CA2653422A1 - Atomizer - Google Patents
Atomizer Download PDFInfo
- Publication number
- CA2653422A1 CA2653422A1 CA002653422A CA2653422A CA2653422A1 CA 2653422 A1 CA2653422 A1 CA 2653422A1 CA 002653422 A CA002653422 A CA 002653422A CA 2653422 A CA2653422 A CA 2653422A CA 2653422 A1 CA2653422 A1 CA 2653422A1
- Authority
- CA
- Canada
- Prior art keywords
- amino
- phenyl
- quinazoline
- methoxy
- chloro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000012530 fluid Substances 0.000 claims abstract description 26
- 239000000443 aerosol Substances 0.000 claims abstract description 7
- 238000000889 atomisation Methods 0.000 claims abstract description 7
- 230000037431 insertion Effects 0.000 claims description 10
- 238000003780 insertion Methods 0.000 claims description 10
- 239000007921 spray Substances 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 4
- 239000003595 mist Substances 0.000 claims description 4
- 208000034423 Delivery Diseases 0.000 claims 1
- 238000012384 transportation and delivery Methods 0.000 claims 1
- -1 EGFR-inhibitors Substances 0.000 description 39
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 26
- 150000003839 salts Chemical class 0.000 description 24
- 210000001331 nose Anatomy 0.000 description 19
- 150000001875 compounds Chemical class 0.000 description 16
- 239000002253 acid Substances 0.000 description 13
- FIMXSEMBHGTNKT-UHFFFAOYSA-N Scopine Natural products CN1C2CC(O)CC1C1C2O1 FIMXSEMBHGTNKT-UHFFFAOYSA-N 0.000 description 11
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 10
- 150000004677 hydrates Chemical class 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000005557 antagonist Substances 0.000 description 9
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 229940121647 egfr inhibitor Drugs 0.000 description 7
- 239000012453 solvate Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 5
- 150000001450 anions Chemical class 0.000 description 5
- 230000003454 betamimetic effect Effects 0.000 description 5
- 150000003842 bromide salts Chemical class 0.000 description 5
- 239000003246 corticosteroid Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 description 4
- 239000000812 cholinergic antagonist Substances 0.000 description 4
- 125000005635 hydromethanesulphonate group Chemical group 0.000 description 4
- 210000004877 mucosa Anatomy 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- ODELFXJUOVNEFZ-UHFFFAOYSA-N 2,2-diphenylpropanoic acid Chemical compound C=1C=CC=CC=1C(C(O)=O)(C)C1=CC=CC=C1 ODELFXJUOVNEFZ-UHFFFAOYSA-N 0.000 description 3
- GXAMYUGOODKVRM-UHFFFAOYSA-M 9-hydroxyfluorene-9-carboxylate Chemical compound C1=CC=C2C(O)(C([O-])=O)C3=CC=CC=C3C2=C1 GXAMYUGOODKVRM-UHFFFAOYSA-M 0.000 description 3
- DTZDZCNXNYMMOW-UHFFFAOYSA-N 9-hydroxyxanthene-9-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)(O)C3=CC=CC=C3OC2=C1 DTZDZCNXNYMMOW-UHFFFAOYSA-N 0.000 description 3
- PUPWRKQSVGUBQS-UHFFFAOYSA-N 9-methylfluorene-9-carboxylic acid Chemical compound C1=CC=C2C(C)(C(O)=O)C3=CC=CC=C3C2=C1 PUPWRKQSVGUBQS-UHFFFAOYSA-N 0.000 description 3
- CBNOKZSYCBHRAD-UHFFFAOYSA-N 9-methylxanthene-9-carboxylic acid Chemical compound C1=CC=C2C(C)(C(O)=O)C3=CC=CC=C3OC2=C1 CBNOKZSYCBHRAD-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 239000000808 adrenergic beta-agonist Substances 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 3
- 210000003928 nasal cavity Anatomy 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 229910021653 sulphate ion Inorganic materials 0.000 description 3
- ZMXHONJJTQSZKY-UHFFFAOYSA-N 2,2-bis(3,4-difluorophenyl)-2-hydroxyacetic acid Chemical compound C=1C=C(F)C(F)=CC=1C(O)(C(=O)O)C1=CC=C(F)C(F)=C1 ZMXHONJJTQSZKY-UHFFFAOYSA-N 0.000 description 2
- RCORMCWYMRPHPO-UHFFFAOYSA-N 2,2-bis(3-fluorophenyl)-2-hydroxyacetic acid Chemical compound C=1C=CC(F)=CC=1C(O)(C(=O)O)C1=CC=CC(F)=C1 RCORMCWYMRPHPO-UHFFFAOYSA-N 0.000 description 2
- YKZXWNCXGVYCKF-UHFFFAOYSA-N 2,2-bis(4-fluorophenyl)-2-hydroxyacetic acid Chemical compound C=1C=C(F)C=CC=1C(O)(C(=O)O)C1=CC=C(F)C=C1 YKZXWNCXGVYCKF-UHFFFAOYSA-N 0.000 description 2
- MAGCRYYXZYUDSY-UHFFFAOYSA-N 2-fluoro-2,2-diphenylacetic acid Chemical compound C=1C=CC=CC=1C(F)(C(=O)O)C1=CC=CC=C1 MAGCRYYXZYUDSY-UHFFFAOYSA-N 0.000 description 2
- ZMPRRFPMMJQXPP-UHFFFAOYSA-N 2-sulfobenzoic acid Chemical class OC(=O)C1=CC=CC=C1S(O)(=O)=O ZMPRRFPMMJQXPP-UHFFFAOYSA-N 0.000 description 2
