000 claims description 2
- YJLSARIGMMOOGK-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) 2-methyl-3-(6-methyl-12-oxo-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-11-yl)-4-oxoquinazoline-7-carboxylate Chemical compound C=1C(C)=CC=2CCN(C3=O)C=2C=1C(C=1C=CC=CC=1)=NC3N(C(C1=CC=2)=O)C(C)=NC1=CC=2C(=O)OC1=C(F)C(F)=C(F)C(F)=C1F YJLSARIGMMOOGK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- LMUOPFLPXGNHCL-UHFFFAOYSA-N 11-(6-methoxy-2-methyl-4-oxoquinazolin-3-yl)-6-methyl-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-12-one Chemical compound O=C1C2=CC(OC)=CC=C2N=C(C)N1C(C(N1CCC=2C=C(C)C=C3C1=2)=O)N=C3C1=CC=CC=C1 LMUOPFLPXGNHCL-UHFFFAOYSA-N 0.000 claims description 2
- GBHSNPOCVNFENX-UHFFFAOYSA-N 11-[7-(hydroxymethyl)-2-methyl-4-oxoquinazolin-3-yl]-6-methyl-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-12-one Chemical compound C=1C(C)=CC=2CCN(C(C(N=3)N4C(C5=CC=C(CO)C=C5N=C4C)=O)=O)C=2C=1C=3C1=CC=CC=C1 GBHSNPOCVNFENX-UHFFFAOYSA-N 0.000 claims description 2
- VAUTUGGBWWRHIY-UHFFFAOYSA-N 2-hydroxyethyl 2-methyl-3-(6-methyl-12-oxo-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-11-yl)-4-oxoquinazoline-7-carboxylate Chemical compound C=1C(C)=CC=2CCN(C(C(N=3)N4C(C5=CC=C(C=C5N=C4C)C(=O)OCCO)=O)=O)C=2C=1C=3C1=CC=CC=C1 VAUTUGGBWWRHIY-UHFFFAOYSA-N 0.000 claims description 2
- IFMSCYUQRZNAFK-UHFFFAOYSA-N 2-methoxyethyl 2-methyl-3-(6-methyl-12-oxo-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-11-yl)-4-oxoquinazoline-7-carboxylate Chemical compound C=1C(C(=O)OCCOC)=CC=C(C2=O)C=1N=C(C)N2C(C(N1CCC=2C=C(C)C=C3C1=2)=O)N=C3C1=CC=CC=C1 IFMSCYUQRZNAFK-UHFFFAOYSA-N 0.000 claims description 2
- WWCKONRFPLGFIA-UHFFFAOYSA-N 2-methyl-3-(6-methyl-12-oxo-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-11-yl)-4-oxoquinazoline-7-carboxamide Chemical compound C=1C(C)=CC=2CCN(C(C(N=3)N4C(C5=CC=C(C=C5N=C4C)C(N)=O)=O)=O)C=2C=1C=3C1=CC=CC=C1 WWCKONRFPLGFIA-UHFFFAOYSA-N 0.000 claims description 2
- MNGFGZLQQZOPHM-UHFFFAOYSA-N 2-methyl-3-(6-methyl-12-oxo-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-11-yl)-N-(2-morpholin-4-ylethyl)-4-oxoquinazoline-7-carboxamide Chemical compound C=1C(C)=CC=2CCN(C3=O)C=2C=1C(C=1C=CC=CC=1)=NC3N(C(C1=CC=2)=O)C(C)=NC1=CC=2C(=O)NCCN1CCOCC1 MNGFGZLQQZOPHM-UHFFFAOYSA-N 0.000 claims description 2
- WVQTWDYRWFPRCI-UHFFFAOYSA-N 2-methyl-3-(9-methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)-4-oxo-3,4-dihydroquinazoline-7-carboxylic acid Chemical compound COC1=CC=2CCC=C(C(N(C=3)N4C(C5=CC=C(C=C5N=C4C)C(O)=O)=O)=O)C=2N1C=3C1=CC=CC=C1 WVQTWDYRWFPRCI-UHFFFAOYSA-N 0.000 claims description 2
- GSXVPNLAOHBBKA-VWLOTQADSA-N 2-methyl-3-[(11S)-6-methyl-12-oxo-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-11-yl]-4-oxoquinazoline-7-carboxylic acid Chemical compound C=1C(C)=CC=2CCN(C([C@@H](N=3)N4C(C5=CC=C(C=C5N=C4C)C(O)=O)=O)=O)C=2C=1C=3C1=CC=CC=C1 GSXVPNLAOHBBKA-VWLOTQADSA-N 0.000 claims description 2
- FCWJJOXVDUODGO-UHFFFAOYSA-N 2-morpholin-4-ylethyl 2-methyl-3-(6-methyl-12-oxo-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-11-yl)-4-oxoquinazoline-7-carboxylate Chemical compound C=1C(C)=CC=2CCN(C3=O)C=2C=1C(C=1C=CC=CC=1)=NC3N(C(C1=CC=2)=O)C(C)=NC1=CC=2C(=O)OCCN1CCOCC1 FCWJJOXVDUODGO-UHFFFAOYSA-N 0.000 claims description 2
- LQAPQOZOEQHAPS-UHFFFAOYSA-N 3-(6-amino-12-oxo-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-11-yl)-2-methyl-4-oxoquinazoline-7-carboxylic acid Chemical compound CC1=NC2=CC(C(O)=O)=CC=C2C(=O)N1C(C(N1CCC=2C=C(N)C=C3C1=2)=O)N=C3C1=CC=CC=C1 LQAPQOZOEQHAPS-UHFFFAOYSA-N 0.000 claims description 2
