JP4223954B2 - 界面活性剤として使用するための化合物 - Google Patents
界面活性剤として使用するための化合物 Download PDFInfo
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- JP4223954B2 JP4223954B2 JP2003537793A JP2003537793A JP4223954B2 JP 4223954 B2 JP4223954 B2 JP 4223954B2 JP 2003537793 A JP2003537793 A JP 2003537793A JP 2003537793 A JP2003537793 A JP 2003537793A JP 4223954 B2 JP4223954 B2 JP 4223954B2
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 130
- 239000004094 surface-active agent Substances 0.000 title description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000012453 solvate Substances 0.000 claims abstract description 14
- 125000003709 fluoroalkyl group Chemical group 0.000 claims abstract description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 5
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical group FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 44
- 239000003380 propellant Substances 0.000 claims description 36
- -1 7,10,13,16-tetraoxaheptadec-1-yloxy Chemical group 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 claims description 14
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 13
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 11
- 239000008249 pharmaceutical aerosol Substances 0.000 claims description 10
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical group FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 9
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims description 7
- 229960002052 salbutamol Drugs 0.000 claims description 7
- 229960005018 salmeterol xinafoate Drugs 0.000 claims description 7
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 claims description 5
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 claims description 5
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 claims description 5
- 229950000210 beclometasone dipropionate Drugs 0.000 claims description 4
- 229960000289 fluticasone propionate Drugs 0.000 claims description 4
- LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 claims description 3
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims description 3
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- OEXHQOGQTVQTAT-JRNQLAHRSA-N ipratropium Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 OEXHQOGQTVQTAT-JRNQLAHRSA-N 0.000 claims description 3
- 229960001888 ipratropium Drugs 0.000 claims description 3
- 229960001802 phenylephrine Drugs 0.000 claims description 3
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 claims description 3
- 125000006545 (C1-C9) alkyl group Chemical group 0.000 claims description 2
- OBRNDARFFFHCGE-PERKLWIXSA-N (S,S)-formoterol fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1=CC(OC)=CC=C1C[C@H](C)NC[C@@H](O)C1=CC=C(O)C(NC=O)=C1.C1=CC(OC)=CC=C1C[C@H](C)NC[C@@H](O)C1=CC=C(O)C(NC=O)=C1 OBRNDARFFFHCGE-PERKLWIXSA-N 0.000 claims description 2
- HUYWAWARQUIQLE-UHFFFAOYSA-N Isoetharine Chemical compound CC(C)NC(CC)C(O)C1=CC=C(O)C(O)=C1 HUYWAWARQUIQLE-UHFFFAOYSA-N 0.000 claims description 2
- 229960000193 formoterol fumarate Drugs 0.000 claims description 2