- ULMFXAMQUGLVGA-LJQANCHMSA-N 3-[[2-methoxy-4-[(2-methylphenyl)sulfonylcarbamoyl]phenyl]methyl]-1-methyl-n-[(2r)-4,4,4-trifluoro-2-methylbutyl]indole-5-carboxamide Chemical compound C=1C=C(CC=2C3=CC(=CC=C3N(C)C=2)C(=O)NC[C@H](C)CC(F)(F)F)C(OC)=CC=1C(=O)NS(=O)(=O)C1=CC=CC=C1C ULMFXAMQUGLVGA-LJQANCHMSA-N 0.000 description 2
- CVDXFPBVOIERBH-JWQCQUIFSA-N 4-[(4ar,10bs)-9-ethoxy-8-methoxy-2-methyl-3,4,4a,10b-tetrahydro-1h-benzo[c][1,6]naphthyridin-6-yl]-n,n-di(propan-2-yl)benzamide Chemical compound N([C@@H]1CCN(C)C[C@@H]1C=1C=C(C(=CC=11)OC)OCC)=C1C1=CC=C(C(=O)N(C(C)C)C(C)C)C=C1 CVDXFPBVOIERBH-JWQCQUIFSA-N 0.000 description 2
- PYUGFOWNYMLROI-KPKJPENVSA-N 8-[(e)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl]-2-(2h-tetrazol-5-yl)chromen-4-one Chemical compound C1=CC(F)=CC=C1CCCCOC(C=C1)=CC=C1\C=C\C1=CC=CC2=C1OC(C=1NN=NN=1)=CC2=O PYUGFOWNYMLROI-KPKJPENVSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 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
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 241000112708 Vates Species 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 230000001078 anti-cholinergic effect Effects 0.000 description 2
- 229940125715 antihistaminic agent Drugs 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- CFBUZOUXXHZCFB-OYOVHJISSA-N chembl511115 Chemical compound COC1=CC=C([C@@]2(CC[C@H](CC2)C(O)=O)C#N)C=C1OC1CCCC1 CFBUZOUXXHZCFB-OYOVHJISSA-N 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- 229940052760 dopamine agonists Drugs 0.000 description 2
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 2
- 229960003133 ergot alkaloid Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- LMOINURANNBYCM-UHFFFAOYSA-N metaproterenol Chemical compound CC(C)NCC(O)C1=CC(O)=CC(O)=C1 LMOINURANNBYCM-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- FSDOTMQXIKBFKJ-UHFFFAOYSA-N n-(2,5-dichloropyridin-3-yl)-8-methoxyquinoline-5-carboxamide Chemical compound C12=CC=CN=C2C(OC)=CC=C1C(=O)NC1=CC(Cl)=CN=C1Cl FSDOTMQXIKBFKJ-UHFFFAOYSA-N 0.000 description 2
- DPHDSIQHVGSITN-UHFFFAOYSA-N n-(3,5-dichloropyridin-4-yl)-2-[1-[(4-fluorophenyl)methyl]-5-hydroxyindol-3-yl]-2-oxoacetamide Chemical compound C1=C(C(=O)C(=O)NC=2C(=CN=CC=2Cl)Cl)C2=CC(O)=CC=C2N1CC1=CC=C(F)C=C1 DPHDSIQHVGSITN-UHFFFAOYSA-N 0.000 description 2
- 229960002657 orciprenaline Drugs 0.000 description 2
- 150000002942 palmitic acid derivatives Chemical class 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 125000005547 pivalate group Chemical group 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
- MCKJPJYRCPANCC-XLXYOEISSA-N (8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthrene-17-carboxylic acid Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(O)=O)[C@@H]4[C@@H]3CCC2=C1 MCKJPJYRCPANCC-XLXYOEISSA-N 0.000 description 1
- NDAUXUAQIAJITI-LBPRGKRZSA-N (R)-salbutamol Chemical compound CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-LBPRGKRZSA-N 0.000 description 1
- LITNEAPWQHVPOK-FFSVYQOJSA-N 2(1h)-pyrimidinone, 5-[3-[(1s,2s,4r)-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl]tetrahydro- Chemical compound C1=C(O[C@@H]2[C@H]3CC[C@H](C3)C2)C(OC)=CC=C1C1CNC(=O)NC1 LITNEAPWQHVPOK-FFSVYQOJSA-N 0.000 description 1
- SPCKHVPPRJWQRZ-UHFFFAOYSA-N 2-benzhydryloxy-n,n-dimethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 SPCKHVPPRJWQRZ-UHFFFAOYSA-N 0.000 description 1
- KVVDRQDTODKIJD-UHFFFAOYSA-N 2-cyclopropylacetic acid Chemical compound OC(=O)CC1CC1 KVVDRQDTODKIJD-UHFFFAOYSA-N 0.000 description 1
- DDYUBCCTNHWSQM-UHFFFAOYSA-N 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(1,3-dioxoisoindol-2-yl)propanamide Chemical compound COC1=CC=C(C(CC(N)=O)N2C(C3=CC=CC=C3C2=O)=O)C=C1OC1CCCC1 DDYUBCCTNHWSQM-UHFFFAOYSA-N 0.000 description 1
- LIXBJWRFCNRAPA-NSHDSACASA-N 4-[(1r)-2-(tert-butylamino)-1-hydroxyethyl]-3-chlorophenol Chemical compound CC(C)(C)NC[C@H](O)C1=CC=C(O)C=C1Cl LIXBJWRFCNRAPA-NSHDSACASA-N 0.000 description 1
- UTUUPXBCDMQYRR-HSZRJFAPSA-N 4-[(2r)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine Chemical compound COC1=CC=C([C@H](CC=2C=CN=CC=2)C=2C=CC=CC=2)C=C1OC1CCCC1 UTUUPXBCDMQYRR-HSZRJFAPSA-N 0.000 description 1
- LIXBJWRFCNRAPA-UHFFFAOYSA-N 4-[2-(tert-butylamino)-1-hydroxyethyl]-3-chlorophenol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C=C1Cl LIXBJWRFCNRAPA-UHFFFAOYSA-N 0.000 description 1
- DAFYYTQWSAWIGS-UHFFFAOYSA-N 4-[2-[6-[2-[(2,6-dichlorophenyl)methoxy]ethoxy]hexylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCOCC=2C(=CC=CC=2Cl)Cl)=C1 DAFYYTQWSAWIGS-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- DHSSDEDRBUKTQY-UHFFFAOYSA-N 6-prop-2-enyl-4,5,7,8-tetrahydrothiazolo[4,5-d]azepin-2-amine Chemical compound C1CN(CC=C)CCC2=C1N=C(N)S2 DHSSDEDRBUKTQY-UHFFFAOYSA-N 0.000 description 1