- UPPVFNJVXPOKDU-UHFFFAOYSA-N 3-amino-1H-pyrrolo[2,3-g][1,2]benzodiazepin-2-one Chemical compound C1=CC2=NN=CC=CC2=C2C1=C(N)C(=O)N2 UPPVFNJVXPOKDU-UHFFFAOYSA-N 0.000 claims description 2
- ZCGHSRSNETYNGK-UHFFFAOYSA-N 6-amino-11-(2,5-dimethyl-4-oxoquinazolin-3-yl)-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-12-one Chemical compound O=C1C=2C(C)=CC=CC=2N=C(C)N1C(C(N1CCC=2C=C(N)C=C3C1=2)=O)N=C3C1=CC=CC=C1 ZCGHSRSNETYNGK-UHFFFAOYSA-N 0.000 claims description 2
- OTCUEKHKDLNSDY-UHFFFAOYSA-N 6-amino-11-(2,8-dimethyl-4-oxoquinazolin-3-yl)-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-12-one Chemical compound CC1=CC=CC(C2=O)=C1N=C(C)N2C(C(N1CCC=2C=C(N)C=C3C1=2)=O)N=C3C1=CC=CC=C1 OTCUEKHKDLNSDY-UHFFFAOYSA-N 0.000 claims description 2
- QJWNEJHSZQCMHD-UHFFFAOYSA-N 6-amino-11-(5-chloro-2-methyl-4-oxoquinazolin-3-yl)-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-12-one Chemical compound CC1=NC2=CC=CC(Cl)=C2C(=O)N1C(C(N1CCC=2C=C(N)C=C3C1=2)=O)N=C3C1=CC=CC=C1 QJWNEJHSZQCMHD-UHFFFAOYSA-N 0.000 claims description 2
- ZSAGZZJKZGCMMI-UHFFFAOYSA-N 6-amino-9-phenyl-11-(2,6,8-trimethyl-4-oxoquinazolin-3-yl)-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-12-one Chemical compound O=C1C2=CC(C)=CC(C)=C2N=C(C)N1C(C(N1CCC=2C=C(N)C=C3C1=2)=O)N=C3C1=CC=CC=C1 ZSAGZZJKZGCMMI-UHFFFAOYSA-N 0.000 claims description 2
- YAZFTFZVEWVKPB-UHFFFAOYSA-N 6-methyl-11-(2-methyl-4-oxoquinazolin-3-yl)-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-12-one Chemical compound C=1C(C)=CC=2CCN(C(C(N=3)N4C(C5=CC=CC=C5N=C4C)=O)=O)C=2C=1C=3C1=CC=CC=C1 YAZFTFZVEWVKPB-UHFFFAOYSA-N 0.000 claims description 2
- RAEPAPKGAQSTPE-UHFFFAOYSA-N 6-methyl-11-[2-methyl-4-oxo-7-(2H-tetrazol-5-yl)quinazolin-3-yl]-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-12-one Chemical compound C=1C(C)=CC=2CCN(C3=O)C=2C=1C(C=1C=CC=CC=1)=NC3N(C(C1=CC=2)=O)C(C)=NC1=CC=2C=1N=NNN=1 RAEPAPKGAQSTPE-UHFFFAOYSA-N 0.000 claims description 2
- CNFZEERAPPNIJJ-UHFFFAOYSA-N 9-methoxy-3-(2-methyl-4-oxo-4h-quinazolin-3-yl)-1-phenyl-6,7-dihydro-3h-[1,4]diazepino [6,7,1-hi] indol-4-one Chemical compound COC1=CC=2CCC=C(C(N(C=3)N4C(C5=CC=CC=C5N=C4C)=O)=O)C=2N1C=3C1=CC=CC=C1 CNFZEERAPPNIJJ-UHFFFAOYSA-N 0.000 claims description 2
- HPEANCAKDYEIGD-UHFFFAOYSA-N 9-methyl-3-(2-hydroxymethyl-4-oxo-4h-quinazolin-3-yl)-1-phenyl-6,7-dihydro-3h-[1,4]diazepino[6,7,1-hi]indol-4-one Chemical compound CC1=CC=2CCC=C(C(N(C=3)N4C(C5=CC=CC=C5N=C4CO)=O)=O)C=2N1C=3C1=CC=CC=C1 HPEANCAKDYEIGD-UHFFFAOYSA-N 0.000 claims description 2
- CDDVNLAUEVRDEY-UHFFFAOYSA-N C=1C(C(=O)OC)=CC=C(C2=O)C=1N=C(C)N2C(C(N1CCC=2C=C(N)C=C3C1=2)=O)N=C3C1=CC=CC=C1 Chemical compound C=1C(C(=O)OC)=CC=C(C2=O)C=1N=C(C)N2C(C(N1CCC=2C=C(N)C=C3C1=2)=O)N=C3C1=CC=CC=C1 CDDVNLAUEVRDEY-UHFFFAOYSA-N 0.000 claims description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
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- FVYYJFYVVMSXJA-UHFFFAOYSA-N ethyl 2-[3-(6-methyl-12-oxo-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-11-yl)-4-oxoquinazolin-2-yl]acetate Chemical compound CCOC(=O)CC1=NC2=CC=CC=C2C(=O)N1C(C(N1CCC=2C=C(C)C=C3C1=2)=O)N=C3C1=CC=CC=C1 FVYYJFYVVMSXJA-UHFFFAOYSA-N 0.000 claims description 2
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- WUDQSCHRNSAITB-UHFFFAOYSA-N ethyl 2-(4-oxo-3,1-benzoxazin-2-yl)acetate Chemical compound C1=CC=C2C(=O)OC(CC(=O)OCC)=NC2=C1 WUDQSCHRNSAITB-UHFFFAOYSA-N 0.000 description 1