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- 239000011859 microparticle Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 34
- 238000004519 manufacturing process Methods 0.000 abstract description 14
- 230000008569 process Effects 0.000 abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract 2
- 239000003814 drug Substances 0.000 description 39
- 238000009472 formulation Methods 0.000 description 32
- 229940079593 drug Drugs 0.000 description 26
- 239000000443 aerosol Substances 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000002671 adjuvant Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 238000011002 quantification Methods 0.000 description 10
- 238000001819 mass spectrum Methods 0.000 description 9
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 6
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 6
- 229960004017 salmeterol Drugs 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 5
- 230000008021 deposition Effects 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- 229940092705 beclomethasone Drugs 0.000 description 4
- 229940124630 bronchodilator Drugs 0.000 description 4
- 239000000168 bronchodilator agent Substances 0.000 description 4
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 4
- 238000011049 filling Methods 0.000 description 4
- 229960002848 formoterol Drugs 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 208000023504 respiratory system disease Diseases 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000000043 antiallergic agent Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 230000005465 channeling Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 125000004773 chlorofluoromethyl group Chemical group [H]C(F)(Cl)* 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940109248 cromoglycate Drugs 0.000 description 3
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 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 3
- 239000012458 free base Substances 0.000 description 3
- 238000002664 inhalation therapy Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 239000012286 potassium permanganate Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
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- 159000000000 sodium salts Chemical class 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
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- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
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- YYAZJTUGSQOFHG-IAVNQIGZSA-N [(6s,8s,10s,11s,13s,14s,16r,17r)-6,9-difluoro-17-(fluoromethylsulfanylcarbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] propanoate;2-(hydroxymethyl)-4-[1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]eth Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)C1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O YYAZJTUGSQOFHG-IAVNQIGZSA-N 0.000 description 2
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- 229910052783 alkali metal Inorganic materials 0.000 description 2