- XMOAAORIXBPOCZ-UHFFFAOYSA-N 9-(difluoromethyl)xanthene-9-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)(C(F)F)C3=CC=CC=C3OC2=C1 XMOAAORIXBPOCZ-UHFFFAOYSA-N 0.000 description 1
- ZRDOWGBNGIHJTG-UHFFFAOYSA-N 9-(hydroxymethyl)xanthene-9-carboxylic acid Chemical compound C1=CC=C2C(CO)(C(O)=O)C3=CC=CC=C3OC2=C1 ZRDOWGBNGIHJTG-UHFFFAOYSA-N 0.000 description 1
- QPVQJRWUNUHSJL-UHFFFAOYSA-N 9-ethylxanthene-9-carboxylic acid Chemical compound C1=CC=C2C(CC)(C(O)=O)C3=CC=CC=C3OC2=C1 QPVQJRWUNUHSJL-UHFFFAOYSA-N 0.000 description 1
- BHEFSGMUMYBJRZ-UHFFFAOYSA-N 9-fluorofluorene-9-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)(F)C3=CC=CC=C3C2=C1 BHEFSGMUMYBJRZ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 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 description 1
- SMDWTNSXNDYDPS-KOMQPUFPSA-N C1C[C@@H](NS(=O)(=O)CC)CC[C@@H]1OC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=C(F)C(Cl)=C1 Chemical compound C1C[C@@H](NS(=O)(=O)CC)CC[C@@H]1OC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=C(F)C(Cl)=C1 SMDWTNSXNDYDPS-KOMQPUFPSA-N 0.000 description 1
- SAJCPZOYOQZTDU-KOMQPUFPSA-N CN[C@H]1CC[C@@H](CC1)Oc1cc2cnc(Nc3ccc(F)c(Cl)c3)nc2cc1OC Chemical compound CN[C@H]1CC[C@@H](CC1)Oc1cc2cnc(Nc3ccc(F)c(Cl)c3)nc2cc1OC SAJCPZOYOQZTDU-KOMQPUFPSA-N 0.000 description 1
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 description 1
- KORNTPPJEAJQIU-KJXAQDMKSA-N Cabaser Chemical compound C1=CC([C@H]2C[C@H](CN(CC=C)[C@@H]2C2)C(=O)N(CCCN(C)C)C(=O)NCC)=C3C2=CNC3=C1 KORNTPPJEAJQIU-KJXAQDMKSA-N 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-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
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- 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
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 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
- 229960003910 promethazine Drugs 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
- 229960002720 reproterol Drugs 0.000 description 1
- 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 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229960001457 rimiterol Drugs 0.000 description 1
- IYMMESGOJVNCKV-SKDRFNHKSA-N rimiterol Chemical compound C([C@@H]1[C@@H](O)C=2C=C(O)C(O)=CC=2)CCCN1 IYMMESGOJVNCKV-SKDRFNHKSA-N 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
- 229950004432 rofleponide Drugs 0.000 description 1
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 1
- 229960002586 roflumilast Drugs 0.000 description 1
- 229960001879 ropinirole Drugs 0.000 description 1
- UHSKFQJFRQCDBE-UHFFFAOYSA-N ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 description 1
- HGEYJZMMUGWEOT-UHFFFAOYSA-N roxindole Chemical compound C12=CC(O)=CC=C2NC=C1CCCCN(CC=1)CCC=1C1=CC=CC=C1 HGEYJZMMUGWEOT-UHFFFAOYSA-N 0.000 description 1
- 229950001879 salmefamol Drugs 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229950010289 soterenol Drugs 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- 229960004558 terguride Drugs 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 229950010302 tiaramide Drugs 0.000 description 1
- HTJXMOGUGMSZOG-UHFFFAOYSA-N tiaramide Chemical compound C1CN(CCO)CCN1C(=O)CN1C(=O)SC2=CC=C(Cl)C=C21 HTJXMOGUGMSZOG-UHFFFAOYSA-N 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical class 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
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 229950003899 tofimilast Drugs 0.000 description 1
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 1
- 229960004045 tolterodine Drugs 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- LENLQGBLVGGAMF-UHFFFAOYSA-N tributyl([1,2,4]triazolo[1,5-a]pyridin-6-yl)stannane Chemical compound C1=C([Sn](CCCC)(CCCC)CCCC)C=CC2=NC=NN21 LENLQGBLVGGAMF-UHFFFAOYSA-N 0.000 description 1
- OYYDSUSKLWTMMQ-JKHIJQBDSA-N trospium Chemical class [N+]12([C@@H]3CC[C@H]2C[C@H](C3)OC(=O)C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCC1 OYYDSUSKLWTMMQ-JKHIJQBDSA-N 0.000 description 1
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229960004764 zafirlukast Drugs 0.000 description 1
- XJBCFFLVLOPYBV-UHFFFAOYSA-N zinterol Chemical compound C=1C=C(O)C(NS(C)(=O)=O)=CC=1C(O)CNC(C)(C)CC1=CC=CC=C1 XJBCFFLVLOPYBV-UHFFFAOYSA-N 0.000 description 1
- 229950004209 zinterol Drugs 0.000 description 1