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- 238000001050 pharmacotherapy Methods 0.000 description 1
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- 239000002798 polar solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
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- 108090000623 proteins and genes Proteins 0.000 description 1
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- BSYFXFLGOGQHFU-UHFFFAOYSA-N pyrrolo[2,3-g][1,2]benzodiazepine Chemical class N1=NC=CC=C2C3=NC=CC3=CC=C21 BSYFXFLGOGQHFU-UHFFFAOYSA-N 0.000 description 1
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- 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 235000008521 threonine Nutrition 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- VHKIEYIESYMHPT-UHFFFAOYSA-N triethyl(methoxycarbonylsulfamoyl)azanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC VHKIEYIESYMHPT-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
- C07D487/06—Peri-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
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
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)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pain & Pain Management (AREA)
- Gastroenterology & Hepatology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR97/05422 | 1997-04-30 | ||
| FR9705422A FR2762841B1 (fr) | 1997-04-30 | 1997-04-30 | Diazepino-indolones inhibitrices de phosphodiesterases iv |
| PCT/EP1998/002827 WO1998049169A1 (en) | 1997-04-30 | 1998-04-30 | Phosphodiesterase 4-inhibiting diazepinoindolones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2278217A1 true CA2278217A1 (en) | 1998-11-05 |
Family
ID=9506517
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002278217A Abandoned CA2278217A1 (en) | 1997-04-30 | 1998-04-30 | Phosphodiesterase 4-inhibiting diazepinoindolones |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US6239130B1 (enExample) |
| EP (1) | EP0980374B1 (enExample) |
| JP (1) | JP2001522367A (enExample) |
| KR (1) | KR20010020386A (enExample) |
| AT (1) | ATE232534T1 (enExample) |
| AU (1) | AU729495B2 (enExample) |
| BR (1) | BR9809429A (enExample) |
| CA (1) | CA2278217A1 (enExample) |
| DE (1) | DE69811360T2 (enExample) |
| DK (1) | DK0980374T3 (enExample) |
| ES (1) | ES2190083T3 (enExample) |
| FR (1) | FR2762841B1 (enExample) |
| HR (1) | HRP980231B1 (enExample) |
| MX (1) | MXPA99006979A (enExample) |
| NZ (1) | NZ337589A (enExample) |
| WO (1) | WO1998049169A1 (enExample) |
| ZA (1) | ZA983704B (enExample) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1389468A4 (en) * | 2001-05-23 | 2007-01-10 | Tanabe Seiyaku Co | COMPOSITIONS PROMOTING THE GUISON OF A BONE FRACTURE |
| US8252794B2 (en) | 2001-05-23 | 2012-08-28 | Mitsubishi Tanabe Pharma Corporation | Composition for regenerative treatment of cartilage disease |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2795731B1 (fr) * | 1999-07-02 | 2001-09-07 | Warner Lambert Co | PROCEDE DE PREPARATION DE [1,4] DIAZEPINO [6,7,1-hi] INDOL-4-ONES SUBSTITUEES |
| BR0108908A (pt) * | 2000-03-03 | 2002-12-24 | Pfizer Prod Inc | Derivados de éteres de pirazol como agentes antiinflamatórios/analgésicos |
| EP1161949A1 (en) | 2000-06-09 | 2001-12-12 | Warner-Lambert Company | Use od diazepinoindoles for the treatment of chronic obstructive pulmonary disease |