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- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 150000007860 aryl ester derivatives Chemical class 0.000 description 2
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- 238000010945 base-catalyzed hydrolysis reactiony Methods 0.000 description 2
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- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
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- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
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- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 2
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
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- WVLAAKXASPCBGT-UHFFFAOYSA-N reproterol Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CCCNCC(O)C1=CC(O)=CC(O)=C1 WVLAAKXASPCBGT-UHFFFAOYSA-N 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
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- 150000003431 steroids Chemical class 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
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- 229960004708 noscapine Drugs 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229960002657 orciprenaline Drugs 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- NVOYVOBDTVTBDX-PMEUIYRNSA-N oxitropium Chemical compound CC[N+]1(C)[C@H]2C[C@@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)[C@H](CO)C1=CC=CC=C1 NVOYVOBDTVTBDX-PMEUIYRNSA-N 0.000 description 1
- 229960000797 oxitropium Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 description 1
- 229960004448 pentamidine Drugs 0.000 description 1
- KOZAWTKVXJYUKG-UHFFFAOYSA-N pentatriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO KOZAWTKVXJYUKG-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000006223 plastic coating Substances 0.000 description 1
- 229920001084 poly(chloroprene) Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012429 release testing Methods 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 229950004432 rofleponide Drugs 0.000 description 1
- IXTCZMJQGGONPY-XJAYAHQCSA-N rofleponide Chemical compound C1([C@@H](F)C2)=CC(=O)CC[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3O[C@@H](CCC)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O IXTCZMJQGGONPY-XJAYAHQCSA-N 0.000 description 1
- 229940021597 salmeterol and fluticasone Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 description 1
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-O tert-butylammonium Chemical compound CC(C)(C)[NH3+] YBRBMKDOPFTVDT-UHFFFAOYSA-O 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical compound O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
- 229940110309 tiotropium Drugs 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229960000859 tulobuterol Drugs 0.000 description 1
- 238000003466 welding Methods 0.000 description 1
- 239000008207 working material Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K23/00—Use of substances as emulsifying, wetting, dispersing, or foam-producing agents
- C09K23/007—Organic compounds containing halogen