- XJSMBWUHHJFJFV-VTIMJTGVSA-N α-dihydroergocryptine Chemical compound C([C@H]1N(C)C2)C([C]34)=CN=C4C=CC=C3[C@H]1C[C@H]2C(=O)N[C@@]1(C(C)C)C(=O)N2[C@@H](CC(C)C)C(=O)N3CCC[C@H]3[C@]2(O)O1 XJSMBWUHHJFJFV-VTIMJTGVSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0065—Inhalators with dosage or measuring devices
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
- A61M11/006—Sprayers or atomisers specially adapted for therapeutic purposes operated by applying mechanical pressure to the liquid to be sprayed or atomised
- A61M11/007—Syringe-type or piston-type sprayers or atomisers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0001—Details of inhalators; Constructional features thereof
- A61M15/0021—Mouthpieces therefor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0065—Inhalators with dosage or measuring devices
- A61M15/0066—Inhalators with dosage or measuring devices with means for varying the dose size
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/08—Inhaling devices inserted into the nose
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B11/00—Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use
- B05B11/01—Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use characterised by the means producing the flow
- B05B11/10—Pump arrangements for transferring the contents from the container to a pump chamber by a sucking effect and forcing the contents out through the dispensing nozzle
- B05B11/109—Pump arrangements for transferring the contents from the container to a pump chamber by a sucking effect and forcing the contents out through the dispensing nozzle the dispensing stroke being affected by the stored energy of a spring
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Biophysics (AREA)
- Otolaryngology (AREA)
- Mechanical Engineering (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
In an atomizer (1) for dispensing a defined amount of a fluid (2), in particular one containing a pharmaceutical, as aerosol through a nozzle (12) from a pressure chamber (11), wherein a mechanical pressure generator (5) acts on the measured fluid (2) in the pressure chamber and is abruptly released for the atomization, a nosepiece (19) is assigned to the nozzle (12).
Description
Atomizer Description The invention relates to an atomizer for delivering a specific amount of a fluid, particularly one that contains a medicament, as an aerosol through a nozzle from a pressurised store, wherein a mechanical pressure generator acts upon the measured amount of fluid in the pressurised store which is to be released abruptly for atomization.
Zo It is known to administer a medicament in the form of a spray through the nose or mouth in order to absorb it through the mucosa in the nasal cavity or through the lungs.
In addition, EP 0 521 061 B1 discloses a metering device for delivering a measured amount of a liquid as a spray with droplets of a size suitable for inhalation into the lungs by releasing the measured amount of liquid through an atomizing means comprising a cham-ber for holding the measured amount of liquid, an energy store and means for delivering a predetermined amount of energy to the energy store. Moreover, means are provided for releasing the predetermined amount of energy from the energy store to the chamber in or-der to expose the liquid contained therein to a predetermined rise in pressure from a low pressure to a higher pressure and initiate the release of liquid from the chamber. Atomis-ing means serve to atomize the measured amount of the liquid placed under pressure.
The compounds listed below may be used in the device according to the invention on their own or in combination. In the compounds mentioned below, W is a pharmacologically active substance and is selected (for exainple) from among the betamimetics, anticholiner-gics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine ago-nists, H1-antihistamines, PAF-antagonists and P13-kinase inhibitors. Moreover, double or triple combinations of W may be combined and used in the device according to the inven-tion. Combinations of W might be, for example:
- W denotes a betamimetic, combined with an anticholinergic, corticosteroid, inhibitor, EGFR-inhibitor or LTD4-antagonist, - W denotes an anticholinergic, combined with a betamimetic, corticosteroid, iiihibitor, EGFR-inhibitor or LTD4-antagonist, PCT P0 ] -2031 2 - W denotes a corticosteroid, combined with a PDE4-inhibitor, EGFR-inhibitor or LTD4-antagonist - W denotes a PDE4-inhibitor, combined with an EGFR-inhibitor or LTD4-antagonist - W denotes an EGFR-inhibitor, combined with an LTD4-antagonist.