| EP1188438A1 (en) * | 2000-09-15 | 2002-03-20 | Warner-Lambert Company | Pharmaceutical composition for preventing or treating a disease associated with an excess of Il-12 production |
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| US20090042951A1 (en) * | 2004-02-20 | 2009-02-12 | Robert Danziger | Blood Pressure Reduction in Salt-Sensitive Hypertension |
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| AU2006237300B2 (en) * | 2005-04-19 | 2011-10-13 | Takeda Gmbh | Roflumilast for the treatment of pulmonary hypertension |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2725719B1 (fr) * | 1994-10-14 | 1996-12-06 | Jouveinal Inst Rech | Diazepino-indoles inhibiteurs de phosphodiesterases iv |
-
1997
- 1997-04-30 FR FR9705422A patent/FR2762841B1/fr not_active Expired - Fee Related
-
1998
- 1998-04-29 HR HR980231A patent/HRP980231B1/xx not_active IP Right Cessation
- 1998-04-30 MX MXPA99006979A patent/MXPA99006979A/es unknown
- 1998-04-30 NZ NZ337589A patent/NZ337589A/xx unknown
- 1998-04-30 EP EP98925598A patent/EP0980374B1/en not_active Expired - Lifetime
- 1998-04-30 JP JP54662498A patent/JP2001522367A/ja not_active Abandoned
- 1998-04-30 US US09/380,883 patent/US6239130B1/en not_active Expired - Fee Related
- 1998-04-30 CA CA002278217A patent/CA2278217A1/en not_active Abandoned
- 1998-04-30 BR BR9809429-7A patent/BR9809429A/pt not_active IP Right Cessation
- 1998-04-30 ES ES98925598T patent/ES2190083T3/es not_active Expired - Lifetime
- 1998-04-30 KR KR1019997010008A patent/KR20010020386A/ko not_active Ceased
- 1998-04-30 DK DK98925598T patent/DK0980374T3/da active
- 1998-04-30 AU AU77652/98A patent/AU729495B2/en not_active Ceased
- 1998-04-30 DE DE69811360T patent/DE69811360T2/de not_active Expired - Fee Related
- 1998-04-30 WO PCT/EP1998/002827 patent/WO1998049169A1/en not_active Ceased
- 1998-04-30 AT AT98925598T patent/ATE232534T1/de not_active IP Right Cessation
- 1998-04-30 ZA ZA9803704A patent/ZA983704B/xx unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1389468A4 (en) * | 2001-05-23 | 2007-01-10 | Tanabe Seiyaku Co | COMPOSITIONS PROMOTING THE GUISON OF A BONE FRACTURE |
| US7659273B2 (en) | 2001-05-23 | 2010-02-09 | Mitsubishi Tanabe Pharma Corporation | Composition for accelerating bone fracture healing |
| US8252794B2 (en) | 2001-05-23 | 2012-08-28 | Mitsubishi Tanabe Pharma Corporation | Composition for regenerative treatment of cartilage disease |
| US8399466B2 (en) | 2001-05-23 | 2013-03-19 | Mitsubishi Tanabe Pharma Corporation | Composition for regenerative treatment of cartilage disease |
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA99006979A (es) | 2005-04-19 |
| HRP980231B1 (en) | 2002-06-30 |
| ATE232534T1 (de) | 2003-02-15 |
| US6239130B1 (en) | 2001-05-29 |
| ES2190083T3 (es) | 2003-07-16 |
| WO1998049169A1 (en) | 1998-11-05 |
| EP0980374B1 (en) | 2003-02-12 |
| KR20010020386A (ko) | 2001-03-15 |
| FR2762841A1 (fr) | 1998-11-06 |
| AU729495B2 (en) | 2001-02-01 |
| ZA983704B (en) | 1999-10-25 |
| DK0980374T3 (da) | 2003-05-05 |
| DE69811360D1 (de) | 2003-03-20 |
| NZ337589A (en) | 2000-10-27 |
| DE69811360T2 (de) | 2003-10-09 |
| JP2001522367A (ja) | 2001-11-13 |
| AU7765298A (en) | 1998-11-24 |
| HRP980231A2 (en) | 2000-04-30 |
| FR2762841B1 (fr) | 1999-07-02 |
| EP0980374A1 (en) | 2000-02-23 |
| BR9809429A (pt) | 2000-06-13 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |