EP1059924A1 - Triazolo-pyridazine derivatives for the treatment of chronic obstructive pulmonary diseases - Google Patents
Triazolo-pyridazine derivatives for the treatment of chronic obstructive pulmonary diseasesInfo
- Publication number
- EP1059924A1 EP1059924A1 EP99937873A EP99937873A EP1059924A1 EP 1059924 A1 EP1059924 A1 EP 1059924A1 EP 99937873 A EP99937873 A EP 99937873A EP 99937873 A EP99937873 A EP 99937873A EP 1059924 A1 EP1059924 A1 EP 1059924A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- amino
- hydroxy
- alkoxy
- optionally
- 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.)
- Withdrawn
Links
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 title claims description 11
- CBHTTYDJRXOHHL-UHFFFAOYSA-N 2h-triazolo[4,5-c]pyridazine Chemical class N1=NC=CC2=C1N=NN2 CBHTTYDJRXOHHL-UHFFFAOYSA-N 0.000 title abstract description 28
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 85
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 210000000621 bronchi Anatomy 0.000 claims abstract description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 149
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 109
- 125000005843 halogen group Chemical group 0.000 claims description 107
- -1 hydroxy, amino, carboxyl Chemical group 0.000 claims description 107
- 125000001424 substituent group Chemical group 0.000 claims description 93
- 125000003545 alkoxy group Chemical group 0.000 claims description 90
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 79
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 70
- 125000003282 alkyl amino group Chemical group 0.000 claims description 68
- 229910052757 nitrogen Inorganic materials 0.000 claims description 51
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 43
- 150000001875 compounds Chemical class 0.000 claims description 36
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 31
- 125000000623 heterocyclic group Chemical group 0.000 claims description 30
- 125000002252 acyl group Chemical group 0.000 claims description 26
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 21
- 125000005842 heteroatom Chemical group 0.000 claims description 21
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 21
- 239000001301 oxygen Substances 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 20
- 125000004434 sulfur atom Chemical group 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 16
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 14
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 11
- 230000008030 elimination Effects 0.000 claims description 11
- 238000003379 elimination reaction Methods 0.000 claims description 11
- 201000009732 pulmonary eosinophilia Diseases 0.000 claims description 10
- 206010020751 Hypersensitivity Diseases 0.000 claims description 9
- 206010035664 Pneumonia Diseases 0.000 claims description 9
- 239000000924 antiasthmatic agent Substances 0.000 claims description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 230000001088 anti-asthma Effects 0.000 abstract description 3
- ABSYJOKYMQTMMK-UHFFFAOYSA-N 2,2-dimethyl-3-[(7-propan-2-yl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)oxy]propane-1-sulfonamide Chemical compound N1=C(OCC(C)(C)CS(N)(=O)=O)C(C(C)C)=CC2=NC=NN21 ABSYJOKYMQTMMK-UHFFFAOYSA-N 0.000 abstract 1
- 239000000443 aerosol Substances 0.000 description 17
- 239000007789 gas Substances 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000000654 additive Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000011049 filling Methods 0.000 description 9
- 238000002156 mixing Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 8
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 7
- 108010003541 Platelet Activating Factor Proteins 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000011630 iodine Substances 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000000825 pharmaceutical preparation Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 5
- 206010006482 Bronchospasm Diseases 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 230000007885 bronchoconstriction Effects 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 4
- 239000007792 gaseous phase Substances 0.000 description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000043 antiallergic agent Substances 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 230000013764 eosinophil chemotaxis Effects 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 2
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 2
- OHMHBGPWCHTMQE-UHFFFAOYSA-N 2,2-dichloro-1,1,1-trifluoroethane Chemical compound FC(F)(F)C(Cl)Cl OHMHBGPWCHTMQE-UHFFFAOYSA-N 0.000 description 2
- FAYFZSXZSOWNFP-UHFFFAOYSA-N 6-chloro-5-propan-2-ylpyridazin-3-amine Chemical compound CC(C)C1=CC(N)=NN=C1Cl FAYFZSXZSOWNFP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- 206010012438 Dermatitis atopic Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- QNQZLLARUINIPD-UHFFFAOYSA-N N'-(6-chloro-5-propan-2-ylpyridazin-3-yl)-N-hydroxymethanimidamide Chemical compound CC(C)C1=CC(NC=NO)=NN=C1Cl QNQZLLARUINIPD-UHFFFAOYSA-N 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010039085 Rhinitis allergic Diseases 0.000 description 2
- ZBVKEHDGYSLCCC-UHFFFAOYSA-N Seratrodast Chemical compound O=C1C(C)=C(C)C(=O)C(C(CCCCCC(O)=O)C=2C=CC=CC=2)=C1C ZBVKEHDGYSLCCC-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 201000010105 allergic rhinitis Diseases 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 201000008937 atopic dermatitis Diseases 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 229960004574 azelastine Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 230000007797 corrosion Effects 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 150000001925 cycloalkenes Chemical class 0.000 description 2
- ZXIJMRYMVAMXQP-UHFFFAOYSA-N cycloheptene Chemical compound C1CCC=CCC1 ZXIJMRYMVAMXQP-UHFFFAOYSA-N 0.000 description 2
- 238000007872 degassing Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229920001971 elastomer Polymers 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 230000002327 eosinophilic effect Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 229960004958 ketotifen Drugs 0.000 description 2
- 238000004898 kneading Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 229960003090 seratrodast Drugs 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 210000003437 trachea Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- WGPBJZSTPQVIHZ-UHFFFAOYSA-N 2-ethyl-2-(hydroxymethyl)butane-1-sulfonamide Chemical compound CCC(CC)(CO)CS(N)(=O)=O WGPBJZSTPQVIHZ-UHFFFAOYSA-N 0.000 description 1
- JRZDBBCBIQEJLA-UHFFFAOYSA-N 3,6-dichloro-4-propan-2-ylpyridazine Chemical compound CC(C)C1=CC(Cl)=NN=C1Cl JRZDBBCBIQEJLA-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012468 Dermatitis herpetiformis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940098165 atrovent Drugs 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- LFYJSSARVMHQJB-QIXNEVBVSA-N bakuchiol Chemical compound CC(C)=CCC[C@@](C)(C=C)\C=C\C1=CC=C(O)C=C1 LFYJSSARVMHQJB-QIXNEVBVSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 description 1
- 229960003719 cefdinir Drugs 0.000 description 1
- KEWHKYJURDBRMN-XSAPEOHZSA-M chembl2134724 Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-XSAPEOHZSA-M 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- HHHKFGXWKKUNCY-FHWLQOOXSA-N cilazapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N2[C@@H](CCCN2CCC1)C(O)=O)=O)CC1=CC=CC=C1 HHHKFGXWKKUNCY-FHWLQOOXSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- CFBGXYDUODCMNS-UHFFFAOYSA-N cyclobutene Chemical compound C1CC=C1 CFBGXYDUODCMNS-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- OOXWYYGXTJLWHA-UHFFFAOYSA-N cyclopropene Chemical compound C1C=C1 OOXWYYGXTJLWHA-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- LHUZAYREVYDAGJ-UHFFFAOYSA-N dichloromethane;ethyl acetate;methanol Chemical compound OC.ClCCl.CCOC(C)=O LHUZAYREVYDAGJ-UHFFFAOYSA-N 0.000 description 1
- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960003449 epinastine Drugs 0.000 description 1
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- WHQLQYRFIHPMNA-UHFFFAOYSA-N ethyl acetate;oxolane Chemical compound C1CCOC1.CCOC(C)=O WHQLQYRFIHPMNA-UHFFFAOYSA-N 0.000 description 1
- LSLYOANBFKQKPT-UHFFFAOYSA-N fenoterol Chemical compound C=1C(O)=CC(O)=CC=1C(O)CNC(C)CC1=CC=C(O)C=C1 LSLYOANBFKQKPT-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 229940107791 foradil Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- ICLWTJIMXVISSR-UHFFFAOYSA-N gallamine Chemical compound CCN(CC)CCOC1=CC=CC(OCCN(CC)CC)=C1OCCN(CC)CC ICLWTJIMXVISSR-UHFFFAOYSA-N 0.000 description 1
- 229960003054 gallamine Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000011597 hartley guinea pig Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229960002288 procaterol Drugs 0.000 description 1
- FKNXQNWAXFXVNW-BLLLJJGKSA-N procaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)[C@@H](NC(C)C)CC FKNXQNWAXFXVNW-BLLLJJGKSA-N 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000375 suspending agent 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
- KFVSLSTULZVNPG-UHFFFAOYSA-N terbutaline sulfate Chemical compound [O-]S([O-])(=O)=O.CC(C)(C)[NH2+]CC(O)C1=CC(O)=CC(O)=C1.CC(C)(C)[NH2+]CC(O)C1=CC(O)=CC(O)=C1 KFVSLSTULZVNPG-UHFFFAOYSA-N 0.000 description 1
- 229960000351 terfenadine Drugs 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
- 229960000278 theophylline Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000721 toxic potential Toxicity 0.000 description 1
- HLIDDDMWPWGYSH-UHFFFAOYSA-N triazolo[1,5-b]pyridazine Chemical compound N1=CC=CC2=CN=NN21 HLIDDDMWPWGYSH-UHFFFAOYSA-N 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
Definitions
- the present invention relates to an agent for acting on bronchi which comprises triazolopyridazine derivatives such as 6- ( 2 , 2-dimethyl-3 -sulfamoyl-l-propoxy) -7- isopropyl (l , 2 , 4) triazolo (l , 5-b] pyridazine , etc . .
- triazolopyridazine derivatives such as 6- ( 2 , 2-dimethyl-3 -sulfamoyl-l-propoxy) -7- isopropyl (l , 2 , 4) triazolo (l , 5-b] pyridazine , etc . .
- Triazolopyridazine derivatives represented by the formula:
- R 1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom
- X is an oxygen atom or S(0) p (p is a whole number of 0 to 2)
- Y is a group of the formula:
- R 4 and R 5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring
- R 6 and R 7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R 6 and R 7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group
- m is a whole number of 0 to 4
- n is a whole number of 0 to 4
- the present inventors diligently made extensive studies in order to solve the problems and, as a result, they found that it could make actions of the derivatives act at bronchi locally by preparing an inhalation, etc. comprising 6- (2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [l , 2 , 4) triazolo Cl,5-b] pyridazine or a salt thereof. And, they further studied based on the finding, the present invention has been accompliched.
- a agent for acting on bronchi which comprises a compound of the formula:
- R 1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom
- X is an oxygen atom or S(0) p (p is a whole number of 0 to 2)
- Y is a group of the formula:
- R 4 and R 5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring
- R 6 and R 7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R 6 and R 7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group
- m is a whole number of 0 to 4
- n is a whole number of 0 to 4 , or a salt thereof
- R 1 is (i) a hydrogen atom, (ii) a C 1 _ 6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- ordi-Cj.j alkylamino, Ci.
- R 2 and R 3 respectively is (i) a hydrogen atom or (ii) a C 1 . 6 alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or i-C ⁇ alkylamino, C 1-6 alkoxy, C ⁇ alkylcarbonyloxy and a halogen atom or (iii) a C 3 .
- X is an oxygen atom or S(0) p (p is a whole number of 0 to 2).
- Y is (a) a group of the formula: R 4 —C—
- R 4 and R 5 respectively is (i) a hydrogen atom or (ii) a C ⁇ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C ⁇ alkylamino, C ⁇ alkoxy, C x _ 6 alkylcarbonyloxy and a halogen atom) , or
- R 6 and R 7 respectively is (i) a hydrogen atom, (ii) a C 1-6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro. mono- or di-C 1 . 6 alkylamino, C 1 , 6 alkoxy, C ⁇ , 6 alkylcarbonyloxy and a halogen atom, (iii) a C 3 . 6 cycloalkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C 1 .
- R 6 and R 7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms, optionally having substituents selected from the group consisting of (i) C 1 _ 6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C ⁇ alkylamino, ⁇ _ 6 alkoxy, C ⁇ alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C 1 _ 6 alkyl, C ⁇ acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Ci. s alkoxy and (vii) a halogen atom
- R 1 is hydrogen atom or a C ⁇ alkyl group
- R 2 is a hydrogen atom or a C 1 _ 3 alkyl group
- R 3 is a hydrogen atom or a C 1 _ 6 alkyl group
- X is an oxygen atom
- Y is a group of the formula: wherein R 4' and R 5' each is (i) a hydrogen atom or (ii) a C ⁇ alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-C ⁇ alkylamino, C 1 _ 6 alkoxy, C 1 _ 6 alkyl-carbonyloxy and halogen atom, R 6 and R 7 respectively is a hydrogen atom or a C 1 . 3 alkyl group, m and n is 1.
- the agent as defined in (1) which is an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD) , an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia,
- COPD chronic obstructive pulmonary disease
- R 1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom
- X is an oxygen atom or S(0) p (p is a whole number of 0 to 2)
- Y is a group of the formula: R 4
- R 4 and R 5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring
- R 6 and R 7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R 6 and R 7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group
- m is a whole number of 0 to 4
- n is a whole number of 0 to 4 , or a salt thereof for preparing an agent for acting on bronchi, (8)
- R 1 is (i) a hydrogen atom, (ii) a C ⁇ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C ⁇ alkylamino, Ci. 6 alkoxy, C 1 . 6 alkylcarbonyloxy and a halogen atom or (iii) a halogen atom,
- R 2 and R 3 respectively is (i) a hydrogen atom or (ii) a C 1-6 alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C ⁇ alkylamino, C 1 _ 6 alkoxy, C 1-6 alkylcarbonyloxy and a halogen atom or (iii) a C 3 .
- X is an oxygen atom or S(0) p (p is a whole number of 0 to
- Y is (a) a group of the formula:
- R 4 and R 5 respectively is (i) a hydrogen atom or (ii) a C ⁇ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C x _ 6 alkylamino, C ⁇ alkoxy, C 1 _ 6 alkylcarbonyloxy and a halogen atom) , or
- a divalent group derived from a 3- to 7-membered cyclic hydrocarbon or 3- to 7-membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in adidtion to carbon atoms, optionally having substituents selected from the group consisting of (i) 1 , alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C x , 6 alkylamino, C 1 _ alkoxy, C ⁇ alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C 1 . 6 alkyl, C ⁇ acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) alkoxy and (vii) a halogen atom,
- R 6 and R 7 respectively is (i) a hydrogen atom, (ii) a C ⁇ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C ⁇ alkylamino, C 1 . 6 alkoxy, C 1 . 6 alkylcarbonyloxy and a halogen atom, (iii) a C 3 . 6 cycloalkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or i-C ⁇ alkylamino, alkoxy, C 1 . 6 alkylcarbonyloxy and a halogen atom, or (iv) a C 6 .
- aryl group optionally having substituents selected from the group consisting of (a) Cj.g alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C ⁇ alkylamino, C x _ 6 alkoxy, C ⁇ alkylcarbonyloxy and a halogen atom, (b) an amino which may be substituted by C 1 . 6 alkyl, C ⁇ acyl or 5- to 7-membered cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f) nitro, (g) C 1 _ 6 alkoxy, (h) C ⁇ alkylcarbonyloxy and (i) a halogen atom, or
- R ⁇ and R 7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms, optionally having substituents selected from the group consisting of (i) C 1 mentally alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or alkylamino, C 1-6 alkoxy, C x _ 6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C ⁇ alkyl, Cj.
- R 4' and R 5' each is (i) a hydrogen atom or (ii) a C ⁇ alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-Cj.g alkylamino, Cj_. 6 alkoxy, C 1 _ 6 alkyl-carbonyloxy and halogen atom, R 6 and R 7 respectively is a hydrogen atom or a C x _ 3 alkyl group, m and n is 1,
- the agent is an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD) , an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia,
- COPD chronic obstructive pulmonary disease
- a method for preventing or treating asthma, chronic obstructive pulmonary disease (COPD), hypersensitive pneumonia or simple pulmonary eosinophilia which comprises administering an effective amount of a compound of the formula:
- R 1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom
- X is an oxygen atom or S(0) p (p is a whole number of 0 to 2)
- Y is a group of the formula:
- R 4 and R 5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring
- R 6 and R 7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R 6 and R 7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group
- m is a whole number of 0 to 4
- n is a whole number of 0 to 4 , or a salt thereof to bronchi of mammals ,
- R 1 is (i) a hydrogen atom, (ii) a C x _ 6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C 1 . 6 alkylamino, Cj_ 6 alkoxy, C ⁇ alkylcarbonyloxy and a halogen atom or (iii) a halogen atom,
- R 2 and R 3 respectively is (i) a hydrogen atom or (ii) a C x _ 6 alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or alkylamino, C x _ 6 alkoxy, C x _ 6 alkylcarbonyloxy and a halogen atom or (iii) a C 3 .
- alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or alkylamino, C ⁇ alkoxy, C 1-6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C ⁇ alkyl, acyl or 5- to 7-membered cyclic amino, (iii) hydroxy,
- X is an oxygen atom or S(0) p (p is a whole number of 0 to
- Y is (a) a group of the formula:
- R 4 and R 5 respectively is (i) a hydrogen atom or (ii) a C ⁇ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or i-C ⁇ alkylamino, C ⁇ _ 6 alkoxy, C ⁇ alkylcarbonyloxy and a halogen atom) , or
- a divalent group derived from a 3- to 7-membered cyclic hydrocarbon or 3- to 7-membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in adidtion to carbon atoms, optionally having substituents selected from the group consisting of (i) alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C x .
- R 6 and R 7 respectively is (i) a hydrogen atom, (ii) a C ⁇ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C j .g alkylamino, C 1 _ 6 alkoxy, C x . 6 alkylcarbonyloxy and a halogen atom, (iii) a C 3 .
- alkylcarbonyloxy and a halogen atom (b) an amino which may be substituted by C ⁇ alkyl, C ⁇ acyl or 5- to 7-membered cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f) nitro, (g) C ⁇ alkoxy, (h) C ⁇ alkylcarbonyloxy and (i) a halogen atom, or
- R 6 and R 7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms , optionally having substituents selected from the group consisting of (i) C ⁇ alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C x _ 6 alkyl, C ⁇ acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) C x . 6 alkoxy and (vii) a halogen atom, m is a whole number of 0 to 4; n is a whole
- R 4' and R 5 each is (i) a hydrogen atom or (ii) a C 1 alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-Cj.g alkylamino, C x _ 6 alkoxy, C 1 . 6 alkyl-carbonyloxy and halogen atom, R 6 and R 7 respectively is a hydrogen atom or a C x _ 3 alkyl group, m and n is 1 , and
- An aerosol which comprises 6- ( 2 , 2-dimethyl-3- sulfamoyl-1-propoxy) -7-isopropyl [l,2,4] triazolo [l,5-b] pyridazine or a salt thereof and sprays (e.g., an aerosol for acting on bronchi),
- R 1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom
- R 2 and R 3 respectively is a hydrogen atom or an optionally substituted lower alkyl group, or R 2 and R 3 may, taken together with the adjacent
- X is an oxygen atom or S(0) p (p is a whole number of 0 to 2);
- Y is a group of the formula:
- R 4 and R 5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring
- R 6 and R 7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R 6 and R 7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group
- m is a whole number of 0 to 4
- n is a whole number of 0 to 4 , or a salt thereof and about 0.1 to 99wt% of additives for inhalation to the total composition
- the inhalation as defined in (21) which is an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD) , an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia,
- R 1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom
- X is an oxygen atom or S(0) p (p is a whole number of 0 to 2)
- Y is a group of the formula:
- R 5 (R 4 and R 5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring;
- R 6 and R 7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R 6 and R 7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group;
- m is a whole number of 0 to 4 ;
- n is a whole number of 0 to 4 , or a salt thereof and sprays which comprises
- triazolopyridazine derivatives [I] used for the agent of the present invention contains asymmetric carbon within its structure, it may occur as optically active isomers as well as racemic mixtures and that these isomers and mixtures also fall within the scope of the triazolopyridazine derivatives [I].
- triazolopyridazine derivatives [I] used for the agent of the present invention which contain 6- (2, 2- dimethyl-3-sulfamoyl-l-propoxy) -7-isopropyl [l ,2, 4] triazolo Cl,5-b] pyridazine, are known compounds described in EP-A-0562439, EP-A-0648491 or O96/08496.
- examples of the "lower alkyl group" represented by R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 include a straight or branched C ⁇ alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl and so on.
- Examples of the "cycloalkyl group" represented by R 2 , R 3 , R 6 or R 7 include a C 3 . 6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
- substituents of the "lower alkyl group” and “cycloalkyl group” include 1 to 4 substituents selected from among hydroxy, amino, carboxyl, nitro, mono- or di-lower alkylamino (e.g. mono- or alkylamino groups such as methylamino, ethylamino, propylamino, dimethylamino , diethylamino , etc.), lower alkoxy (e.g. C ⁇ alkoxy groups such as methoxy, ethoxy, propoxy, hexyloxy, etc.), lower alkylcarbonyloxy (e.g. C ⁇ alkylcarbonyloxy groups such as acetoxy, ethylcarbonyloxy, etc.), halogen (e.g. fluorine, chlorine, bromine and iodine) and so on.
- mono- or alkylamino e.g. mono- or alkylamino groups such as methylamino, eth
- substituents of the "aryl group” include 1 to 5 substituents selected from among optionally substituted lower alkyl, optionally substituted amino, acetamido, hydroxy, carboxyl, nitro, lower alkoxy (e.g. x _ 6 alkoxy groups such as methoxy, ethoxy, propoxy, etc. ) , lower alkylcarbonyloxy (e.g. C x . 6 alkylcarbonyloxy groups such as acetoxy, ethylcarbonyloxy, etc.), halogen atoms (e.g. fluorine, chlorine, bromine and iodine) and so on.
- substituents by which the lower alkyl e.g.
- C x . 6 alkyl group such as methyl, ethyl, n-propyl, etc.
- C x . 6 alkyl group such as methyl, ethyl, n-propyl, etc.
- substituents selected from among hydroxy, amino, mono- or di-lower alkylamino (e.g. mono- or di-C ⁇ alkylamino groups such as methylamino, ethylamino, propylamino. dimethylamino , diethylamino , etc.), lower alkoxy (e.g. C 1 . 6 alkoxy groups such as methoxy, ethoxy, propoxy, hexyloxy, etc.), halogen (e.g. fluorine, chlorine, bromine and iodine) and so on.
- hydroxy, amino, mono- or di-lower alkylamino e.g. mono- or di-C ⁇ alkylamino groups such as
- substituents by which the amino group mentioned above may have include 1 or 2 substituents selected from among C ⁇ alkyl (e.g. methyl, ethyl, propyl, etc.), 5- to 7-membered cyclic amino (e.g. pyrrolidino, morpholino, piperidino, piperazino, etc.) and so on.
- C ⁇ alkyl e.g. methyl, ethyl, propyl, etc.
- 5- to 7-membered cyclic amino e.g. pyrrolidino, morpholino, piperidino, piperazino, etc.
- halogen represented by R 1
- examples of the "halogen” represented by R 1 include fluorine, chlorine, bromine, iodine and so on.
- a 5- to 7-membered cyclic hydrocarbon such as C 5 . 7 cycloalkenes (e.g.
- cyclopentene cyclohexene, cycloheptene, etc.
- benzene and so on and a 5- or 6- membered nitrogen-containing heterocyclic group consisting of carbon and nitrogen atoms e.g., pyrrole, pyridine, piperidine , etc.
- nitrogen-containing heterocyclic group consisting of carbon and nitrogen atoms
- Examples of the "3- to 7-membered homocyclic ring" of the "divalent group derived from the 3- to 7-membered homocyclic ring" represented by Y include a 3- to 7-membered homocyclic ring consisting exclusively of carbon atoms, for instance.
- C 3 . 7 cycloalkanes such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc.
- C 3 . 7 cycloalkenes such as cyclopropene , cyclobutene, cyclopentene, cyclohexene, cycloheptene, etc. and benzene can be mentioned as the common species.
- Examples of the "divalent group derived from the 3- to 7-membered homocyclic ring” include a group resulting from either elimination of two hydrogen atoms from a single carbon atom in the 3- to 7-membered homocyclic ring or elimination of one hydrogen atom from each of two different carbon atoms .
- the following groups can be included by way of example:
- Examples of the "3- to 7-membered heterocyclic ring" of the "divalent group derived from the 3- to 7-membered heterocyclic ring" represented by Y include a 3- to 7- membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from among nitrogen, oxygen, sulfur and other atoms in adidtion to carbon atoms, for instance.
- oxetane, tetrahydrofuran , tetrahydropyran, pyrrole, azetidine, pyrrolidine, piperidine, piperazine, tetraydrothiophene , homopiperidine, morpholine, etc. can be employed.
- divalent group derived from the "3- to 7-membered heterocyclic ring” is a group resulting from either elimination of two hydrogen atoms from a single carbon atom in the 3- to 7-membered heterocyclic ring or elimination of one hydrogen atom from each of two different atoms .
- the following groups can be included
- nitrogen-containing heterocyclic group formed by R 6 and R 7 with the adjacent nitrogen atom
- examples of the "nitrogen-containing heterocyclic group" formed by R 6 and R 7 with the adjacent nitrogen atom include a group resulting from elimination of one hydrogen atom from a nitrogen atom in a ring such as a 3- to 13- membered nitrogen-containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain one to four hetero atoms , for example , selected from nitrogen, oxygen, sulfur and other atoms.
- the following 3- to 9-membered nitrogen- containing heterocyclic groups can be generally used:
- substituents by which the "3- to 7- membered homocyclic ring", “3- to 7-membered heterocyclic ring” and “nitrogen-containing heterocyclic group” may have include 1 to 5 substituents selected from among an optionally substituted lower alkyl, an optionally substituted amino, hydroxy, carboxyl, nitro, lower alkoxy (e.g. C ⁇ alkoxy groups such as methoxy, ethoxy, propoxy, etc. ) , halogen (e.g. fluorine, chlorine, bromine and iodine) and so on.
- substituents by which the lower alkyl e.g.
- C ⁇ alkyl group such as methyl, ethyl, n-propyl, etc.) mentioned just above may have, include 1 to 4 substituents selected from among hydroxy, amino, mono- or di-lower alkylamino (e.g. mono- or alkylamino groups such as methylamino , ethylamino , propylamino , dimethylamino , diethylamino, etc.), lower alkoxy (e.g. C ⁇ alkoxy groups such as methoxy, ethoxy, propoxy, hexyloxy, etc.), lower alkylcarbonyloxy (e.g.
- mono- or alkylamino groups such as methylamino , ethylamino , propylamino , dimethylamino , diethylamino, etc.
- lower alkoxy e.g. C ⁇ alkoxy groups such as methoxy, ethoxy, propoxy, hex
- C ⁇ alkylcarbonyloxy groups such as acetoxy, ethylcarbonyloxy, etc.), halogen (e.g. fluorine, chlorine, bromine and iodine) and so on.
- substituents by which the amino group mentioned above may have include 1 to 2 substituents selected from among C ⁇ alkyl (e.g. methyl, ethyl, propyl, etc.), acyl (e.g. Q. x . b acyl groups such as formyl, acetyl, propionyl, butyryl, etc.), 5- to 7-membered cyclic amino (e.g. pyrrolidino, morpholino, piperidino, piperazino, etc. ) and so on.
- R 1 are a hydrogen atom or a C ⁇ alkyl group (e.g. methyl, ethyl, n-propyl, etc.) and more preferable examples are a hydrogen atom and so on.
- R 2 are a hydrogen atom or a C ⁇ alkyl group (e.g. methyl, ethyl, n-propyl, etc.) and more preferable examples are a hydrogen atom and so on.
- R 3 are a hydrogen atom or a C ⁇ alkyl group (e.g. methyl, ethyl, n-propyl, i-propyl, etc.) and more preferable examples are a branched C 3 . 6 alkyl group (e.g. i-propyl, etc.).
- Particularly preferred is the case of cyclohexene, benzene or the like.
- X is preferably an oxygen atom or S and more preferably an oxygen atom.
- Y are a group of the formula:
- R 4' and R 5' each is (i) a hydrogen atom or (ii) a C ⁇ alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or alkyl-carbonyloxy and halogen atom, and so on.
- Examples of the "C ⁇ alkyl group" represented by R 4' and R 5' are methyl, ethyl, n-propyl, i-propyl and so on, and more preferable examples are methyl, ethyl and so on.
- Y is a divalent group derived from a 3- to 7-membered homocyclic ring or heterocyclic ring which may be substituted.
- Y is preferably a group of the formula:
- Y More preferably examples of Y include the follow:
- R 6 and R 7 are a hydrogen atom, a C j . 3 alkyl group (e.g. methyl, ethyl, n-propyl, etc.) and so on, and particularly a hydrogen atom is preferred.
- Preferable example of m is a whole number of 1 to 4 , more preferable example is a whole number of 1 to 3 and most preferable example is 1.
- n is a whole number of 1 to 4 and more preferable example is 1.
- triazolopyridazine derivatives [ I ] used for the agent of the present invention are all compounds prepared in Examples of EP-A-0562439 and WO96/08496, and most preferable example is 6- (2, 2- dimethyl-3-sulfamoyl-l-propoxy) -7-isopropyl [l , 2 , 4] triazolo [l,5-b] pyridazine or a salt thereof.
- the salt of triazolopyridazine derivatives [I] is preferably a physiologically acceptable acid addition salt.
- Such salts include salt with inorganic acids (e.g., hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) and salts with organic acids (e.g., acetic acid, formic acid, propionic acid, fumaricacid, maleicacid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) .
- inorganic acids e.g., hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid
- organic acids e.g., acetic acid, formic acid, propionic acid, fumaricacid, maleicacid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulf
- the triazolopyridazine derivatives [I] have an acidic group, such as -COOH, they may form a salt with an inorganic base (e.g., an alkali metal or alkaline earth metal such as sodium, potassium, calcium or magnesium; or ammonia) or an organic base (e.g., a tri-C ⁇ alkylamine such as triethylamine) .
- an inorganic base e.g., an alkali metal or alkaline earth metal such as sodium, potassium, calcium or magnesium; or ammonia
- an organic base e.g., a tri-C ⁇ alkylamine such as triethylamine
- triazolopyridazine derivatives [ I ] or salts thereof can be prepared according to the descriptions of EP-A- 0562439 or O96/08496, particularly the descriptions of Examples of the references .
- the agent for acting on bronchi of the present invention makes the triazolopyridazine derivatives [I] or salts thereof act on bronchi specifically, on the other hand do not make them act on a whole body. And, the agent of the present invention may act on tissues around bronchi such as trachea, lung, etc..
- agent of the present invention can show the local actions of triazolopyridazine derivatives [ I ] or salts thereof, types of the agent are not limited.
- the agent of the present invention can be preferably used as an inhalation.
- additives for the inhalation may be any additives generally used in an inhalation, and examples are solid fillers such as pressurizing agents, white sugar, lactose, glucose, mannitol and sorbitol, liquid fillers e.g.
- inert liquid such as propylene glycol
- binders such as methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone , polyethylene glycol and white sugar
- lubricants such as magnesium stearate, light silicate anhydride, talk and sodium lauryl sulfate
- taste correctives such as citric acid, menthol, glythylithin ammonium salt, glycine and orange powder
- preservatives such as sodium benzoate, sodium bisulfite, methyl parabene and propyl parabene, stabilizers such as citric acid and sodium citrate
- suspending agents such as methyl cellulose, polyvinylpyrrolidone, lecithin and sorbitan trioleate
- dispersing agents such as surface active agents, solvents such as water, isotonicity agents such as sodium chloride, pH a justor such as sulfuric acid and hydrochloric acid, and solubilizers such as ethanol.
- the pressurizing agents include liquefied gas pressurizing agents, compressed gas etc.
- the liquefied gas pressurizing agents include e.g. hydrocarbon fluoride (e.g. substitute Freon such as HCFC22, HCFC-123, HCFC-134a, and HCFC142), liquefied petroleum, and dimethyl ether.
- the compressed gas includes e.g. soluble gas (e.g. carbon dioxide gas, nitrous oxide gas etc. ) and insoluble gas (e.g. nitrogen gas ) .
- the pharmaceutical preparation of the invention may contain as active ingredients any pharmaceutical ingredients other than triazolopyridazine derivative [I] or salts thereof.
- pharmaceutical active ingredients include anti-asthma agents (e.g. theophylline , procaterol, ketotifen, azelastine, seratrodast (bronica) etc.), anti-allergy agents (e.g. ketotifen, terfenadine, azelastine, epinastine etc.), anti-inflammatory agents (e.g. diclophenac sodium, ibuprofen, indomethacin etc.), antimicrobial agents (e.g.
- cefixme, cefdinir, ofloxacin, tosfloxacin etc. ) and anti-fungus agents e.g. fluconazole. itraconazole etc.
- these ingredients are not particularly limited insofar and can be used in a suitable ratio.
- the content of the triazolopyridazine derivative [I] or salts thereof in the pharmaceutical preparation of the invention vary depending on the disease treated, the age or sex of the patient and the conditions of the disease, the content is in the range of usually about 0.01 to 99.9 % by weight, preferably about 0.1 to 50 % by weight , more preferably about 0.5 to 20 % by weight , relative to the whole of the pharmaceutical preparation.
- the content of various additives such as additives for an inhalation varies depending on the disease treated, the age or sex of the patient and the conditions of the disease, the content is in the range of usually about 0.1 to 99 % by weight, preferably about 10 to 99 % by weight, more preferably about 50 to 99 % by weight, most preferably about 70 to 99 % by weight, relative to the whole of the pharmaceutical preparation.
- the content of other pharmaceutical ingredients than the triazolopyridazine derivative [I] or salts thereof varies depending on the disease treated, the age or sex of the patient and the conditions of the disease, the content is in the range of usually about 0.01 to 99.9 % by weight, preferably about 0.1 to 50 % by weight , more preferably about 0.5 to 20 % by weight, relative to the whole of the pharmaceutical preparation.
- the agent of the invention can be formed into a powder for inharation, a suspension for inharation, a liquid preparation for inharation or a capsule for inharation by a method known in the art and administered by means of a suitable inhaler.
- the agent of the invention can be used as an aerosol.
- the aerosol is made completely contamination-free during use, and because the inside of the aerosol is maintained always under pressure, the content introduced in the can is completely prevented from being contaminated from the outside.
- the aerosol is composed usually of 5 elements i.e. a vessel, a valve, a button, a content and a pressurizing agent, and is classified into a 2-phase system, a 3-phase system and a membrane system (double vessel).
- the vessel used is a vessel stipulated under a high-pressure gas regulation , and its material is metal (e.g. tin, aluminum), glass or plastics.
- metal vessel e.g. tin, aluminum
- the glass vessel is excellent in solvent resistance and corrosion resistance and is easily processed, so it can be easily formed into a deformed vessel.
- the valve is a part most influential over the jet characteristics and sealing properties of the aerosol.
- the valve is constituted usually of a mountain cup, a stem, a housing, a spring, a dip tube and gasket rubber, and use is made of a valve equipped with a gas-phase hole or a quantification valve.
- the stem is pressed whereby the stem hole closed with sealing gasket rubber is allowed to communicate with the inside of the vessel so that the content is released through the stem hole.
- the button used includes a straight button, a brake cap button, a button for foam, and a button with a long nozzle.
- the content is the topical working agent (inhalation) of the invention described above.
- the pressurizing agent is the same as described above .
- a 2-phase system aerosol using a liquefied gas pressurizing agent as the pressurizing agent forms an uniform liquid phase in which a suspension (stock solution) containing the triazolopyridazine derivative [ I ] or salts thereof are made compatible with the pressurizing agent, and the inside of the vessel is composed of 2 phases i.e. a liquid phase and a gaseous phase of a gas of the pressurizing agent in an upper space in the vessel.
- fine droplets can be obtained due to the propellant force of the pressurizing agent when the liquefied pressurizing agent under pressure in the vessel is jetted out through a valve under normal pressure.
- compressed gas the compressed gas present under compression in an upper space merely presses the stock solution.
- the former consists of a 2-phase emulsification state of the liquid phase and a gaseous phase in an upper space
- the latter consists of a powder solid phase, a liquefied gaseous phase, and a gaseous phase in an upper space.
- the membrane system is a system in which only the stock solution itself is jetted out from a double vessel in which the pressurizing agent is filled in an outer vessel and the stock solution is filled in an inner vessel communicating with a valve.
- the agent of the invention is used as an aerosol, it is formed preferably into a powder aerosol.
- Production of the aerosol consists usually of the 2 steps of preparing the content and filling the content and the pressurizing agent .
- Preparation of the content can be conducted in any method known in the art, and the following methods are used: (1) a method of mixing the triazolopyridazine derivative [I] or a salt thereof with an adjuvant and a solvent to form a uniform suspension, (2) a method of kneading the triazolopyridazine derivative [I] or a salt thereof with a surface active agent to form powder, and (3) a method of mixing the triazolopyridazine derivative [I] or a salt thereof with water-soluble additives for inhalation and then stirring, heating and cooling the mixture into an emulsion.
- Filling of the content and the pressurizing agent consists usually of the steps of washing the vessel, filling the content, degassing the inside of the vessel, filling the pressurizing agent, and attaching the valve thereto.
- Filling of the pressurizing agent involves filling under cooling, filling under pressure, or undercup filling.
- crimp conditions are confirmed in order to examine whether the valve is correctly fitted. Further, in order to examine linkage from the product, a hot water test is conducted and water droplets are removed.
- a flame-length test and tests for changes with time are conducted in order to confirm the storage and safety of the aerosol for use.
- the devices used for administration may be commercial inhalers, and examples include Ventolin Rotacaps, Glaxo), Spin Heller * (Fujisawa Pharmaceutical Co., Ltd.), Intal Spincaps (Fisonz), Atrovent and Berotec Inhaletten (Boehringer Ingelheim) , Foradil (Chiba), Bentodisks (Glaxo), Pabrizer * (Teijin Ltd. ) , Bricanyl Turbuhaler (Astra) , Miat Insufflator) .
- the triazolopyridazine derivatives [I] or salts thereof used for the agent of the present invention possess excellent an anti-allergic action, an anti-asthmatic action, an anti-PAF (platelet activating factor) action, an inhibitory action of eosinophil chemotaxis, an inhibitory action of local eosinophilic infiltration in allergic and asthmatic reactions , and is with a low toxic potential (acute toxicity: LD 50 >2g/kg).
- the agent of the present invention can act specifically on the bronchus or its surrounding tissues by administering it topically into the mouth, throat etc.
- Topical administration of the triazolopyridazine derivative [I] or its salts achieve a minimum effective amount, thus eliminating general and high-dosage administration. Accordingly, it can be administered into even children easily and safely. In particular, outstanding local acting effects can be demonstrated in the case of an inhalation or an aerosol.
- the agent of the present invention can be used safety as an anti-asthmatic agent, an anti- PAF agent, an anti-allergic agent, an agent for inhibiting eosinophil chemotaxis , an agent for preventing or treating diseases related to eosinophilic infiltration (for example, allergic diseases such as urticaria, atopic dermatitis, allergic rhinitis, hypersensitive pneumonia, etc,; diseases of the skin such as eczema, dermatitis herpetiformis , psoriasis, etc., and respiratory diseases such as simple pulmonary eosinophilia (PIE syndrome), chronic obstructive pulmonary disease (COPD), etc.), particularly as an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD), an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia, in mammals (e.g., humans, mice,
- the dose of the agents of the present invention varies depending on age, body weight, symptoms, route and frequency of administration and other factors , they may be administered at about 0.001 to 10 mg/kg, preferably about 0.01 to 10 mg/kg, more preferably about 0.1 to 10 mg/kg, particularly preferably about 0.1 to 5 mg/kg in one to two portions daily for an adult .
- Preferable route of administration may be direct inhalation into mouth, etc. by using tools for inhalation.
- Detection of the fractions containing each object compound in the Reference Examples was carried out under TLC (Thin Layer Chromatography) monitoring.
- TLC monitoring Merck's 60F 254 was used as the TLC plate and a UV detector for detection .
- Merck' s silica gel 60 (70 to 230 mesh) was used as a silica gel for column chromatography.
- mice Male Hartley guinea pigs (body weights about 500 g) were used. Bronchoconstriction induced by PAF, 1 ⁇ g/kg i.v. , in guinea pigs was measured using to the method of Konzett-Roessle . With the guinea pig immobilized in the dorsal position, tracheotomy was performed under urethane (1.5 g/kg i.v.) anesthesia and the trachea was connected through a cannula to a respirator. The side branch of the tracheal cannula was connected to a transducer (Model 7020, Ugobasile).
- Solubitantriolate 20.0 mg Suspensions for inhalation can be prepared by mixing the above components.
- Quantitative valve can be used for 50 11 1 .
- Liquid preparations for inhalation can be prepared by mixing the above components .
- the liquid preparation for inhalation can be used by using Nebulizer (Trade Mark) .
- the powders for inhalation can be prepared by mixing the above components .
- the capsules for inhalation can be used by using Spinhalor
- the agent of the present invention can make an anti-asthmatic action, etc., of the triazoropyridazine derivatives [I] such as 6- (2 , 2-dimethyl-3-sulfamoyl-1- propoxy) -7-isopropyl [l,2,4] triazolo Cl,5-b] pyridazine, etc., or salts thereof act on bronchi or tissues around bronchi specifically, and therefore, since local administering could be performed by a minimum effective amount of by the triazolopyridazine derivatives [I], it could avoid to administer an amount of the triazolopyridazine derivatives [I] into a whole body.
- the triazoropyridazine derivatives [I] such as 6- (2 , 2-dimethyl-3-sulfamoyl-1- propoxy) -7-isopropyl [l,2,4] triazolo Cl,5-b] pyridazine, etc., or salts thereof act on bron
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The agent of the present invention can make an anti-asthmatic action, etc., of the triazolopyridazine derivatives [I] such as 6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-isopropyl[1,2,4]triazolo[1,5-b]pyridazine, etc., or salts thereof act on bronchi or tissues around bronchi specifically, and therefore, since local administering could be performed by a minimum effective amount of by the triazolopyridazine derivatives [I], it could avoid to administer an amount of the triazolopyridazine derivatives [I] into a whole body.
Description
TRIAZOLO-PYRIDAZINE DERIVATIVES FOR THE TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASES
Technical Field
The present invention relates to an agent for acting on bronchi which comprises triazolopyridazine derivatives such as 6- ( 2 , 2-dimethyl-3 -sulfamoyl-l-propoxy) -7- isopropyl (l , 2 , 4) triazolo (l , 5-b] pyridazine , etc . .
Background
Triazolopyridazine derivatives represented by the formula:
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom or an optionally substituted lower alkyl group, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p (p is a whole number of 0 to 2); Y is a group of the formula:
R4 —C—
(R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted
aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4 ; n is a whole number of 0 to 4 , are compounds which are useful for an anti-asthmatic agent, an anti-PAF (platelet activating factor) agent, an anti-allergic agent, an agent for inhibiting eosinophil chemotaxis , an agent for preventing or treating allergic rhinitis or an agent for preventing or treating atopic dermatitis (EP-A-0562439 , EP-A-0648491 and WO96/08496).
And, it is desired to develop agents which show actions of the triazolopyridazine derivatives [I] locally.
Disclosure of Invention
The present inventors diligently made extensive studies in order to solve the problems and, as a result, they found that it could make actions of the derivatives act at bronchi locally by preparing an inhalation, etc. comprising 6- (2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [l , 2 , 4) triazolo Cl,5-b] pyridazine or a salt thereof. And, they further studied based on the finding, the present invention has been accompliched.
More specifically, the present invention provides ( 1 ) A agent for acting on bronchi which comprises a compound of the formula:
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom or an optionally substituted lower alkyl group, or R2 and R3 may, taken together with the adjacent
-C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p (p is a whole number of 0 to 2); Y is a group of the formula:
R4 I
— c—
I R5
(R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4; n is a whole number of 0 to 4 , or a salt thereof, ( 2 ) The agent as defined in ( 1 ) , wherein R1 is (i) a hydrogen atom, (ii) a C1_6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- ordi-Cj.j alkylamino, Ci.j alkoxy, C1.6 alkylcarbonyloxy and a halogen atom or (iii) a halogen atom,
R2 and R3 respectively is (i) a hydrogen atom or (ii) a C1.6 alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or i-C^ alkylamino, C1-6 alkoxy, C^ alkylcarbonyloxy and a halogen atom or (iii) a C3.6 cycloalkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono-
alkylamino, C1_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms , optionally
having substituents selected from the group consisting of (i) C1_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C^ alkylamino, C1-6 alkoxy, C^ alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C^ alkyl, C1-6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Cj.6 alkoxy and (vii) a halogen atom;
X is an oxygen atom or S(0)p (p is a whole number of 0 to 2).
Y is (a) a group of the formula: R4 —C—
(R4 and R5 respectively is (i) a hydrogen atom or (ii) a C^ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C^ alkylamino, C^ alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom) , or
(b) a divalent group derived from a 3- to 7-membered cyclic hydrocarbon or 3- to 7-membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in adidtion to carbon atoms, optionally having substituents selected from the group consisting of (i) Cx_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cj__6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by Cx_6 alkyl, Cx_6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Cj.j alkoxy and (vii) a halogen atom,
R6 and R7 respectively is (i) a hydrogen atom, (ii) a C1-6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro.
mono- or di-C1.6 alkylamino, C1,6 alkoxy, Cλ,6 alkylcarbonyloxy and a halogen atom, (iii) a C3.6 cycloalkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C1.6 alkylamino, C1_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, or (iv) a C6.14 aryl group optionally having substituents selected from the group consisting of (a) C^ alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C^ alkylamino, Cx_6 alkoxy, Cx.6 alkylcarbonyloxy and a halogen atom, (b) an amino which may be substituted by C^ alkyl, C^ acyl or 5- to 7-membered cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f) nitro, (g) Cx.6 alkoxy, (h) C1_6 alkylcarbonyloxy and (i) a halogen atom, or
R6 and R7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms, optionally having substituents selected from the group consisting of (i) C1_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C^ alkylamino, λ_6 alkoxy, C^ alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C1_6 alkyl, C^ acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Ci.s alkoxy and (vii) a halogen atom, m is a whole number of 0 to 4; n is a whole number of 0 to 4,
( 3 ) The agent as defined in ( 1 ) , wherein R1 is hydrogen atom or a C^ alkyl group, R2 is a hydrogen atom or a C1_3 alkyl group, R3 is a hydrogen atom or a C1_6 alkyl group, X is an oxygen atom, Y is a group of the formula:
wherein R4' and R5' each is (i) a hydrogen atom or (ii) a C^ alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-C^ alkylamino, C1_6 alkoxy, C1_6 alkyl-carbonyloxy and halogen atom, R6 and R7 respectively is a hydrogen atom or a C1.3 alkyl group, m and n is 1.
( 4 ) The agent as defined in ( 1 ) , wherein the compound is 6- ( 2 , 2-dimethyl-3-sulfamoyl-l-propoxy) -7-isopropyl
[l,2,4] triazolo [l,5-b] pyridazine,
(5) The agent as defined in (1) , which is an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD) , an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia,
(6) The agent as defined in (1) , which is an inhalation for acting on bronchi,
(7) Use of a compound of the formula:
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted cycloalkyl group, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p (p is a whole number of 0 to 2) ; Y is a group of the formula:
R4
I
— c—
(R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4 ; n is a whole number of 0 to 4 , or a salt thereof for preparing an agent for acting on bronchi, (8) The use as defined in (7), wherein
R1 is (i) a hydrogen atom, (ii) a C^ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C^ alkylamino, Ci.6 alkoxy, C1.6 alkylcarbonyloxy and a halogen atom or (iii) a halogen atom,
R2 and R3 respectively is (i) a hydrogen atom or (ii) a C1-6 alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C^ alkylamino, C1_6 alkoxy, C1-6 alkylcarbonyloxy and a halogen atom or (iii) a C3.6 cycloalkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C^ alkylamino, Cj_6 alkoxy, C1-6 alkylcarbonyloxy and a halogen atom, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms , optionally having substituents selected from the group consisting of (i) C1_6 alkyl optionally having substituents selected from
the group consisting of hydroxy, amino, mono- or di-C^ alkylamino, C1-6 alkoxy, C^6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C1,6 alkyl, acyl or 5- to 7-membered cyclic amino, (iii) hydroxy,
(iv) carboxyl, (v) nitro, (vi) C1_6 alkoxy and (vii) a halogen atom;
X is an oxygen atom or S(0)p (p is a whole number of 0 to
2),
Y is (a) a group of the formula:
R4
I
—C—
(R4 and R5 respectively is (i) a hydrogen atom or (ii) a C^ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino, C^ alkoxy, C1_6 alkylcarbonyloxy and a halogen atom) , or
(b) a divalent group derived from a 3- to 7-membered cyclic hydrocarbon or 3- to 7-membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in adidtion to carbon atoms, optionally having substituents selected from the group consisting of (i) 1, alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cx,6 alkylamino, C1_ alkoxy, C^ alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C1.6 alkyl, C^ acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) alkoxy and (vii) a halogen atom,
R6 and R7 respectively is (i) a hydrogen atom, (ii) a C^ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C^ alkylamino, C1.6 alkoxy, C1.6 alkylcarbonyloxy and a halogen atom, (iii) a C3.6 cycloalkyl group optionally
having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or i-C^ alkylamino, alkoxy, C1.6 alkylcarbonyloxy and a halogen atom, or (iv) a C6.14 aryl group optionally having substituents selected from the group consisting of (a) Cj.g alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C^ alkylamino, Cx_6 alkoxy, C^ alkylcarbonyloxy and a halogen atom, (b) an amino which may be substituted by C1.6 alkyl, C^ acyl or 5- to 7-membered cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f) nitro, (g) C1_6 alkoxy, (h) C^ alkylcarbonyloxy and (i) a halogen atom, or
Rδ and R7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms, optionally having substituents selected from the group consisting of (i) C1„6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or
alkylamino, C1-6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C^ alkyl, Cj.6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) alkoxy and (vii) a halogen atom, m is a whole number of 0 to 4; n is a whole number of 0 to 4,
( 9 ) The use as defined in ( 7 ) , wherein R1 is hydrogen atom or a C1_3 alkyl group, R2 is a hydrogen atom or a C^-j alkyl group, R3 is a hydrogen atom or a C1-6 alkyl group, X is an oxygen atom, Y is a group of the formula:
•c-
,5'
R wherein R4' and R5' each is (i) a hydrogen atom or (ii) a C^ alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-Cj.g alkylamino, Cj_.6 alkoxy, C1_6 alkyl-carbonyloxy and halogen atom, R6 and R7 respectively is a hydrogen atom or a Cx_3 alkyl group, m and n is 1,
(10) The use as defined in (7), wherein the compound is 6- ( 2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl
[l,2,4] triazolo [l,5-b] pyridazine,
(11) The use as defined in (7), wherein the agent is an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD) , an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia,
(12) The use as defined in (7), wherein the agent is an inhalation for acting on bronchi,
(13) A method for preventing or treating asthma, chronic obstructive pulmonary disease (COPD), hypersensitive pneumonia or simple pulmonary eosinophilia which comprises administering an effective amount of a compound of the formula:
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted cycloalkyl group, or R2
and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p (p is a whole number of 0 to 2) ; Y is a group of the formula:
R4
I
—c—
I R5
(R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4 ; n is a whole number of 0 to 4 , or a salt thereof to bronchi of mammals ,
(14) The method as defined in (13), wherein R1 is (i) a hydrogen atom, (ii) a Cx_6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C1.6 alkylamino, Cj_6 alkoxy, C^ alkylcarbonyloxy and a halogen atom or (iii) a halogen atom,
R2 and R3 respectively is (i) a hydrogen atom or (ii) a Cx_6 alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or
alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom or (iii) a C3.6 cycloalkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C^ alkylamino, C1-6 alkoxy, Cj__6 alkylcarbonyloxy and a halogen atom, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen
and sulfur atoms in addition to carbon atoms , optionally having substituents selected from the group consisting of
(i) alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or
alkylamino, C^ alkoxy, C1-6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C^ alkyl, acyl or 5- to 7-membered cyclic amino, (iii) hydroxy,
(iv) carboxyl, (v) nitro, (vi) C1.6 alkoxy and (vii) a halogen atom;
X is an oxygen atom or S(0)p (p is a whole number of 0 to
2).
Y is (a) a group of the formula:
R4
I
—c—
(R4 and R5 respectively is (i) a hydrogen atom or (ii) a C^ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or i-C^ alkylamino, Cλ_6 alkoxy, C^ alkylcarbonyloxy and a halogen atom) , or
(b) a divalent group derived from a 3- to 7-membered cyclic hydrocarbon or 3- to 7-membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in adidtion to carbon atoms, optionally having substituents selected from the group consisting of (i)
alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cx.6 alkylamino, C1-6 alkoxy, C^ alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C^ alkyl, C1_6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Cx.6 alkoxy and (vii) a halogen atom,
R6 and R7 respectively is (i) a hydrogen atom, (ii) a C^ alkyl group optionally having substituents selected from
the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cj.g alkylamino, C1_6 alkoxy, Cx.6 alkylcarbonyloxy and a halogen atom, (iii) a C3.6 cycloalkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C^ alkylamino, Cj.g alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, or (iv) a C6.14 aryl group optionally having substituents selected from the group consisting of (a) Cx.6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or
alkylamino, Cx_6 alkoxy, Cj_.β alkylcarbonyloxy and a halogen atom, (b) an amino which may be substituted by C^ alkyl, C^ acyl or 5- to 7-membered cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f) nitro, (g) C^ alkoxy, (h) C^ alkylcarbonyloxy and (i) a halogen atom, or
R6 and R7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms , optionally having substituents selected from the group consisting of (i) C^ alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or
alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by Cx_6 alkyl, C^ acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Cx.6 alkoxy and (vii) a halogen atom, m is a whole number of 0 to 4; n is a whole number of 0 to 4,
(15) The method as defined in (13), wherein R1 is hydrogen atom or a Cx_3 alkyl group, R2 is a hydrogen atom or a C^ alkyl group, R3 is a hydrogen atom or a C^ alkyl group, X
is an oxygen atom, Y is a group of the formula:
R4'
I
— c—
wherein R4' and R5 each is (i) a hydrogen atom or (ii) a C1 alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-Cj.g alkylamino, Cx_6 alkoxy, C1.6 alkyl-carbonyloxy and halogen atom, R6 and R7 respectively is a hydrogen atom or a Cx_3 alkyl group, m and n is 1 , and
(16) The method as defined in (13), wherein the compound is 6- ( 2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl
[l,2,4J triazolo [l,5-b] pyridazine. Furthermore, the present invention provides:
(17) The agent as defined in (1), which is an aerosol for acting on bronchi,
(18) The use as defined in (8), wherein the agent is an aerosol for acting on bronchi,
(19) An inhalation which comprises 6- ( 2 , 2-dimethyl-3- sulfamoyl-1-propoxy) -7-isopropyl Cl,2,4] triazolo [l,5-b) pyridazine or a salt thereof and sprays (e.g. , an inhalation for acting on bronchi) ,
(20) An aerosol which comprises 6- ( 2 , 2-dimethyl-3- sulfamoyl-1-propoxy) -7-isopropyl [l,2,4] triazolo [l,5-b] pyridazine or a salt thereof and sprays (e.g., an aerosol for acting on bronchi),
(21) An inhalation which comprises about 0.01 to 99.9 wt% of a compound of the formula:
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom or an optionally substituted lower alkyl group, or R2 and R3 may, taken together with the adjacent
-C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p (p is a whole number of 0 to 2); Y is a group of the formula:
R4
I
—C—
I R5
(R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4 ; n is a whole number of 0 to 4 , or a salt thereof and about 0.1 to 99wt% of additives for inhalation to the total composition,
(22) The inhalation as defined in (21) , wherein the compound is 6- ( 2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl
[l,2,4] triazolo [l,5-b] pyridazine,
(23) The inhalation as defined in (21) which is a powder for inharation, a capsule for inharation, a suspension for fot inharation or a liquid preparation for inharation,
(24) The inhalation as defined in (21) which is an aerosol,
(25) The inhalation as defined in (21) , wherein the additive for inhalation is spray,
(26) The inhalation as defined in (21) which is an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD) , an agent for
preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia, (27) A method for producing the inhalation as defined in (21), which comprises mixing about 0.01 to 99.9 wt% of a compound of the formula:
R
wherein each symbol is the same as defined in claim 13, or a salt thereof and about 0.1 to 99wt% of additives for inhalation to the total composition, and
(28) A method for preparing an aerosol comprising a compound of the formula:
[|]
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom or an optionally substituted lower alkyl group, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p (p is a whole number of 0 to 2); Y is a group of the formula:
R4
I
R5 (R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived
from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4 ; n is a whole number of 0 to 4 , or a salt thereof and sprays which comprises
(i) (a) mixing the compound [I] or a salt thereof with an adjuvant and a solvent to form a uniform suspension, (b) kneading the compound [ I ] or a salt thereof with a surface active agent to form powder, and (c) mixing the compound [I] or a salt thereof with water-soluble additives for inhalation and then stirring, heating and cooling the mixture into an emulsion, and
(ii) filing the suspension, powder or emulsion into the vessel and degassing the inside of the vessel, and (iii) filing the pressurizing agent into the vessel and attaching the valve to vessel.
It should be understood that where the triazolopyridazine derivatives [I] used for the agent of the present invention contains asymmetric carbon within its structure, it may occur as optically active isomers as well as racemic mixtures and that these isomers and mixtures also fall within the scope of the triazolopyridazine derivatives [I].
The triazolopyridazine derivatives [I] used for the agent of the present invention, which contain 6- (2, 2- dimethyl-3-sulfamoyl-l-propoxy) -7-isopropyl [l ,2, 4] triazolo Cl,5-b] pyridazine, are known compounds described in EP-A-0562439, EP-A-0648491 or O96/08496.
In the formula mentioned above, examples of the "lower
alkyl group" represented by R1, R2, R3, R4, R5, R6 or R7 include a straight or branched C^ alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl and so on.
Examples of the "cycloalkyl group" represented by R2, R3 , R6 or R7 include a C3.6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
Examples of the "aryl group" represented by R6 or R7 include a C6_14 aryl group such as phenyl , naphthyl and so on.
Examples of the substituents of the "lower alkyl group" and "cycloalkyl group" include 1 to 4 substituents selected from among hydroxy, amino, carboxyl, nitro, mono- or di-lower alkylamino (e.g. mono- or
alkylamino groups such as methylamino, ethylamino, propylamino, dimethylamino , diethylamino , etc.), lower alkoxy (e.g. C^ alkoxy groups such as methoxy, ethoxy, propoxy, hexyloxy, etc.), lower alkylcarbonyloxy (e.g. C^ alkylcarbonyloxy groups such as acetoxy, ethylcarbonyloxy, etc.), halogen (e.g. fluorine, chlorine, bromine and iodine) and so on.
Examples of the substituents of the "aryl group" include 1 to 5 substituents selected from among optionally substituted lower alkyl, optionally substituted amino, acetamido, hydroxy, carboxyl, nitro, lower alkoxy (e.g. x_6 alkoxy groups such as methoxy, ethoxy, propoxy, etc. ) , lower alkylcarbonyloxy (e.g. Cx.6 alkylcarbonyloxy groups such as acetoxy, ethylcarbonyloxy, etc.), halogen atoms (e.g. fluorine, chlorine, bromine and iodine) and so on. In this connection, examples of the substituents by which the lower alkyl (e.g. Cx.6 alkyl group such as methyl, ethyl, n-propyl, etc.) mentioned just above may have, include 1 to 4 substituents selected from among hydroxy, amino, mono- or di-lower alkylamino (e.g. mono- or di-C^ alkylamino groups such as methylamino, ethylamino, propylamino.
dimethylamino , diethylamino , etc.), lower alkoxy (e.g. C1.6 alkoxy groups such as methoxy, ethoxy, propoxy, hexyloxy, etc.), halogen (e.g. fluorine, chlorine, bromine and iodine) and so on. Examples of the substituents by which the amino group mentioned above may have include 1 or 2 substituents selected from among C^ alkyl (e.g. methyl, ethyl, propyl, etc.), 5- to 7-membered cyclic amino (e.g. pyrrolidino, morpholino, piperidino, piperazino, etc.) and so on.
Examples of the "halogen" represented by R1 include fluorine, chlorine, bromine, iodine and so on.
Examples of the "5- to 7-membered ring formed in combination with the adjacent -C=C- group" include a 5- to 7-membered ring which may contain 1 to 4 hetero atoms selected from among nitrogen, oxygen, sulfur, etc. in addition to carbon atoms. Thus, in particular, a 5- to 7-membered cyclic hydrocarbon such as C5.7 cycloalkenes (e.g. , cyclopentene, cyclohexene, cycloheptene, etc.), benzene and so on and a 5- or 6- membered nitrogen-containing heterocyclic group consisting of carbon and nitrogen atoms (e.g., pyrrole, pyridine, piperidine , etc.), can be mentioned as the common species .
Examples of the "3- to 7-membered homocyclic ring" of the "divalent group derived from the 3- to 7-membered homocyclic ring" represented by Y include a 3- to 7-membered homocyclic ring consisting exclusively of carbon atoms, for instance. Thus, for example, C3.7 cycloalkanes such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc., C3.7 cycloalkenes such as cyclopropene , cyclobutene, cyclopentene, cyclohexene, cycloheptene, etc. and benzene can be mentioned as the common species.
Examples of the "divalent group derived from the 3- to 7-membered homocyclic ring" include a group resulting from either elimination of two hydrogen atoms from a single carbon
atom in the 3- to 7-membered homocyclic ring or elimination of one hydrogen atom from each of two different carbon atoms . To be specific, the following groups can be included by way of example:
Particularly, the following groups may be used as the common species :
More preferable examples in above groups include the following groups :
Examples of the "3- to 7-membered heterocyclic ring" of the "divalent group derived from the 3- to 7-membered heterocyclic ring" represented by Y include a 3- to 7- membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from among nitrogen, oxygen, sulfur and other atoms in adidtion to carbon atoms, for instance. Thus, oxetane, tetrahydrofuran , tetrahydropyran, pyrrole, azetidine, pyrrolidine, piperidine, piperazine, tetraydrothiophene , homopiperidine, morpholine, etc. can
be employed.