The compounds used as betamimetics are preferably compounds selected from among al-buterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ri-todrine, salmefamol, salmeterol, soterenol, sulphonterol, terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035, HOKU-81, KUL-1248 and - 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide - 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-lH-quinolin-2-one - 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone - 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol - 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino] ethanol - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl -2 -propylamino] ethanol - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino] ethanol - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino } ethanol - 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one - 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol - 6-hydroxy-8- { 1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl } -4H-benzo[ 1,4]oxazin-3-one - 6-hydroxy-8-{ 1-hydroxy-2-[2-( ethyl 4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl} -4H-benzo [ 1,4] oxazin-3 -one - 6-hydroxy-8-{ 1-hydroxy-2-[2-(4-phenoxy-acetic acid)-1,1-dimethyl-ethylamino]-ethyi}-4H-benzo[1,4]oxazin-3-one - 8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo [ 1,4] oxazin-3 -one ~
~
- 6-hydroxy-8-{ 1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo [ 1,4] oxazin- 3 -one - 6-hydroxy-8- { 1-hydroxy-2-[2-(4-isopropyl-phenyl)-1. i dimethyl-ethylamino]
-ethyl } -4H-benzo[ 1,4] oxazin-3-one - 8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-benzo[1,4]oxazin-3-one - 8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one - 4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-lo ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid - 8-{2-[2-(3.4-difluoro-phenyl)-l,l-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one - 1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol - 2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino } -ethyl)-benzaldehyde - N-[2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino }-ethyl)-phenyl]-formamide - 8-hydroxy-5-(1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino } -ethyl)-1 H-quinolin-2-one - 8 -hydroxy-5- [1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1 H-quinolin-2-one - 5-[2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1 H-quinolin-2-one - [3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5 -m ethyl-phenyl] -urea - 4-(2- { 6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino } -1-hydroxy-ethyl)-hydroxymethyl-phenol - 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzylsulphonamide - 3 -(3-{ 7-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-3o propyl)-benzylsulphonamide - 4-(2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol - N-Adamantan-2-yl-2-(3 - { 2-[2-hydroxy-2-(4-hydroxy-3 -hydroxymethyl-phenyl)-ethylamino]-propyi } -phenyl)-acetamide optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention the acid addition salts of the betamimetics are prefera-CA 02653422 2008-11-25 pC,h p01-20' ) 1 bly selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hy-drophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hy-drocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
The anticholinergics used are preferably compounds selected from among the tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyr-ronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine. In the above-mentioned salts the cations are the pharmacologically active con-stituents. As anions the above-mentioned salts may preferably contain the chloride, bro-mide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions. Of all the salts the chlorides, bromides, iodides and methanesulphonates are particularly preferred.
Other preferred anticholinergics are selected from among the salts of formula 0N o p X- HO s s AC-i wherein X - denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, iodide, sulphate, phosphate, methanesuipho-nate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, preferably an anion with a single negative charge, particularly pref-erably an anion selected from among the fluoride, chloride, bromide, methanesulphonate and p-toluenesulphonate, particularly preferably bromide, optionally in the form of the ra-cemates, enantiomers or hydrates thereof. Of particular importance are those pharmaceuti-cal combinations which contain the enantiomers of formula AC-1-en PCT PO l -203 l O O
X- HO
s s AC-1-en wherein X may have the above-mentioned meanings. Other preferred anticholinergics are selected from the salts of formula AC-2 OH
N\
R X
wherein R denotes either methyl or ethyl and wherein X may have the above-mentioned meanings. In an alternative embodiment the compound of formula AC-2 may also be pre-1 o sent in the form of the free base AC-2-base.
OH
NJ-"
y AC-2-base Other specified compounds are:
i5 - tropenol 2,2-diphenylpropionate methobromide, - scopine 2,2-diphenylpropionate methobromide, - scopine 2-fluoro-2,2-diphenylacetate methobromide, - tropenol 2-fluoro-2,2-diphenylacetate methobromide;
- tropenol 3,3',4,4'-tetrafluorobenzilate methobromide, 20 - scopine 3,3',4,4'-tetrafluorobenzilate methobromide, - tropenol 4,4'-difluorobenzilate methobromide, - scopine 4,4'-difluorobenzilate methobromide, - tropenol 3,3'-difluorobenzilate methobromide, - scopine 3,3'- difluorobenzilate methobromide;
CA 02653422 2008-11-25 PC'f PO 1-2031 tropenol 9-hydroxy-fluorene-9-carboxylate methobromide;
tropenol9-fluoro-fluorene-9-carboxylate methobromide;
- scopine 9-hydroxy-fluorene-9-carboxylate methobromide=, - scopine 9-fluoro-fluorene-9-carboxylate methobromide;
tropenol 9-methyl-fluorene-9-carboxylate methobromide;
- scopine 9-methyl-fluorene-9-carboxylate methobromide;
- cyclopropyltropine benzilate methobromide;
- cyclopropyltropine 2,2-diphenylpropionate methobromide;
- cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide;
- cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide;
- cyclopropyltropine 9-methyl-xanthene-9-carboxylate methobromide;
- cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide;
- cyclopropyltropine methy14,4'-difluorobenzilate methobromide.
