JP2001522367A - ホスホジエステラーゼ４−阻害ジアゼピノインドロン - Google Patents
ホスホジエステラーゼ４−阻害ジアゼピノインドロンInfo
- Publication number
- JP2001522367A JP2001522367A JP54662498A JP54662498A JP2001522367A JP 2001522367 A JP2001522367 A JP 2001522367A JP 54662498 A JP54662498 A JP 54662498A JP 54662498 A JP54662498 A JP 54662498A JP 2001522367 A JP2001522367 A JP 2001522367A
- Authority
- JP
- Japan
- Prior art keywords
- oxo
- methyl
- phenyl
- diazepino
- dihydro
- 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 compound C1=CC2=NN=CC=CC2=C2C1=CC(=O)N2 ZWOMUDQWODQGQH-UHFFFAOYSA-N 0.000 title claims description 4
- 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 description 4
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 title abstract description 4
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 138
- 208000006673 asthma Diseases 0.000 claims abstract description 8
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims abstract description 7
- 206010065687 Bone loss Diseases 0.000 claims abstract description 5
- 206010012438 Dermatitis atopic Diseases 0.000 claims abstract description 5
- 206010067125 Liver injury Diseases 0.000 claims abstract description 5
- 201000008937 atopic dermatitis Diseases 0.000 claims abstract description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 5
- 206010040070 Septic Shock Diseases 0.000 claims abstract description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 4
- 230000036303 septic shock Effects 0.000 claims abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- -1 2-methyl-4-oxo-4H-quinazolin-3-yl Chemical group 0.000 claims description 146
- 238000000034 method Methods 0.000 claims description 136
- 239000000460 chlorine Substances 0.000 claims description 93
- 239000000543 intermediate Substances 0.000 claims description 83
- 239000002904 solvent Substances 0.000 claims description 60
- 239000002253 acid Substances 0.000 claims description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- 150000002148 esters Chemical class 0.000 claims description 28
- 150000002431 hydrogen Chemical class 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 23
- 150000001412 amines Chemical class 0.000 claims description 19
- KRZJRNZICWNMOA-GXSJLCMTSA-N (3s,4r)-4,8-dihydroxy-3-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1=CC=C2[C@@H](O)[C@@H](OC)CC(=O)C2=C1O KRZJRNZICWNMOA-GXSJLCMTSA-N 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- KCKIKSJECTZLJA-UHFFFAOYSA-N indol-4-one Chemical compound O=C1C=CC=C2N=CC=C12 KCKIKSJECTZLJA-UHFFFAOYSA-N 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 150000004678 hydrides Chemical class 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 9
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 9
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 claims description 8
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims description 8
- 230000009435 amidation Effects 0.000 claims description 8
- 238000007112 amidation reaction Methods 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 239000002609 medium Substances 0.000 claims description 8
- 230000009467 reduction Effects 0.000 claims description 8
- 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 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 230000032050 esterification Effects 0.000 claims description 6
- 238000005886 esterification reaction Methods 0.000 claims description 6
- 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 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 5
- 239000004472 Lysine Substances 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 208000011231 Crohn disease Diseases 0.000 claims description 4
- 239000004471 Glycine Substances 0.000 claims description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 4
- 230000006181 N-acylation Effects 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 4
- 239000004220 glutamic acid Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 231100000753 hepatic injury Toxicity 0.000 claims description 4
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 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
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 4
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 4
- HVUUBQWZWIBQGA-SANMLTNESA-N (11S)-11-(2,6-dimethyl-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 N([C@H](C(N1CCC=2C=C(C)C=C3C1=2)=O)N1C(C)=NC2=CC=C(C=C2C1=O)C)=C3C1=CC=CC=C1 HVUUBQWZWIBQGA-SANMLTNESA-N 0.000 claims description 3
- HXSPYSYFRCKEPX-UHFFFAOYSA-N 11-(5-chloro-2-methyl-4-oxoquinazolin-3-yl)-6-nitro-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(C=C3C1=2)[N+]([O-])=O)=O)N=C3C1=CC=CC=C1 HXSPYSYFRCKEPX-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- HVQANRLCVWQRKC-UHFFFAOYSA-N 11-(7-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 C=1C(OC)=CC=C(C2=O)C=1N=C(C)N2C(C(N1CCC=2C=C(C)C=C3C1=2)=O)N=C3C1=CC=CC=C1 HVQANRLCVWQRKC-UHFFFAOYSA-N 0.000 claims description 3
- FGVLFFGUYNXWKT-UHFFFAOYSA-N 11-[2-(methoxymethyl)-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 COCC1=NC2=CC=CC=C2C(=O)N1C(C(N1CCC=2C=C(C)C=C3C1=2)=O)N=C3C1=CC=CC=C1 FGVLFFGUYNXWKT-UHFFFAOYSA-N 0.000 claims description 3
- YHBWXWLDOKIVCJ-UHFFFAOYSA-N 2-[2-(2-methoxyethoxy)ethoxy]acetic acid Chemical compound COCCOCCOCC(O)=O YHBWXWLDOKIVCJ-UHFFFAOYSA-N 0.000 claims description 3
- GSXVPNLAOHBBKA-RUZDIDTESA-N 2-methyl-3-[(11R)-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-RUZDIDTESA-N 0.000 claims description 3
- 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
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- GRHZLQBPAJAHDM-SPRQWYLLSA-N [(3as,4r,6ar)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl] n-[(2s,4s,5s)-5-[[2-(2,6-dimethylphenoxy)acetyl]amino]-4-hydroxy-1,6-diphenylhexan-2-yl]carbamate Chemical compound CC1=CC=CC(C)=C1OCC(=O)N[C@H]([C@@H](O)C[C@H](CC=1C=CC=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)CC1=CC=CC=C1 GRHZLQBPAJAHDM-SPRQWYLLSA-N 0.000 claims description 3
- 150000001370 alpha-amino acid derivatives Chemical class 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
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 150000002466 imines Chemical class 0.000 claims description 3
- 230000001900 immune effect Effects 0.000 claims description 3
- 230000002757 inflammatory effect Effects 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
- 150000003335 secondary amines Chemical class 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
- RHAUFQSERALOMZ-SANMLTNESA-N (11S)-11-(2,5-dimethyl-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(C)C=CC=C5N=C4C)=O)=O)C=2C=1C=3C1=CC=CC=C1 RHAUFQSERALOMZ-SANMLTNESA-N 0.000 claims description 2
- PKVZSJLYYVGXRM-QHCPKHFHSA-N (11S)-11-(2-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl)-6-nitro-9-phenyl-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-12-one Chemical compound N([C@H](C(N1CCC=2C=C(C=C3C1=2)[N+]([O-])=O)=O)N1C(=O)C2=CC=NC=C2N=C1C)=C3C1=CC=CC=C1 PKVZSJLYYVGXRM-QHCPKHFHSA-N 0.000 claims description 2
- 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
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- RGERZKVLIURXPY-UHFFFAOYSA-N 11-(2-methyl-4-oxoquinazolin-3-yl)-6-nitro-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=C2C(=O)N1C(C(N1CCC=2C=C(C=C3C1=2)[N+]([O-])=O)=O)N=C3C1=CC=CC=C1 RGERZKVLIURXPY-UHFFFAOYSA-N 0.000 claims description 2
- RMPDEUYKGHVHHO-UHFFFAOYSA-N 11-(5-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=C1C=2C(OC)=CC=CC=2N=C(C)N1C(C(N1CCC=2C=C(C)C=C3C1=2)=O)N=C3C1=CC=CC=C1 RMPDEUYKGHVHHO-UHFFFAOYSA-N 0.000 claims description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 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
- LFEQSBPRIVCNRV-UHFFFAOYSA-N 4-(2-morpholin-4-ylethylamino)-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)NCCN1CCOCC1 LFEQSBPRIVCNRV-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
- 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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 206010019663 Hepatic failure Diseases 0.000 claims description 2
- 239000003377 acid catalyst Substances 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 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
- 231100000835 liver failure Toxicity 0.000 claims description 2
- 208000007903 liver failure Diseases 0.000 claims description 2
- 229910001510 metal chloride Inorganic materials 0.000 claims description 2
- 230000003278 mimic effect Effects 0.000 claims description 2
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 claims description 2
- 150000002905 orthoesters Chemical class 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- MOEXNCSUAQSQAX-SANMLTNESA-N (11S)-11-(2,8-dimethyl-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=CC=CC(C)=C5N=C4C)=O)=O)C=2C=1C=3C1=CC=CC=C1 MOEXNCSUAQSQAX-SANMLTNESA-N 0.000 claims 1
- AFXHOTSLLBQULZ-WXTKOERCSA-N (2S)-2-[[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-carbonyl]amino]-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound C=1C(C)=CC=2CCN(C(C(N=3)N4C(C5=CC=C(C=C5N=C4C)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(O)=O)=O)=O)C=2C=1C=3C1=CC=CC=C1 AFXHOTSLLBQULZ-WXTKOERCSA-N 0.000 claims 1
- AZQNANWJQLZKCT-UHFFFAOYSA-N 11-(5-chloro-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=C(Cl)C=CC=C5N=C4C)=O)=O)C=2C=1C=3C1=CC=CC=C1 AZQNANWJQLZKCT-UHFFFAOYSA-N 0.000 claims 1
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- 239000002798 polar solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 208000015891 sexual disease Diseases 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- YSHOWEKUVWPFNR-UHFFFAOYSA-O triethyl(methoxycarbonylsulfamoyl)azanium Chemical compound CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC YSHOWEKUVWPFNR-UHFFFAOYSA-O 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 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
- C07D487/06—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)
- Physical Education & Sports Medicine (AREA)
- Pulmonology (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 (2)
| Publication Number | Publication Date |
|---|---|
| JP2001522367A true JP2001522367A (ja) | 2001-11-13 |
| JP2001522367A5 JP2001522367A5 (https=) | 2005-12-02 |
Family
ID=9506517
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP54662498A Abandoned JP2001522367A (ja) | 1997-04-30 | 1998-04-30 | ホスホジエステラーゼ４−阻害ジアゼピノインドロン |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US6239130B1 (https=) |
| EP (1) | EP0980374B1 (https=) |
| JP (1) | JP2001522367A (https=) |
| KR (1) | KR20010020386A (https=) |
| AT (1) | ATE232534T1 (https=) |
| AU (1) | AU729495B2 (https=) |
| BR (1) | BR9809429A (https=) |
| CA (1) | CA2278217A1 (https=) |
| DE (1) | DE69811360T2 (https=) |
| DK (1) | DK0980374T3 (https=) |
| ES (1) | ES2190083T3 (https=) |
| FR (1) | FR2762841B1 (https=) |
| HR (1) | HRP980231B1 (https=) |
| MX (1) | MXPA99006979A (https=) |
| NZ (1) | NZ337589A (https=) |
| WO (1) | WO1998049169A1 (https=) |
| ZA (1) | ZA983704B (https=) |
Families Citing this family (19)
| 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 |
| AU2001232175B2 (en) * | 2000-03-03 | 2005-07-07 | Pfizer Products Inc. | Pyrazole ether derivatives as anti-inflammatory/analgesic agents |
| 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 |
| EP1199074A1 (en) * | 2000-09-15 | 2002-04-24 | Warner-Lambert Company | Pharmaceutical composition for preventing or treating a disease associated with an excess of il-12 production |