Examples of the divalent group derived from the "3- to 7-membered heterocyclic ring" is a group resulting from either elimination of two hydrogen atoms from a single carbon atom in the 3- to 7-membered heterocyclic ring or elimination of one hydrogen atom from each of two different atoms . Thus , for example, the following groups can be included
Examples of the "nitrogen-containing heterocyclic group" formed by R6 and R7 with the adjacent nitrogen atom include a group resulting from elimination of one hydrogen atom from a nitrogen atom in a ring such as a 3- to 13- membered nitrogen-containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain one to four hetero atoms , for example , selected from nitrogen, oxygen, sulfur and other atoms. Specifically, the following 3- to 9-membered nitrogen- containing heterocyclic groups can be generally used:
Examples of the substituents by which the "3- to 7- membered homocyclic ring", "3- to 7-membered heterocyclic ring" and "nitrogen-containing heterocyclic group" may have, include 1 to 5 substituents selected from among an optionally substituted lower alkyl, an optionally substituted amino, hydroxy, carboxyl, nitro, lower alkoxy (e.g. C^ alkoxy groups such as methoxy, ethoxy, propoxy, etc. ) , halogen (e.g. fluorine, chlorine, bromine and iodine) and so on. In this connection, examples of the substituents by which the lower alkyl (e.g. C^ alkyl group such as methyl, ethyl, n-propyl, etc.) mentioned just above may have, include 1 to 4 substituents selected from among hydroxy, amino, mono- or di-lower alkylamino (e.g. mono- or
alkylamino groups such as methylamino , ethylamino , propylamino , dimethylamino , diethylamino, etc.), lower alkoxy (e.g. C^ alkoxy groups such as methoxy, ethoxy, propoxy, hexyloxy, etc.), lower alkylcarbonyloxy (e.g. C^ alkylcarbonyloxy groups such as acetoxy, ethylcarbonyloxy, etc.), halogen (e.g. fluorine, chlorine, bromine and iodine) and so on. Examples of the substituents by which the amino group mentioned above may have, include 1 to 2 substituents selected from among C^ alkyl (e.g. methyl, ethyl, propyl, etc.), acyl (e.g. Q.x.b acyl groups such as formyl, acetyl, propionyl, butyryl, etc.), 5- to 7-membered cyclic amino (e.g. pyrrolidino, morpholino, piperidino, piperazino, etc. ) and so on.
Preferable examples of R1 are a hydrogen atom or a C^ alkyl group (e.g. methyl, ethyl, n-propyl, etc.) and more
preferable examples are a hydrogen atom and so on.
Preferable examples of R2 are a hydrogen atom or a C^ alkyl group (e.g. methyl, ethyl, n-propyl, etc.) and more preferable examples are a hydrogen atom and so on.
Preferable examples of R3 are a hydrogen atom or a C^ alkyl group (e.g. methyl, ethyl, n-propyl, i-propyl, etc.) and more preferable examples are a branched C3.6 alkyl group (e.g. i-propyl, etc.).
Also preferred is the case in which R2 and R3 form a 5- to 7-membered homocyclic ring in combination with the adjacent -C=C- group. Particularly preferred is the case of cyclohexene, benzene or the like.
X is preferably an oxygen atom or S and more preferably an oxygen atom.
Preferable examples of Y are a group of the formula:
R4' I
— c—
wherein R4' and R5' each is (i) a hydrogen atom or (ii) a C^ alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or
alkyl-carbonyloxy and halogen atom, and so on.
Examples of the "C^ alkyl group" represented by R4' and R5' are methyl, ethyl, n-propyl, i-propyl and so on, and more preferable examples are methyl, ethyl and so on.
Also preferred are cases in which Y is a divalent group derived from a 3- to 7-membered homocyclic ring or heterocyclic ring which may be substituted.
Y is preferably a group of the formula:
Thus , for example , the following groups can be frequently used as the common species of Y:
More preferably examples of Y include the follow:
Preferable examples of R6 and R7 are a hydrogen atom, a Cj.3 alkyl group (e.g. methyl, ethyl, n-propyl, etc.) and so on, and particularly a hydrogen atom is preferred.
Preferable example of m is a whole number of 1 to 4 , more preferable example is a whole number of 1 to 3 and most preferable example is 1.
Preferable example of n is a whole number of 1 to 4 and more preferable example is 1.
The most useful is the case in which both m and n represent 1.
Preferable specific examples of the triazolopyridazine derivatives [ I ] used for the agent of the present invention are all compounds prepared in Examples of EP-A-0562439 and WO96/08496, and most preferable example is 6- (2, 2- dimethyl-3-sulfamoyl-l-propoxy) -7-isopropyl [l , 2 , 4] triazolo [l,5-b] pyridazine or a salt thereof.
The salt of triazolopyridazine derivatives [I] is preferably a physiologically acceptable acid addition salt.
Such salts include salt with inorganic acids (e.g., hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) and salts with organic acids (e.g., acetic acid, formic acid, propionic acid, fumaricacid, maleicacid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) .
Provided that the triazolopyridazine derivatives [I] have an acidic group, such as -COOH, they may form a salt with an inorganic base (e.g., an alkali metal or alkaline earth metal such as sodium, potassium, calcium or magnesium; or ammonia) or an organic base (e.g., a tri-C^ alkylamine such as triethylamine) .
The triazolopyridazine derivatives [ I ] or salts thereof can be prepared according to the descriptions of EP-A- 0562439 or O96/08496, particularly the descriptions of Examples of the references .
The agent for acting on bronchi of the present invention makes the triazolopyridazine derivatives [I] or salts thereof act on bronchi specifically, on the other hand do not make them act on a whole body. And, the agent of the present invention may act on tissues around bronchi such as trachea, lung, etc..
So long as the agent of the present invention can show the local actions of triazolopyridazine derivatives [ I ] or salts thereof, types of the agent are not limited. For example, the agent of the present invention can be preferably used as an inhalation.
For example, if the pharmaceutical preparation of the invention is used as an inhalation, additives for the inhalation may be any additives generally used in an inhalation, and examples are solid fillers such as pressurizing agents, white sugar, lactose, glucose, mannitol and sorbitol, liquid fillers e.g. inert liquid such
as propylene glycol, binders such as methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone , polyethylene glycol and white sugar, lubricants such as magnesium stearate, light silicate anhydride, talk and sodium lauryl sulfate, taste correctives such as citric acid, menthol, glythylithin ammonium salt, glycine and orange powder, preservatives such as sodium benzoate, sodium bisulfite, methyl parabene and propyl parabene, stabilizers such as citric acid and sodium citrate, suspending agents such as methyl cellulose, polyvinylpyrrolidone, lecithin and sorbitan trioleate, dispersing agents such as surface active agents, solvents such as water, isotonicity agents such as sodium chloride, pH a justor such as sulfuric acid and hydrochloric acid, and solubilizers such as ethanol.
The pressurizing agents include liquefied gas pressurizing agents, compressed gas etc. The liquefied gas pressurizing agents include e.g. hydrocarbon fluoride (e.g. substitute Freon such as HCFC22, HCFC-123, HCFC-134a, and HCFC142), liquefied petroleum, and dimethyl ether. The compressed gas includes e.g. soluble gas (e.g. carbon dioxide gas, nitrous oxide gas etc. ) and insoluble gas (e.g. nitrogen gas ) .
Further, the pharmaceutical preparation of the invention may contain as active ingredients any pharmaceutical ingredients other than triazolopyridazine derivative [I] or salts thereof. Examples of such pharmaceutical active ingredients include anti-asthma agents (e.g. theophylline , procaterol, ketotifen, azelastine, seratrodast (bronica) etc.), anti-allergy agents (e.g. ketotifen, terfenadine, azelastine, epinastine etc.), anti-inflammatory agents (e.g. diclophenac sodium, ibuprofen, indomethacin etc.), antimicrobial agents (e.g. cefixme, cefdinir, ofloxacin, tosfloxacin etc. ) and anti-fungus agents (e.g. fluconazole.
itraconazole etc. ) . Insofar as the object of the invention can be achieved, these ingredients are not particularly limited insofar and can be used in a suitable ratio.
Although the content of the triazolopyridazine derivative [I] or salts thereof in the pharmaceutical preparation of the invention vary depending on the disease treated, the age or sex of the patient and the conditions of the disease, the content is in the range of usually about 0.01 to 99.9 % by weight, preferably about 0.1 to 50 % by weight , more preferably about 0.5 to 20 % by weight , relative to the whole of the pharmaceutical preparation.
Although the content of various additives such as additives for an inhalation varies depending on the disease treated, the age or sex of the patient and the conditions of the disease, the content is in the range of usually about 0.1 to 99 % by weight, preferably about 10 to 99 % by weight, more preferably about 50 to 99 % by weight, most preferably about 70 to 99 % by weight, relative to the whole of the pharmaceutical preparation.
The content of other pharmaceutical ingredients than the triazolopyridazine derivative [I] or salts thereof varies depending on the disease treated, the age or sex of the patient and the conditions of the disease, the content is in the range of usually about 0.01 to 99.9 % by weight, preferably about 0.1 to 50 % by weight , more preferably about 0.5 to 20 % by weight, relative to the whole of the pharmaceutical preparation.
If the agent of the invention is used as an inhalation, it can be formed into a powder for inharation, a suspension for inharation, a liquid preparation for inharation or a capsule for inharation by a method known in the art and administered by means of a suitable inhaler.
Furthermore, the agent of the invention can be used as an aerosol. The aerosol is made completely
contamination-free during use, and because the inside of the aerosol is maintained always under pressure, the content introduced in the can is completely prevented from being contaminated from the outside.
The aerosol is composed usually of 5 elements i.e. a vessel, a valve, a button, a content and a pressurizing agent, and is classified into a 2-phase system, a 3-phase system and a membrane system (double vessel).
The vessel used is a vessel stipulated under a high-pressure gas regulation , and its material is metal (e.g. tin, aluminum), glass or plastics. There are 3 types of metal vessel, that is, a 3-piece side seam can, a 2-piece seamless can and a 1-piece mono-block can. The glass vessel is excellent in solvent resistance and corrosion resistance and is easily processed, so it can be easily formed into a deformed vessel.
The valve is a part most influential over the jet characteristics and sealing properties of the aerosol. The valve is constituted usually of a mountain cup, a stem, a housing, a spring, a dip tube and gasket rubber, and use is made of a valve equipped with a gas-phase hole or a quantification valve. In the mechanism of the valve, the stem is pressed whereby the stem hole closed with sealing gasket rubber is allowed to communicate with the inside of the vessel so that the content is released through the stem hole.
The button used includes a straight button, a brake cap button, a button for foam, and a button with a long nozzle.
The content is the topical working agent (inhalation) of the invention described above.
The pressurizing agent is the same as described above .
A 2-phase system aerosol using a liquefied gas
pressurizing agent as the pressurizing agent forms an uniform liquid phase in which a suspension (stock solution) containing the triazolopyridazine derivative [ I ] or salts thereof are made compatible with the pressurizing agent, and the inside of the vessel is composed of 2 phases i.e. a liquid phase and a gaseous phase of a gas of the pressurizing agent in an upper space in the vessel. In this system, fine droplets can be obtained due to the propellant force of the pressurizing agent when the liquefied pressurizing agent under pressure in the vessel is jetted out through a valve under normal pressure. In the case of compressed gas, the compressed gas present under compression in an upper space merely presses the stock solution. In the 3-phase system, there are an emulsification system and a suspension system; the former consists of a 2-phase emulsification state of the liquid phase and a gaseous phase in an upper space , and the latter consists of a powder solid phase, a liquefied gaseous phase, and a gaseous phase in an upper space. The membrane system is a system in which only the stock solution itself is jetted out from a double vessel in which the pressurizing agent is filled in an outer vessel and the stock solution is filled in an inner vessel communicating with a valve.
If the agent of the invention is used as an aerosol, it is formed preferably into a powder aerosol.
Production of the aerosol consists usually of the 2 steps of preparing the content and filling the content and the pressurizing agent .
Preparation of the content can be conducted in any method known in the art, and the following methods are used: (1) a method of mixing the triazolopyridazine derivative [I] or a salt thereof with an adjuvant and a solvent to form a uniform suspension, (2) a method of kneading the triazolopyridazine derivative [I] or a salt thereof with
a surface active agent to form powder, and (3) a method of mixing the triazolopyridazine derivative [I] or a salt thereof with water-soluble additives for inhalation and then stirring, heating and cooling the mixture into an emulsion.
Filling of the content and the pressurizing agent consists usually of the steps of washing the vessel, filling the content, degassing the inside of the vessel, filling the pressurizing agent, and attaching the valve thereto. Filling of the pressurizing agent involves filling under cooling, filling under pressure, or undercup filling.