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K23/00—Use of substances as emulsifying, wetting, dispersing, or foam-producing agents
- C09K23/42—Ethers, e.g. polyglycol ethers of alcohols or phenols
- C09K23/44—Ether carboxylic acids
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- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
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- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
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- General Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Materials Engineering (AREA)
- Otolaryngology (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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- Mechanical Coupling Of Light Guides (AREA)
- Emulsifying, Dispersing, Foam-Producing Or Wetting Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
WO92/00061は、フルオロカーボン噴射剤と共に使用する非フッ素化界面活性剤を開示している。
nおよびNは、独立して、2〜12の整数を表す;
m1およびm2は、独立して、1〜15の整数を表す;
R1およびR2は、独立して、-(CO)xC1-9アルキルまたは-(CO)xC1-9フルオロアルキルを表し、該フルオロアルキル部分は、少なくとも1つのフッ素原子および3個以下の連続的なペルフルオロカーボン原子を含有し、xは0または1を表す)の化合物またはその塩もしくは溶媒和物を提供する。
好ましくは、m1およびm2は、独立して、2〜10、特に3〜9の整数を表す。
好ましくは、R1およびR2は、独立して、-(CO)xC1-5アルキルまたは-(CO)xC1-5フルオロアルキルを表し、該フルオロアルキル部分は、少なくとも1つのフッ素原子および3個以下の連続的なペルフルオロカーボン原子、より好ましくは、所望により3個以下のフッ素原子により置換されていてもよい-C1-3アルキルを含有する。
好ましくは、式(I)の化合物は遊離酸として存在する。
したがって、本発明は、実質的に溶解した医薬と前記の式(I)の化合物とを含んでなる医薬製剤も提供する。好ましくは、該医薬製剤は、フルオロカーボンもしくは水素含有クロロフルオロカーボン噴射剤またはそれらの混合物を更に含むエアゾール剤である。
「加圧式定量噴霧式吸入器」またはMDIなる語は、容器(缶)、該容器を覆う密封用の蓋および該容器中に配置された製剤定量化用バルブを含む一式の装置を意味する。MDI系は適当なチェネリング装置を含む。適当なチャネリング装置は、例えば、バルブアクチュエータと、充填吸収容器から定量化バルブを介して患者の鼻または口に医薬が運搬される際の通路となりうる円柱状または円錐状通路、例えばマウスピースアクチュエータとを含む。
すなわち、
(a)式(II)
(b)カルボン酸基が保護されている式(I)の化合物の誘導体の脱保護を含んでなる、式(I)の化合物の製造方法を提供する。
該酸化は、一般には、極端でない温度、例えば0〜60℃、例えば室温で、水中で行う。
保護基は、酸もしくは塩基触媒加水分解、または還元、例えば水素化により除去することができる。該カルボン酸がベンジルエステルとして保護されている場合には、該保護基は例えば水素化により除去することができる。該カルボン酸がC1-3アルキルエステルとして保護されている場合には、該保護基は例えば塩基加水分解により除去することができる。
(i)式(III)
保護基(例えば、ヒドロキシル)の具体例およびそれらの除去手段は、Theodora GreenおよびPeter G.M Wutsによる“Protecting Groups In Organic Synthesis”(John Wiley and Sons Inc 1999)に記載されている。適当なヒドロキシル保護基には、カルボン酸エステル、例えば酢酸エステル、アリールエステル、例えば安息香酸エステル、エーテル、例えばベンジルエーテルおよびp-メトキシベンジルエーテル、テトラヒドロピラニルエーテルおよびシリルエーテル、例えばtert-ブチルジメチルシリルエーテルが含まれるが、これらに限定されるものではない。好ましくは、ヒドロキシル基はベンジルエーテルまたはテトラヒドロピラニル(THP)エーテルとして保護する。特に好ましいのはベンジルエーテルである。
通常、この方法においては少なくとも2モル当量の式(IV1)の化合物を使用する。好ましくは、有意に過剰な、例えば2〜10モル当量の式(IV1)の化合物を使用する。
(1)式(III)の化合物またはその保護誘導体を式(IV1)の化合物またはその保護誘導体と反応させること、あるいは
(2)式(IX)の化合物を式(XIII1)の化合物と反応させること、あるいは
(3)式(IX1)の化合物を式(XVI1)
(1a)エピブロモヒドリンを、塩基性条件下、式(XVII)
(2a)工程(1a)の生成物を水と反応させることを含む方法により製造することができる。
(1b)エピブロモヒドリンを式(XVI2)
(2b)工程(1b)の生成物を水と反応させることを含む方法により製造することができる。
本発明の製剤は、音波処理または高せん断ミキサーにより、適当な容器内の、選択された噴射剤中に、医薬および式(I)の化合物を分散させることにより製造することができる。該方法は、望ましくは、制御された湿度条件下で行う。
充填された容器の商業的生産のための大規模バッチの製造には、医薬エアゾール製造業の当業者によく知られた通常のバルク製造方法および装置を用いることが可能である。したがって、例えば、1つのバルク製造方法においては、定量化バルブをアルミニウム缶上に圧着して空容器を形成させる。微粒子状医薬を充填用容器に加え、液化噴射剤を、界面活性剤を含有する液化噴射剤と共に、該充填用容器を介して製造用容器中に加圧充填する。充填用装置に再循環させる前に該薬物懸濁液を混合し、ついで該薬物懸濁液のアリコートを該定量化バルブを介して該容器中に充填する。
他の医薬に関する適当な投与計画は公知であるか又は当業者に容易に利用可能である。
以下の非限定的な実施例は本発明を例示するものである。
20-(7,10,13,16-テトラオキサヘプタデカ-1-イルオキシ)-2,5,8,11,18-ペンタオキサヘンイコサン-21-酸
(a)2-({6-[2-(ベンジルオキシ)-1-({[6-(テトラヒドロ-2H-ピラン-2-イルオキシ)ヘキシル]オキシ}メチル)エトキシ]ヘキシル}オキシ)テトラヒドロ-2H-ピラン
ジメチルホルムアミド(165ml)中の1-ベンジルグリセロール(3.00g)の0℃の冷却溶液に、水素化ナトリウム(鉱油中の60%分散液, 3.95g)を加え、該反応液を45分間撹拌した。1-テトラヒドロピラン-2-イルオキシ-6-ブロモヘキサン(13.10g)を加え、該反応液を20℃で19時間撹拌した。メタノール(10ml)を0℃で30分かけて分割添加することにより、該反応液をクエンチした。該溶媒を真空中で除去し、残渣を水(125ml)とジクロロメタン(125ml)との間に分配させた。有機層をブライン(150ml)で洗浄し、乾燥させ、該溶媒を真空中で除去した。これを、シクロヘキサン中の8% 酢酸エチルで溶出するシリカゲル(Biotage)カラムクロマトグラフィーにより精製して、表題化合物を淡黄色の油(3.74g)として得た。
Rf 0.34(シクロヘキサン中の8% 酢酸エチル);質量スペクトル m/z 568 [MNH4 +]。
メタノール(80ml)中の工程(a)の生成物(3.74g)の撹拌溶液に、p-トルエンスルホン酸(260mg)を加え、該反応液を20℃で24時間撹拌した。該溶媒を真空中で除去し、残渣を水(125ml)に溶解し、ジクロロメタン(3×125ml)で抽出した。合わせた有機層をブライン(150ml)で洗浄し、乾燥させ、該溶媒を真空中で除去した。これを、シクロヘキサン中の40% 酢酸エチルで溶出するシリカゲル(Biotage)カラムクロマトグラフィーにより精製して、表題化合物を透明な油(1.27g)として得た。
Rf 0.21(シクロヘキサン中の40% 酢酸エチル);質量スペクトル m/z 382.5 [MH+]。
工程(b)の生成物(1.28g)をジメチルホルムアミド(20ml)に溶解し、0℃に冷却した。水素化ナトリウム(鉱油中の60% 分散液, 797mg)をゆっくり加え、該反応液を45分間撹拌した。2-[2-(2-メトキシエトキシ)エトキシ]エチル 4-メチルベンゼンスルホナート(3.17g)を加え、該反応液を20℃で17時間撹拌した。メタノール(10ml)を0℃で30分かけて分割添加することにより、該反応液をクエンチした。該溶媒を真空中で除去し、残渣を水(125ml)に溶解し、ジクロロメタン(3×125ml)で抽出した。合わせた有機層をブライン(150ml)で洗浄し、乾燥させ、該溶媒を真空中で除去した。ジクロロメタン中の1% メタノールで溶出するシリカゲル(Biotage)カラムクロマトグラフィーによる精製により、表題化合物を透明な油(1.26g)として得た。
Rf 0.36(シクロヘキサン中の1% メタノール);質量スペクトル m/z 692 [MNH4 +]。
エタノール(50ml)中の10% 酢酸中の工程(c)の生成物(1.26g)と10% 炭素上パラジウム(126mg)との撹拌溶液を5気圧の水素雰囲気下に72時間配置した。該反応混合物をセライトで濾過し、該溶媒を真空中で除去して、表題化合物を透明な油(1.03g)として得た。
Rf 0.26(DCM中の3% メタノール);質量スペクトル m/z 585 [MH+]。
水酸化ナトリウム水溶液(1.98ml)中の工程(d)の生成物(207mg)の撹拌溶液に、過マンガン酸カリウム水溶液(5.58ml)を加え、該反応液を室温で17時間撹拌した。該反応混合物を濾過し、塩酸(2M)の添加によりpH3に酸性化した。これを水(25ml)で希釈し、DCM(3×25ml)で抽出した。合わせた有機層を乾燥させ、該溶媒を真空中で除去して、表題化合物を透明な油として得た。
保持時間 2.92分;質量スペクトル m/z 597 [MH-]。
38-(7,10,13,16,19,22,25,28,31,34-デカオキサペンタトリアコンタ-1-イルオキシ)-2,5,8,11,14,17,20,23,26,29,36-ウンデカオキサノナトリアコンタン-39-酸
保持時間 2.88分;質量スペクトル m/z 581 [M/2-NH4 +]。
17-(4,7,10,13-テトラオキサテトラデカ-1-イルオキシ)-2,5,8,11,15-ペンタオキサオクタデカン-18-酸
保持時間 2.31分;質量スペクトル m/z 513 [MH-]。
35-(4,7,10,13,16,19,22,25,28,31-デカオキサドトリアコンタ-1-イルオキシ)-2,5,8,11,14,17,20,23,26,29,33-ウンデカオキサヘキサトリアコンタン-36-酸
保持時間 2.42分;質量スペクトル m/z 1040 [MH-]。
内容物の均一性
作動当たりの強度25mcgの、HFA 134a中のサルメテロール キシナホアート(salmeterol xinafoate)製剤、および10% w/w(対薬物比)の式(I)の関連界面活性剤化合物(すなわち、実施例3または実施例4)を、サルメテロール キシナホアート(8.7mg)、HFA 134a(18g)および関連化合物(0.87mg)を使用して、定量化バルブを含有する圧着蓋を備えたアルミニウム缶内で調製した。対照は、界面活性剤を加えないで調製した。該製剤の内容物の均一性を、使用試験中の用量により評価した。試験は、「使用開始時」(BoU)および「使用終了時」(EoU)に、該製剤のそれぞれについて10缶/吸入器の組に対して行った。各吸入器を予備作動(4回噴射して廃棄する)させた後、作動物1および2(BoU)を集めた。ついで、その後116回の各吸入器の作動を自動化法により行い、噴射物を廃棄し、作動物119および120(EoU)を集めた。
60回の作動のそれぞれについての用量当たりの強度25mcgの、HFA 134a中のサルメテロール キシナホアート(salmeterol xinafoate)製剤、および10% w/w(対薬物比)の式(I)の関連界面活性剤化合物(すなわち、実施例3または実施例4)を、サルメテロール キシナホアート(1.50mg)、HFA 134a(3g)および関連化合物(0.15mg)を使用して、定量化バルブを含有する圧着蓋を備えたアルミニウム缶内で調製した。対照は、界面活性剤を加えないで調製した。
Claims (13)
- nおよびNが、独立して、3〜6の整数を表す、請求項1記載の式(I)の化合物またはその塩もしくは溶媒和物。
- m1およびm2が、独立して、3〜9の整数を表す、請求項1または2記載の式(I)の化合物またはその塩もしくは溶媒和物。
- R1が-C1-3アルキルまたはC1-3フルオロアルキルC0-6アルキレン-を表す、請求項1〜3のいずれか1項記載の式(I)の化合物またはその塩もしくは溶媒和物。