- tropenol 9-hydroxy-xanthene-9-carboxylate methobromide;
- scopine 9-hydroxy-xanthene-9-carboxylate methobromide;
- tropenol 9-methyl-xanthene-9-carboxylate methobromide;
- scopine 9-methyl-xanthene-9-carboxylate methobromide;
- tropenol 9-ethyl-xanthene-9-carboxylate methobromide;
- tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide;
- scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide, The above-mentioned compounds may also be used as salts within the scope of the present invention, wherein instead of the methobromide the salts metho-X are used, wherein X
may have the meanings given hereinbefore for X.
As corticosteroids it is preferable to use compounds selected from among beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etipred-nol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, roflepon-ide, triamcinolone, RPR-4 06541, NS-126, ST-26 and - (S)-fluoromethyl 6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-l6-methyl-3-oxo-androsta-1,4-diene-17-carbothi onate - (S)-(2-oxo-tetrahydro-furan-3S-yl)6,9-difluoro-ll-hydroxy-l6-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate, - cyanomethyl 6a,9a.-difluoro-11 [3-hydroxy-16a-methyl-3-oxo-17a-(2,2,3,3-tertamethylcyclopropylcarbonyl)oxy-androsta-l,4-diene-17(3-carboxylate optionally in the form of the racemates, enantiomers or diastereomers thereof and option-ally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof.
Any reference to steroids includes a reference to any salts or derivatives, hydrates or sol-CA 02653422 2008-11-25 PC']' PO 1-2031 vates thereof which may exist. Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
PDE4-inhibitors which may be used are preferably compounds selected from among en-profyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4418, Bay-198004, BY343, CP-325.366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, C1-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and - N-(3,5-dichloro-l-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide - (-)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,1 Ob-hexahydro-8-methoxy-2-methylbenzo [s] [ 1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide - (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone - 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone - cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-l-carboxylic acid]
- 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy-2 fl phenyl)cyclohexan-l-one - cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-ol]
- (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate - (S)-(-)-ethyl [4-(3 -cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]
acetate - 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-2 5 a]pyridine - 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine optionally in the form of the racemates, enantiomers or diastereomers thereof and option-ally in the form of the pharmacologically acceptable acid addition salts thereof, the sol-30 vates and/or hydrates thereof. According to the invention the acid addition salts of the PDE4 inhibitors are preferably selected from among the hydrochloride, hydrobromide, hy-driodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydro-maleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuc-cinate, hydrobenzoate and hydro-p-toluenesulphonate.
The LTD4-antagonists used are preferably compounds selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078.. VUF-K-8707, L-733321 and CA 02653422 2008-11-25 pCT PO 1-20' ) 1 g - 1-(((R)-(3-(2-(6,7-difluoro-2-auinolinyl)ethenyl)phenyl)-3-(2-(2- hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic acid, - 1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid - [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid optionally in the form of the racemates, enantiomers or diastereomers thereof and option-ally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. According to the invention these acid addition salts are preferably se-lected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydro-phosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocit-rate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate. By salts or derivatives which the LTD4-antagonists may optionally be capable of forming are meant, for example: alkali metal salts, such as for example so-dium or potassium salts, alkaline earth metal salts, sulphobenzoates, phosphates, isonicoti-nates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
EGFR-inhibitors which may be used are preferably compounds selected from among cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-l-yl]-2 o amino } -7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{ [4-(N,N-diethylamino)-1-oxo-2-buten-l-yl]-amino } -7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-l-oxo-2-buten-l-yl] amino } -7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-cyclopentyloxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ [4-((R)-6-methyl-2-oxo-morpholin-4-yl)-l-oxo-2-buten-l-yl] amino }-7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-l-oxo-2-buten-l-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl)amino]-6- { [4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten- l -yl] amino } -7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-moapholin-4-yl)-ethoxy]-7-methoxy-quinazo line - 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-l-yl} amino)-7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N;N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-cyclopentyloxy-quinazoline CA 02653422 2008-11-25 PCT pO 1-2.031 - 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-to-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-l-yl] amino } -7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-( { 4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-l-yl } amino)-7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-l-oxo-2-buten-l-yl } amino)-7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-l-yl } amino)-7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline - 4- [(3 -chloro-4-fluorophenyl)amino]-6- { [4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-((S)-tetrahydrofuran-3-yloxy)-quinazoline - 4-[(3 -chioro-4-fluorophenyl)amino]-6-( {4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-l-yl } amino)-7-cyclopentyloxy-quinazoline - 4- [(3-chloro-4-fluorophenyl)amino] -6- { [4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-l-yl] amino } -7-cyclopentyloxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6- { [4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl]amino } -7-[(R)-(tetrahydrofuran-2-yl)methoxy] -quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl]amino } -7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6.7-to-(2-methoxy-ethoxy)-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinyl-carbonyl)amino]-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine - 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-ethoxy-quinoline - 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl } -furan-2-yl)quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-{ [4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-3 o buten-l-yl] amino } -7-methoxy-quinazoline - 4- [(3-chloro-4-fluorophenyl)amino]-6-{ [4-(morpholin-4-yl)-1-oxo-2-buten-l-yl]-amino } -7 - [ (tetrahy drofuran-2-yl )methoxy] -quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-to-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-l-yl } amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-buten-l-yl] amino } -quinazo line - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline CA 02653422 2008-11-25 pCT pO 1-2031 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy] -7- [(R)-(tetrahydrofuran-2-yl)methoxy] -quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy] -6- [(S)-(tetrahydrofuran-2-yl)methoxy] -quinazoline 5 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-l-yl]-ethoxy } -7-methoxy-quinazo line - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[ 1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-1 o methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(methoxymethyl)carbonyl]-piperidin-4-yl-2 o oxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-2 5 quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline 30 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-l-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)aznino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-l-yloxy } -7-rnethoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-3 5 cyclohexan-l-vloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylainino-ethoxy)-quinazoline CA 02653422 2008-11-25 pC`j' p01-203 1 ll - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonyl amino-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy } -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4- {N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-1 o methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy- quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-ethoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[ 1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-2 o methoxy-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-[ 1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-y1)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-l-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[2-(2-oxopyrrolidin-l-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3 -ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline CA 02653422 2008-11-25 j>C'j' PO 1 -2203 ) 1 - 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-l-yloxy)-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6- {cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-{ 1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy} -7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6- { 1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl] -piperidin-4-yloxy } -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl)amino] -6- {1- [(2-methoxyethyl)carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline - 4- [(3 -chloro-4-fl uoro-phenyl)amino] -6- { 1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-znethanesulphonyl-N-methyl-amino)-cyclohexan-l-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy] -7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl)amino] -6-(trans-4-methylamino-cyclohexan- 1 -yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-l-yloxy]-7-methoxy-quinazoline CA 02653422 2008-11-25 pC'r'Po]-2031 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4- {N-[(morpholin-4-yl)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy] -7- [(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hy-dromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofu-marate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
The dopamine agonists used are preferably compounds selected from among bromocriptin, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropini-rol, talipexol, tergurid and viozan, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydrometlianesulphonate, hydronitrate, hydromaleate, hy-droacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydro-benzoate and hydro-p-toluenesulphonate.
H1-Antihistamines which may be used are preferably compounds selected from among epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ke-totifen, emedastine, dimetindene, clemastine, bamipine, cexchloipheniramine, phenirarnine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, pro-methazine, ebastine, desloratidine and meclozine, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobro-mide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hy-drosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
Any inhalable compounds, including also inhalable macromolecules as disclosed in EP 1 003 478, may be used as pharmaceutically effective substances, formulations or mixtures of substances. Preferably, substances, formulations or mixtures of substances administered by inhalation may be used for treating respiratory complaints.
In addition, the compound may come from the groups of ergot alkaloid derivatives, the triptans, the CGRP-inhibitors, the phosphodiesterase-V inhibitors, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharma-cologically acceptable acid addition salts, the solvates and/or hydrates thereof.
Examples of ergot alkaloid derivatives are dihydroergotamine and ergotamine.
An aim of the invention is to provide an atomizer of the kind mentioned hereinbefore which uniformly and reproducibly nebulises a fluid for absorption through the mucosa in the nasal cavity, without the use of propellant.
According to the invention the aim is achieved by associating a nose piece with the nozzle.
The nose piece can be inserted in at least one of the nostrils and using the atomizer the fluid is uniformly and reproducibly nebulised for absorption through the mucosa. Through the nosepiece inserted in the nostril, the finely divided fluid in the form of fine particles reaches the nasal mucosa, from where, by diffusion, the active substance either reaches its site of activity directly or enters the bloodstream and in this way reaches its target area.
High bioavailability is ensured by distribution over a large surface area of the nasal mu-cosa. Obviously, it is possible to construct the nose piece such that it is designed for inser-tion in both nostrils at the same time or for insertion in one nostril.
To enable the nosepiece to be replaced and/or cleaned as necessary, the nose piece is ad-vantageously attached in removable manner.
According to one feature, the nozzle is arranged in a mouthpiece of the atomizer which carries the nosepiece in sealed manner. Accordingiy, the atomizer is to be used with the mouthpiece in known manner as an inhaler for administering an, in particular, lung-bound CA 02653422 2008-11-25 PCT PO 1 -20' ) j fluid for treatment of the airways and with the nosepiece fitted onto the mouthpiece, which is also referred to as the nasal tube, for the nasal administration of solutions, suspensions and so-called solutions, namely a mixture of solution and suspension. A known atomizer is sold under the brand name "Respimat" by Boehringer Ingelheim KG in the form of an 5 inhaler and is described in WO 91/14468 Al and WO 97/12687 Al.
To avoid undesirable turbulence or loss of the fluid during nasal application, the nose piece preferably has a geometry that is congruent with the mouthpiece in the attachment region associated with the mouthpiece. As a result of this feature, there is no need to provide a 10 seal between the attaclunent region of the nose piece and the mouthpiece.
Rather, an inter-lockingly engaging seal resulting from the contour is obtained after the attachment of the nose piece.
As users find it pleasant to inhale through a mouthpiece adapted to the shape of the mouth, 15 the attachment region of the nose piece is usefully designed to be elliptical as a result of the congruent geometries.