After filling, crimp conditions are confirmed in order to examine whether the valve is correctly fitted. Further, in order to examine linkage from the product, a hot water test is conducted and water droplets are removed.
Further, a flame-length test and tests for changes with time (e.g. tests for reduction in weight, jet characteristics, corrosion of the vessel, valve functions and internal pressure) are conducted in order to confirm the storage and safety of the aerosol for use.
When the agent of the invention is used, the devices used for administration may be commercial inhalers, and examples include Ventolin Rotacaps, Glaxo), Spin Heller* (Fujisawa Pharmaceutical Co., Ltd.), Intal Spincaps (Fisonz), Atrovent and Berotec Inhaletten (Boehringer Ingelheim) , Foradil (Chiba), Bentodisks (Glaxo), Pabrizer* (Teijin Ltd. ) , Bricanyl Turbuhaler (Astra) , Miat Insufflator) .
The triazolopyridazine derivatives [I] or salts thereof used for the agent of the present invention possess excellent an anti-allergic action, an anti-asthmatic action, an anti-PAF (platelet activating factor) action, an inhibitory action of eosinophil chemotaxis, an inhibitory action of local eosinophilic infiltration in allergic and asthmatic
reactions , and is with a low toxic potential (acute toxicity: LD50>2g/kg).
The agent of the present invention can act specifically on the bronchus or its surrounding tissues by administering it topically into the mouth, throat etc. Topical administration of the triazolopyridazine derivative [I] or its salts achieve a minimum effective amount, thus eliminating general and high-dosage administration. Accordingly, it can be administered into even children easily and safely. In particular, outstanding local acting effects can be demonstrated in the case of an inhalation or an aerosol.
As mentioned above, the agent of the present invention can be used safety as an anti-asthmatic agent, an anti- PAF agent, an anti-allergic agent, an agent for inhibiting eosinophil chemotaxis , an agent for preventing or treating diseases related to eosinophilic infiltration (for example, allergic diseases such as urticaria, atopic dermatitis, allergic rhinitis, hypersensitive pneumonia, etc,; diseases of the skin such as eczema, dermatitis herpetiformis , psoriasis, etc., and respiratory diseases such as simple pulmonary eosinophilia (PIE syndrome), chronic obstructive pulmonary disease (COPD), etc.), particularly as an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD), an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia, in mammals (e.g., humans, mice, rats, cats, dogs, sheeps , horses, bovines , monkeys, etc. ) .
Although the dose of the agents of the present invention varies depending on age, body weight, symptoms, route and frequency of administration and other factors , they may be administered at about 0.001 to 10 mg/kg, preferably about
0.01 to 10 mg/kg, more preferably about 0.1 to 10 mg/kg, particularly preferably about 0.1 to 5 mg/kg in one to two portions daily for an adult . Preferable route of administration may be direct inhalation into mouth, etc. by using tools for inhalation.
Best Mode for Carrying out the Invention
In the following, the Examples and Reference Examples are merely intended to describe the present invention in further detail and should by no means be construed as defining the metes and bounds of the invention.
Detection of the fractions containing each object compound in the Reference Examples was carried out under TLC (Thin Layer Chromatography) monitoring. In TLC monitoring, Merck's 60F254 was used as the TLC plate and a UV detector for detection . Merck' s silica gel 60 (70 to 230 mesh) was used as a silica gel for column chromatography.
Abbreviations used in the following have the following meanings .
J : coupling constant s : singlet bs : broad singlet t : triplet m : multiplet
Hz : hertz d : doublet q : quartet
NMR : Nuclear Magnetic Resonance
DMSO : Dimethyl sulfoxide
CDC13 : deuteriochlorofor v/v : volume/volume
% : weight % m. p . : melting point i.v. : intravenous injection
δ (ppm) : chemical shift (part per million)
Working Example
Reference Example 1
Production of 3-amino-6-chloro-5-isopropylpyridazine
A mixture of 21.7 g of 3 , 6-dichloro-4- isopropylpyridazine, 170 ml of 25% ammonium hydroxide solution, and 10 ml of ethanol , was heated at 130 to 140 "C in sealed tube for 22 hours. After cooling, the solvent was distilled off. Water was added to the residue and resulting crystals were collected by filtration and washed water and ethyl ether to pronide 11.1 g of the title compound, m.p. 164-165 ° C
NMR (CDC13) δ : 1.26(6H,d, J=7Hz) , 3.16(lH,m) , 4.89(2H,br. s ) , 6.65(lH,s) .
Reference Example 2
Production of N- ( 6-chloro-5-isopropylpyridazine-3-yl) formamide oxime
To a suspension of 8.6 g of 3-amino-6-chloro-5- isopropylpyridazine in 58 ml of toluene was added 6.2 ml of dimethylformamide dimethyl acetal and the reaction mixture was refluxed for 2 hours . The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and elution was carried out with ethyl acetate-methanol (10:1). The fractions containing the objective compound were pooled and concentrated. The residue was dissolved in methanol ( 40 ml) and 1.8 g of hydroxylamine hydrochloride was added to the solution and stirred at room temperature for 2 hours. The resulting crystals were collected by filteration to provide 12.7g of the title compound, m.p. 170-171 ° C Elemental analysis for C8HnN4OCl
/44611
34
Calcd.(%): C, 44.76; H, 5.17; N, 26.10 Found (%): C, 44.62; H, 5.02; N, 26.01
Reference Example 3
Production of 6-chloro-7-isopropyl[ 1 , 2 , 4 ] triazolo! 1 , 5- b]pyridazine
A mixture of 20.04 g of N- ( 6-chloro-5- isopropylpyridazine-3-yl)formamide oxime and 97 g of polypyhosphoric acid was heated at 110 to 115 °C for 1 hour in oil bath. After cooling, the reaction mixture was poured into ice water and extracted with dichloromethane. The extract was washed with water and dried (MgS04) and the solvent was distilled off under reduced pressure. Hexane was added to the residue and the resulting crystals were collected by filtration, to provide 12.7 g of the title compound, m.p. 53-54 °C Elemental analysis for C8H9C1N4
Calcd.(%): C, 48.87; H, 4.61; N, 28.49 Found (%): C, 48.85; H, 4.55; N, 28.48
Reference Example 4
Production of 6- ( 2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7- isopropyl[l,2 , 4] triazolo [ 1, 5-b]pyridazine
To a solution of 0.669 g of 3-hydroxy-2 , 2- di ethyl-1-propanesulfonamide in 30 ml of tetrahydrofuran was added 0.336 g of 60% sodium hydride in oil and the mixture was refluxed for 1 hour. After cooling, to the reaction mixture was added 0.748 g of 6-chloro-7- isopropyl[l ,2 , 4] triazolotl, 5-b]pyridazine and the mixture was refluxed with stirring for 4 hours. After cooling, the reaction mixture was poured into ice water, adjusted to pH6 with lN-hydrochloric acid, and extracted with ethyl acetate-tetrahydrofuran (1:1). The extract was washed with
saturated aqueous solution of sodium chloride and dried (MgS04) and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and elution was carried out with dichloromethane-ethyl acetate-methanol (10:10:1). The fractions containing the objective compound were pooled and concentrated. The resulting crystals were recrystallized from acetone-water to provide 1.10 g of the title compound, m.p. 197-198 " C Elemental analysis for C13H21N503S
Calcd.(%): C, 47.69; H, 6.46; N, 21.39 Found (%): C, 47.84; H, 6.60; N, 21.33
Reference Example 5
The result of a pharmacological test of the compound of Reference Example 4 is shown below.
[Effect on platelet activating factor (PAF) -induced guinea pig bronchoconstriction]
Male Hartley guinea pigs (body weights about 500 g) were used. Bronchoconstriction induced by PAF, 1 μg/kg i.v. , in guinea pigs was measured using to the method of Konzett-Roessle . With the guinea pig immobilized in the dorsal position, tracheotomy was performed under urethane (1.5 g/kg i.v.) anesthesia and the trachea was connected through a cannula to a respirator. The side branch of the tracheal cannula was connected to a transducer (Model 7020, Ugobasile). With the volume of air per feed being controlled at 3-7 ml, the ventilation frequency at 70/min. and the pulmonary loading pressure at 10 cm H20, the volume of overflow air was recorded on a rectigraph (Recte-Hori-8s , San-ei Sokki) through the transducer. After administration of gallamine (1 mg/kg i.v.), PAF, 1 μg/kg, dissolved in physiological saline was administered through a jugular vein cannula and the induced bronchoconstriction was
recorded for 15 minutes . The drug suspended in a 5% solution of gum arabic was administered orally in a dose of 3 mg/kg or 1 mg/kg one hour before PAF treatment. The result is presented in Table 1. [Table 1] Effect on PAF-induced bronchoconstriction in guinea pigs
It will be apparent from Table 1 that the compound of Reference Example 4 has excellent inhibitory activity against PAF (platelet activating factor) induced bronchoconstriction .
Example 1 Suspension for inhalation
(1) Compound of Reference Example 4 20.0 mg
(2) HCFC-123 1560.0 mg
(3) HCFC-134a 2400.0 mg
(4) Solubitantriolate 20.0 mg Suspensions for inhalation can be prepared by mixing the above components. Quantitative valve can be used for 50 11 1 .
Example 2 Liquid preparation for inhalation
(1) Compound of Reference Example 4 20.0 mg
(2) Distilled Water 1000.0 g Liquid preparations for inhalation can be prepared by mixing the above components . The liquid preparation for inhalation can be used by using Nebulizer (Trade Mark) .
Example 3 Powder for inhalation
(1) Compound of Reference Example 4 25 g
(2) Lactose 250 g
The powders for inhalation can be prepared by mixing the above components .
Example 4 Capsule for inhalation
(1) Compound of Reference Example 4 25 g
(2) Lactose 250 g
Mixing the above components , and fill them into capsule
No.2 as 2.5mg of the compound of Reference Example 4 per a capsule to obtain ten thousands of capsules for inhalation.
The capsules for inhalation can be used by using Spinhalor
(Fujisawa Pharm. Ltd. , Japan) as small sized atmizer.
INDUSTRIAL APPLICABILITY The agent of the present invention can make an anti-asthmatic action, etc., of the triazoropyridazine derivatives [I] such as 6- (2 , 2-dimethyl-3-sulfamoyl-1- propoxy) -7-isopropyl [l,2,4] triazolo Cl,5-b] pyridazine, etc., or salts thereof act on bronchi or tissues around bronchi specifically, and therefore, since local administering could be performed by a minimum effective amount of by the triazolopyridazine derivatives [I], it could avoid to administer an amount of the triazolopyridazine derivatives [I] into a whole body.
Claims
1. A agent for acting on bronchi which comprises a compound of the formula:
[|]
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted cycloalkyl group, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p (p is a whole number of 0 to 2) ; Y is a group of the formula:
(R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4 ; n is a whole number of 0 to 4 , or a salt thereof .
2. The agent as claimed in claim 1 , wherein
R1 is (i) a hydrogen atom, (ii) a
alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or
alkylamino.
alkoxy, C1_6 alkylcarbonyloxy and a halogen atom or (iii) a halogen atom,
R2 and R3 respectively is (i) a hydrogen atom or (ii) a C^g alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or
alkoxy,
alkylcarbonyloxy and a halogen atom or (iii) a C3.6 cycloalkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or
alkylamino, Cj.g alkoxy,
alkylcarbonyloxy and a halogen atom, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, optionally having substituents selected from the group consisting of (i) Cj.g alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or
alkylamino, Cj_6 alkoxy, C1_6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by
alkyl, ci-6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) C1.6 alkoxy and (vii) a halogen atom;
X is an oxygen atom or S(0)p (p is a whole number of 0 to 2),
Y is (a) a group of the formula: R4 —C—
_•
(R4 and R5 respectively is (i) a hydrogen atom or (ii) a
alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- ordi-Cj., alkylamino, alkoxy,
alkylcarbonyloxy and a halogen atom) , or (b) a divalent group derived from a 3- to 7-membered cyclic
hydrocarbon or 3- to 7-membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in adidtion to carbon atoms, optionally having substituents selected from the group consisting of (i)
alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or
alkylamino, C1.6 alkoxy,
alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by
alkyl,
acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Cj.g alkoxy and (vii) a halogen atom,
R6 and R7 respectively is (i) a hydrogen atom, (ii) a
alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or
alkylamino,
alkoxy,
alkylcarbonyloxy and a halogen atom, (iii) a C3.6 cycloalkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cj.g alkylamino, Cx_6 alkoxy,
alkylcarbonyloxy and a halogen atom, or (iv) a C6.14 aryl group optionally having substituents selected from the group consisting of (a)
alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or
alkylamino,
alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (b) an amino which may be substituted by
alkyl,
acyl or 5- to 7-membered cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f) nitro, (g)
alkoxy, (h)
alkylcarbonyloxy and (i) a halogen atom, or
R6 and R7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur
atoms, optionally having substituents selected from the group consisting of (i) Cx_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or
alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by
alkyl, Cx.6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) C1_6 alkoxy and (vii) a halogen atom, m is a whole number of 0 to 4; n is a whole number of 0 to 4.