- R1が-CH3、-CH2CH3、-(CH2)2CH3、-CH2(CH3)2、-CHF2、-CF3、-CH2CF3、-CH2CF2CF3または-CF2CF3を表す、請求項4記載の式(I)の化合物またはその塩もしくは溶媒和物。
- R1が-CF3または-CH2CF3を表す、請求項5記載の式(I)の化合物またはその塩もしくは溶媒和物。
- R2が-C1-3アルキルまたはC1-3フルオロアルキルC0-6アルキレン-を表す、請求項1〜6のいずれか1項記載の式(I)の化合物またはその塩もしくは溶媒和物。
- R2が-CH3、-CH2CH3、-(CH2)2CH3、-CH2(CH3)2、-CHF2、-CF3、-CH2CF3、-CH2CF2CF3または-CF2CF3を表す、請求項7記載の式(I)の化合物またはその塩もしくは溶媒和物。
- R2が-CF3またはCH2CF3を表す、請求項8記載の式(I)の化合物またはその塩もしくは溶媒和物。
- 20-(7,10,13,16-テトラオキサヘプタデカ-1-イルオキシ)-2,5,8,11,18-ペンタオキサヘンイコサン-21-酸、
38-(7,10,13,16,19,22,25,28,31,34-デカオキサペンタトリアコンタ-1-イルオキシ)-2,5,8,11,14,17,20,23,26,29,36-ウンデカオキサノナトリアコンタン-39-酸、
17-(4,7,10,13-テトラオキサテトラデカ-1-イルオキシ)-2,5,8,11,15-ペンタオキサオクタデカン-18-酸および
35-(4,7,10,13,16,19,22,25,28,31-デカオキサドトリアコンタ-1-イルオキシ)-2,5,8,11,14,17,20,23,26,29,33-ウンデカオキサヘキサトリアコンタン-36-酸から選ばれる式(I)の化合物またはその塩もしくは溶媒和物。 - 微粒子状医薬、フルオロカーボンもしくは水素含有クロロフルオロカーボン噴射剤またはそれらの混合物、および請求項1〜10のいずれか1項記載の式(I)の化合物を含んでなる医薬エアゾール剤。
- 前記噴射剤が、1,1,1,2-テトラフルオロエタン、1,1,1,2,3,3,3-ヘプタフルオロ-n-プロパンまたはそれらの混合物から選ばれる、請求項11記載の医薬エアゾール剤。
- エフェドリンおよびテオフィリン;フェノテロールおよびイプラトロピウム;イソエタリンおよびフェニレフリン;アルブテロールおよびジプロピオン酸ベクロメタゾン;ブデソニドおよびフマル酸ホルモテロール;ならびにサルメテロール キシナホアート(salmeterol xinafoate)およびプロピオン酸フルチカゾンから選ばれる2以上の微粒子状医薬の組合せを含有する、請求項11または12記載の医薬エアゾール剤。
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GBGB0125127.1A GB0125127D0 (en) | 2001-10-19 | 2001-10-19 | Compounds |
PCT/EP2002/011635 WO2003035237A2 (en) | 2001-10-19 | 2002-10-17 | Compounds for use as surfactants |
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JP2005525300A JP2005525300A (ja) | 2005-08-25 |
JP2005525300A5 JP2005525300A5 (ja) | 2006-01-05 |
JP4223954B2 true JP4223954B2 (ja) | 2009-02-12 |
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US (1) | US7321059B2 (ja) |
EP (1) | EP1436007B1 (ja) |
JP (1) | JP4223954B2 (ja) |
AT (1) | ATE291928T1 (ja) |
AU (1) | AU2002340578A1 (ja) |
DE (1) | DE60203528T2 (ja) |
ES (1) | ES2238606T3 (ja) |
GB (1) | GB0125127D0 (ja) |
WO (1) | WO2003035237A2 (ja) |
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JP4959919B2 (ja) | 2001-12-21 | 2012-06-27 | スリーエム イノベイティブ プロパティズ カンパニー | 官能基を有するポリエチレングリコール賦形剤を用いた医薬用エアロゾル組成物 |
CN1633407A (zh) | 2002-02-13 | 2005-06-29 | 葛兰素集团有限公司 | 用作表面活性剂的羧酸化合物 |
CN102416179B (zh) | 2010-09-28 | 2014-05-07 | 益得生物科技股份有限公司 | 用于哮喘的吸入性复方组合物 |
US10876039B2 (en) | 2017-08-15 | 2020-12-29 | Saudi Arabian Oil Company | Thermally stable surfactants for oil based drilling fluids |
US10676658B2 (en) | 2017-08-15 | 2020-06-09 | Saudi Arabian Oil Company | Oil-based drilling fluids for high pressure and high temperature drilling operations |
US10647903B2 (en) | 2017-08-15 | 2020-05-12 | Saudi Arabian Oil Company | Oil-based drilling fluid compositions which include layered double hydroxides as rheology modifiers and amino amides as emulsifiers |
JP2020531609A (ja) | 2017-08-15 | 2020-11-05 | サウジ アラビアン オイル カンパニーSaudi Arabian Oil Company | 油系掘削流体用の熱安定性界面活性剤 |
US10745606B2 (en) | 2017-08-15 | 2020-08-18 | Saudi Arabian Oil Company | Oil-based drilling fluid compositions which include layered double hydroxides as rheology modifiers |