| ES2427930T3 (es) | 2001-05-23 | 2013-11-04 | Mitsubishi Tanabe Pharma Corporation | Composición terapéutica para el tratamiento regenerativo de enfermedades de los cartílagos |
| KR20040007596A (ko) | 2001-05-23 | 2004-01-24 | 다나베 세이야꾸 가부시키가이샤 | 골절 치료 촉진용 조성물 |
| WO2003007955A2 (en) * | 2001-07-20 | 2003-01-30 | Cancer Research Technology Limited | Biphenyl apurinic/apyrimidinic site endonuclease inhibitors to treat cancer |
| MY140561A (en) | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
| US20050187278A1 (en) * | 2003-08-28 | 2005-08-25 | Pharmacia Corporation | Treatment or prevention of vascular disorders with Cox-2 inhibitors in combination with cyclic AMP-specific phosphodiesterase inhibitors |
| WO2006073413A1 (en) * | 2004-02-20 | 2006-07-13 | The Board Of Trustees Of The University Of Illinois | Blood pressure reduction in salt-sensitive |
| US20050239867A1 (en) * | 2004-04-23 | 2005-10-27 | Zeldis Jerome B | Methods of using and compositions comprising PDE4 modulators for the treatment and management of pulmonary hypertension |
| NZ561746A (en) * | 2005-04-19 | 2011-09-30 | Nycomed Gmbh | Roflumilast for the treatment of pulmonary hypertension |
| WO2008041118A2 (en) * | 2006-10-04 | 2008-04-10 | Pfizer Products Inc. | Pyrido[4,3-d]pyrimidin-4(3h)-one derivatives as calcium receptor antagonists |
| US20090182035A1 (en) * | 2007-04-11 | 2009-07-16 | Alcon Research, Ltd. | Use of a combination of olopatadine and cilomilast to treat non-infectious rhinitis and allergic conjunctivitis |
| TW200902025A (en) * | 2007-04-11 | 2009-01-16 | Alcon Res Ltd | Use of an inhibitor of TNF α plus an antihistamine to treat allergic rhinitis and allergic conjunctivitis |
| CN101784269A (zh) * | 2007-06-26 | 2010-07-21 | 莱西肯医药有限公司 | 治疗由5-羟色胺介导的疾病和病症的方法 |
| US20110082145A1 (en) * | 2009-10-01 | 2011-04-07 | Alcon Research, Ltd. | Olopatadine compositions and uses thereof |
| NZ777336A (en) | 2018-12-28 | 2026-02-27 | Regeneron Pharma | Treatment of respiratory disorders with arachidonate 15-lipoxygenase (alox15) inhibitors |
Family Cites Families (1)
| 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 JP JP54662498A patent/JP2001522367A/ja not_active Abandoned
- 1998-04-30 EP EP98925598A patent/EP0980374B1/en not_active Expired - Lifetime
- 1998-04-30 AU AU77652/98A patent/AU729495B2/en not_active Ceased
- 1998-04-30 DK DK98925598T patent/DK0980374T3/da active
- 1998-04-30 KR KR1019997010008A patent/KR20010020386A/ko not_active Ceased
- 1998-04-30 BR BR9809429-7A patent/BR9809429A/pt not_active IP Right Cessation
- 1998-04-30 ZA ZA9803704A patent/ZA983704B/xx unknown
- 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 DE DE69811360T patent/DE69811360T2/de not_active Expired - Fee Related
- 1998-04-30 NZ NZ337589A patent/NZ337589A/xx unknown
- 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 ES ES98925598T patent/ES2190083T3/es not_active Expired - Lifetime
- 1998-04-30 MX MXPA99006979A patent/MXPA99006979A/es unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NZ337589A (en) | 2000-10-27 |
| DE69811360T2 (de) | 2003-10-09 |
| BR9809429A (pt) | 2000-06-13 |
| ZA983704B (en) | 1999-10-25 |
| WO1998049169A1 (en) | 1998-11-05 |
| EP0980374A1 (en) | 2000-02-23 |
| DE69811360D1 (de) | 2003-03-20 |
| FR2762841A1 (fr) | 1998-11-06 |
| HRP980231B1 (en) | 2002-06-30 |
| KR20010020386A (ko) | 2001-03-15 |
| AU729495B2 (en) | 2001-02-01 |
| ATE232534T1 (de) | 2003-02-15 |
| HRP980231A2 (en) | 2000-04-30 |
| ES2190083T3 (es) | 2003-07-16 |
| AU7765298A (en) | 1998-11-24 |
| MXPA99006979A (es) | 2005-04-19 |
| CA2278217A1 (en) | 1998-11-05 |
| US6239130B1 (en) | 2001-05-29 |
| DK0980374T3 (da) | 2003-05-05 |
| FR2762841B1 (fr) | 1999-07-02 |
| EP0980374B1 (en) | 2003-02-12 |
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