3. The agent as claimed in claim 1 , wherein R1 is hydrogen atom or a
alkyl group, R2 is a hydrogen atom or a Cx_3 alkyl group, R3 is a hydrogen atom or a
alkyl group, X is an oxygen atom, Y is a group of the formula:
R4' I —C— " wherein R4' and R5' each is (i) a hydrogen atom or (ii) a Cx.3 alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-Cj.g alkylamino,
alkyl-carbonyloxy and halogen atom, R6 and R7 respectively is a hydrogen atom or a Cx„3 alkyl group, m and n is 1.
4. The agent as claimed in claim 1 , wherein the compound is 6- ( 2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl
[l,2,4] triazolo Cl,5-b] pyridazine.
5. The agent as claimed in claim 1, which is an anti- asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD), an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia.
6. The agent as claimed in claim 1 , which is an inhalation for acting on bronchi.
7. Use of a compound of the formula:
/44611
42
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted cycloalkyl group, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p
(p is a whole number of 0 to 2); Y is a group of the formula:
—
(R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4 ; n is a whole number of 0 to 4 , or a salt thereof for preparing an agent for acting on bronchi.
8. The use as claimed in claim 7 , wherein R1 is (i) a hydrogen atom, (ii) a
alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or
alkylamino, alkoxy, C1.6 alkylcarbonyloxy and a halogen atom or (iii) a halogen atom, R2 and R3 respectively is (i) a hydrogen atom or (ii) a
alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or alkylamino,
alkoxy,
alkylcarbonyloxy and a halogen atom or (iii) a C3.6 cycloalkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, optionally having substituents selected from the group consisting of (i)
alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C^g alkylamino,
alkoxy,
alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by Cx_6 alkyl, C1-6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Cx_6 alkoxy and (vii) a halogen atom;
X is an oxygen atom or S(0)p (p is a whole number of 0 to 2).
Y is (a) a group of the formula: R<
(R4 and R5 respectively is (i) a hydrogen atom or (ii) a
alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or
alkylamino, C1-6 alkoxy, Cl_6 alkylcarbonyloxy and a halogen atom) , or
(b) a divalent group derived from a 3- to 7-membered cyclic hydrocarbon or 3- to 7-membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in adidtion
to carbon atoms , optionally having substituents selected from the group consisting of (i) Cx_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cx.6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by Cx_6 alkyl, Cx_6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Cj.g alkoxy and (vii) a halogen atom,
R6 and R7 respectively is (i) a hydrogen atom, (ii) a Cx_6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (iii) a C3.6 cycloalkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, or (iv) a C6.14 aryl group optionally having substituents selected from the group consisting of (a) Cx_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cx.6 alkylamino, Cx,6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (b) an amino which may be substituted by Cx_6 alkyl, Cx_6 acyl or 5- to 7-membered cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f ) nitro, (g) Cx.6 alkoxy, (h)
alkylcarbonyloxy and (i) a halogen atom, or
R6 and R7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms, optionally having substituents selected from the group consisting of (i) Cx_6 alkyl optionally having substituents selected from the group consisting of hydroxy.
amino, mono- or di-Cx.6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by Cx_6 alkyl, Cx_6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi)
Cx.g alkoxy and (vii) a halogen atom, m is a whole number of 0 to 4; n is a whole number of 0 to
4.
9. The use as claimed in claim 7 , wherein R1 is hydrogen atom or a Cx_3 alkyl group, R2 is a hydrogen atom or a Cx_3 alkyl group, R3 is a hydrogen atom or a Cx_6 alkyl group, X is an oxygen atom, Y is a group of the formula:
R4' I
I , R5 wherein R4' and R5' each is (i) a hydrogen atom or (ii) a Cx_3 alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-Cx.6 alkylamino, Cx„6 alkoxy, Cx_6 alkyl-carbonyloxy and halogen atom, R6 and R7 respectively is a hydrogen atom or a Cx_3 alkyl group, m and n is 1.
10. The use as claimed in claim 7, wherein the compound is 6- ( 2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl
[l,2,4] triazolo [l,5-b] pyridazine.
11. The use as claimed in claim 7, wherein the agent is an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD) , an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia.
12. The use as claimed in claim 7, wherein the agent is an inhalation for acting on bronchi.
13. A method for preventing or treating asthma, chronic obstructive pulmonary disease (COPD), hypersensitive pneumonia or simple pulmonary eosinophilia which comprises administering an effective amount of a compound of the
formula:
: ; [I]
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted cycloalkyl group, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p (p is a whole number of 0 to 2); Y is a group of the formula:
(R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4 ; n is a whole number of 0 to 4 , or a salt thereof to bronchi of mammals .
14. The method as claimed in claim 13, wherein R1 is (i) a hydrogen atom, (ii) a Cx_6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx.6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom or (iii) a halogen atom,
R2 and R3 respectively is (i) a hydrogen atom or (ii) a Cx.6 alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx.6 alkylamino, Cx.6 alkoxy, Cx.6 alkylcarbonyloxy and a halogen atom or (iii) a C3.6 cycloalkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino,
Cx.6 alkoxy, Cx„5 alkylcarbonyloxy and a halogen atom, or
R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, optionally having substituents selected from the group consisting of
(i) Cx.6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cx_6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by Cx_6 alkyl,
Cx.6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy,
(iv) carboxyl, (v) nitro, (vi) Cx_6 alkoxy and (vii) a halogen atom;
X is an oxygen atom or S(0)p (p is a whole number of 0 to
2),
Y is (a) a group of the formula:
—
(R4 and R5 respectively is (i) a hydrogen atom or (ii) a Cx_6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino, Cx.6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom) , or
(b) a divalent group derived from a 3- to 7-membered cyclic hydrocarbon or 3- to 7-membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from the group
consisting of nitrogen, oxygen and sulfur atoms in adidtion to carbon atoms, optionally having substituents selected from the group consisting of (i) Cx_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cx.6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by Cx_6 alkyl, Cx_6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Cx_6 alkoxy and (vii) a halogen atom,
R6 and R7 respectively is (i) a hydrogen atom, (ii) a Cx_6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino, Cx.6 alkoxy, Cx.6 alkylcarbonyloxy and a halogen atom, (iii) a C3.6 cycloalkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino, Cx„6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, or (iv) a C6.X4 aryl group optionally having substituents selected from the group consisting of (a) Cx_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cx_6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (b) an amino which may be substituted by Cx_6 alkyl, Cx.6 acyl or 5- to 7-membered cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f) nitro, (g) Cx„6 alkoxy, (h) Cx_6 alkylcarbonyloxy and (i) a halogen atom, or
R6 and R7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms, optionally having substituents selected from the group consisting of (i) Cx_6 alkyl optionally having
substituents selected from the group consisting of hydroxy, amino, mono- or di-Cx.6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by Cx.6 alkyl, Cx„6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi)
Cx_6 alkoxy and (vii) a halogen atom, m is a whole number of 0 to 4; n is a whole number of 0 to
4.
15. The method as claimed in claim 13 , wherein R1 is hydrogen atom or a Cx_3 alkyl group, R2 is a hydrogen atom or a Cx_3 alkyl group, R3 is a hydrogen atom or a Cx_6 alkyl group, X is an oxygen atom, Y is a group of the formula:
R4' I
— c—
wherein R4' and R5' each is (i) a hydrogen atom or (ii) a Cx_3 alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino, Cx_6 alkoxy, Cx_6 alkyl-carbonyloxy and halogen atom, R6 and R7 respectively is a hydrogen atom or a Cx.3 alkyl group, m and n is 1.
16. The method as claimed in claim 13, wherein the compound is 6- ( 2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [l,2,4] triazolo [l,5-b] pyridazine.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5158398 | 1998-03-04 | ||
JP5158398 | 1998-03-04 | ||
PCT/JP1999/001010 WO1999044611A1 (en) | 1998-03-04 | 1999-03-03 | Triazolo-pyridazine derivatives for the treatment of chronic obstructive pulmonary diseases |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1059924A1 true EP1059924A1 (en) | 2000-12-20 |
Family
ID=12890971
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99937873A Withdrawn EP1059924A1 (en) | 1998-03-04 | 1999-03-03 | Triazolo-pyridazine derivatives for the treatment of chronic obstructive pulmonary diseases |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1059924A1 (en) |
AU (1) | AU3274199A (en) |
CA (1) | CA2319426A1 (en) |
WO (1) | WO1999044611A1 (en) |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
LT3200B (en) * | 1992-03-18 | 1995-03-27 | Takeda Chemical Industries Ltd | Triazolopyridazine methodfor production thereof and use |
TW304878B (en) * | 1993-09-21 | 1997-05-11 | Takeda Pharm Industry Co Ltd | |
NZ292271A (en) * | 1994-09-16 | 1998-04-27 | Takeda Chemical Industries Ltd | Triazolopyridazine derivatives, preparation, intermediates and pharmaceutical compositions thereof |
-
1999
- 1999-03-03 AU AU32741/99A patent/AU3274199A/en not_active Abandoned
- 1999-03-03 WO PCT/JP1999/001010 patent/WO1999044611A1/en not_active Application Discontinuation
- 1999-03-03 CA CA002319426A patent/CA2319426A1/en not_active Abandoned
- 1999-03-03 EP EP99937873A patent/EP1059924A1/en not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO9944611A1 * |
Also Published As
Publication number | Publication date |
---|---|
CA2319426A1 (en) | 1999-09-10 |
AU3274199A (en) | 1999-09-20 |
WO1999044611A1 (en) | 1999-09-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7078412B2 (en) | Quinuclidine derivatives and medicinal compositions containing the same | |
CN106132403B (en) | Spray-dried formulations | |
TWI272106B (en) | New medicament compositions based on anticholinergically-effective compounds and beta-mimetics | |
US20220218695A1 (en) | Combination of an alpha2-adrenoceptor subtype c (alpha-2c) antagonists with a task1/3 channel blocker for the treatment of sleep apnea | |
JP2013530951A (en) | Heterocyclic compounds as Janus kinase inhibitors | |
CA3147105A1 (en) | Combination of an a2-adrenoceptor subtype c (alpha-2c) antagonists with a task1/3 channel blocker for the treatment of sleep apnea | |
US7214687B2 (en) | Quinuclidine derivatives and medicinal compositions containing the same | |
JPWO2004096274A1 (en) | Intra-airway administration | |
US20030064031A1 (en) | Use of a combination of compounds in a dry powder inhaler | |
EP0620224B1 (en) | Triazolopyridazine derivatives, their production and use | |
EP1059924A1 (en) | Triazolo-pyridazine derivatives for the treatment of chronic obstructive pulmonary diseases | |
ZA200704378B (en) | Pharmaceutical compounds and compositions | |
JPH11315024A (en) | Agent for bronchial tube | |
CA2544322C (en) | Agent for treating chronic pelvic pain syndrome | |
CN100491378C (en) | Novel substituted tetracyclic imidazole derivatives, processes for their preparation, pharamaceutical compositions comprising them and their use as a medicine | |
AU714581B2 (en) | Use of 2-(4-(azolylbutyl)piperazinyl-(methyl)benzimidazole derivatives for preparing drugs for treating or preventing asthma | |
WO2013189588A1 (en) | Heterocyclyl-substituted-phenyl derivatives for the treatment of erectile dysfunction | |
JPWO2004087131A1 (en) | Antitussive | |
JP2000063274A (en) | Inhalant for asthma control | |
JP2002047177A (en) | Agent acting on bronchus | |
TW202342045A (en) | Combination of a task1/3 channel blocker with a p2x3 receptor antagonist for the treatment of sleep apnea | |
WO2023118102A1 (en) | Combination of a task1/3 channel blocker with a muscarinic receptor antagonist for the treatment of sleep apnea | |
WO2019015639A1 (en) | Azacyclic amide derivative composition and preparation thereof | |
JPH0873354A (en) | Prophylactic and remedial agent for respiratory tract anaphylaxis and/or respiratory tract disorder | |
WO2005004875A1 (en) | Medicinal composition for pulmonary administration |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20000804 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
|
17Q | First examination report despatched |
Effective date: 20020212 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN |
|
18W | Application withdrawn |
Withdrawal date: 20020802 |