US10640696B2 (en) | 2017-08-15 | 2020-05-05 | Saudi Arabian Oil Company | Oil-based drilling fluids for high pressure and high temperature drilling operations |
US10793762B2 (en) | 2017-08-15 | 2020-10-06 | Saudi Arabian Oil Company | Layered double hydroxides for oil-based drilling fluids |
US10988659B2 (en) | 2017-08-15 | 2021-04-27 | Saudi Arabian Oil Company | Layered double hydroxides for oil-based drilling fluids |
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US4352789A (en) * | 1980-03-17 | 1982-10-05 | Minnesota Mining And Manufacturing Company | Aerosol compositions containing finely divided solid materials |
DE3903663C1 (ja) * | 1989-02-08 | 1990-09-27 | Huels Ag, 4370 Marl, De | |
IL97065A (en) | 1990-02-02 | 1994-01-25 | Fisons Plc | Repellent preparations for aerosol |
DE69109284T2 (de) * | 1990-03-23 | 1995-08-24 | Minnesota Mining & Mfg | Verwendung von fluorierten löslichen tensiden zur herstellung von aerosolarzneimitteln mit dosierter abgabe. |
DE69101639T2 (de) | 1990-06-27 | 1994-10-06 | Minnesota Mining & Mfg | Anwendung von löslichen fluorhaltigen tensiden zur herstellung von aerosol-präparaten mit dosierter abgabe. |
US5126123A (en) * | 1990-06-28 | 1992-06-30 | Glaxo, Inc. | Aerosol drug formulations |
HUT63554A (en) | 1990-06-29 | 1993-09-28 | Fisons Plc | Aerosol preparations under pressure |
US5376359A (en) * | 1992-07-07 | 1994-12-27 | Glaxo, Inc. | Method of stabilizing aerosol formulations |
GB9419536D0 (en) | 1994-09-28 | 1994-11-16 | Glaxo Inc | Medicaments |
US6451287B1 (en) * | 2000-05-26 | 2002-09-17 | Smithkline Beecham Corporation | Fluorinated copolymer surfactants and use thereof in aerosol compositions |
AU2001290075A1 (en) * | 2000-09-22 | 2002-04-02 | Glaxo Group Limited | Novel alkanoic acid derivatives |
CA2456052A1 (en) | 2001-08-03 | 2003-02-20 | Glaxo Group Limited | Surfactant compounds and uses thereof |
-
2001
- 2001-10-19 GB GBGB0125127.1A patent/GB0125127D0/en not_active Ceased
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2002
- 2002-10-17 DE DE60203528T patent/DE60203528T2/de not_active Expired - Fee Related
- 2002-10-17 AU AU2002340578A patent/AU2002340578A1/en not_active Abandoned
- 2002-10-17 ES ES02774728T patent/ES2238606T3/es not_active Expired - Lifetime
- 2002-10-17 WO PCT/EP2002/011635 patent/WO2003035237A2/en active IP Right Grant
- 2002-10-17 US US10/492,606 patent/US7321059B2/en not_active Expired - Fee Related
- 2002-10-17 JP JP2003537793A patent/JP4223954B2/ja not_active Expired - Fee Related
- 2002-10-17 AT AT02774728T patent/ATE291928T1/de not_active IP Right Cessation
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DE60203528D1 (de) | 2005-05-04 |
DE60203528T2 (de) | 2006-05-11 |
JP2005525300A (ja) | 2005-08-25 |
WO2003035237A2 (en) | 2003-05-01 |
WO2003035237A3 (en) | 2003-08-14 |
ES2238606T3 (es) | 2005-09-01 |
EP1436007B1 (en) | 2005-03-30 |
US20050048024A1 (en) | 2005-03-03 |
EP1436007A2 (en) | 2004-07-14 |
GB0125127D0 (en) | 2001-12-12 |
ATE291928T1 (de) | 2005-04-15 |
US7321059B2 (en) | 2008-01-22 |
AU2002340578A1 (en) | 2003-05-06 |
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