In order to adapt the nose piece to the shape of a human nostril, the nasal insertion region of the nose piece is preferably elliptical in shape. The opening in the nasal insertion region is smaller than the opening in the attachment region. According to a further feature, the cross-section of the nasal section narrows continuously from the attachment region to the nasal insertion region.
Preferably, the pressure generator comprising a piston comprises a holder for the storage container, an associated drive spring with a release button and a conveying tube, while ax-ial tensioning of the drive spring moves the holder with the storage container and the con-veying tube in the opposite direction to the nose piece and sucks fluid out of a storage con-tainer into the pressure chan-iber. According to a further feature the specified amount is adjustable.
Preferably, actuation of the release button causes relaxation of the tensioned drive spring, which moves the conveying tube in the direction of the nose piece and applies pressure to the fluid to expel it through the nozzle. In order to prevent liquid from flowing back out of CA 02653422 2008-11-25 pCT PO 1_2031 16 the pressure chamber into the storage container during the atomization, a non-return valve is associated with the conveying tube.
For using the atomizer for a number of applications that use medicaments, a storage con-tainer for the fluid is replaceably mounted inside a housing. Advantageously, the nozzle comprises a filter system associated with nozzle channels for producing two spray jets that meet to form a spray mist. The nozzle channels are constructed such that two spray jets are formed that meet one another substantially at right angles. The filter system associated with the nozzle channels ensures that solid particles are retained and prevents the nozzle 1 o channels from becoming blocked. Preferably, the nozzle comprises a filter system and at least two nozzle channels for producing at least two spray jets meeting one another in order to produce a spray mist.
It will be appreciated that the features mentioned hereinbefore and those still to be de-scribed hereinafter may be used not only in the particular combination specified but also in other combinations. The scope of the invention is defined only by the claims.
The invention is explained in more detail hereinafter by an illustrative embodiment with reference to the associated drawing. The single Figure of the drawings shows:
Fig. 1 a sectional view of an atomizer according to the invention and Fig. 2 a schematic plan view of a nose piece of the atomizer according to Fig.
1.
The atomizer 1 is used to atomize a fluid 2, particularly a highly effective medicainent, and is in the form of a portable inhaler that operates without propellant gas.
During the atomi-zation of the fluid 2, preferably a liquid, an aerosol is formed which can be breathed in by a user (not shown).
3o The atomizer 1 has a replaceable storage container 3 containing the fluid 2, which is of substantially cylindrical construction and can be inserted in the opened atomizer 1 from below. In the rigid storage container 3 is a bag 4 that holds the fluid 2. For atomizing the fluid 2 in a predetermined adjustable amount, the atomizer 1 has a pressure generator 5 CA 02653422 2008-11-25 PCT p01_2031 comprising a piston 24 with a holder 6 for the container 3, a drive spring 7 with a release button 8 which is to be operated manually to release the tension, a conveying tube 9 with a non-return valve 10 inserted therein, a pressure chamber 11 and a nozzle 12 with an asso-ciated mouthpiece 13.
When the drive spring 7 is axially tensioned by rotating a lower housing part 18 with an inner part 17 releasably attached thereto, relative to an upper housing part 16 formed on the mouthpiece 13, the holder 6 with the storage container 3 and the conveying tube 9 is moved downwards and fluid is sucked out of the container 3 through the non-return valve 10 into the pressure chamber i 1 associated with the piston 24 of the pressure generator 5.
During the subsequent abrupt relaxation of the drive spring 7 by the actuation of the re-lease button 8, the fluid 2 in the pressure chamber 11 is put under pressure by the drive spring 7 moving the conveying tube 9 upwards and is expelled through the nozzle 12, whereupon atomization takes place. The atomization results, for example, in particles in the micron size range, preferably particles about 20 m in size, which form a mist or jet of aerosol. A user can inhale the aerosol, while supply air can be taken in through supply air openings 15 in the mouthpiece 13.
In order to administer fluid 2 as an aerosol through the nose so that it is absorbed through the mucosa in the nasal cavity, a nose piece 19 is removably fitted onto the mouthpiece 13.
The nose piece 19 has a geometry that is congruent with the mouthpiece 13 in the attach-ment region 20 associated with the mouthpiece 13 and is substantially elliptical in cross-section, both in the attachment region 20 and in the nasal insertion region 21. The opening 22 in the nasal insertion region 21 of the nose piece 19 is smaller in size than the opening 23 in the attachment region 20 and broadens out continuously up to the attachment region 20 abutting in sealed manner on the mouthpiece 13. The dimensions of the nose piece 19 are, of course, adapted to the dimensions of a human nostril, the largest and smallest exter-nal diameters being for example 16 mm and 10 mm in size.
Zo It is known to administer a medicament in the form of a spray through the nose or mouth in order to absorb it through the mucosa in the nasal cavity or through the lungs.
In addition, EP 0 521 061 B1 discloses a metering device for delivering a measured amount of a liquid as a spray with droplets of a size suitable for inhalation into the lungs by releasing the measured amount of liquid through an atomizing means comprising a cham-ber for holding the measured amount of liquid, an energy store and means for delivering a predetermined amount of energy to the energy store. Moreover, means are provided for releasing the predetermined amount of energy from the energy store to the chamber in or-der to expose the liquid contained therein to a predetermined rise in pressure from a low pressure to a higher pressure and initiate the release of liquid from the chamber. Atomis-ing means serve to atomize the measured amount of the liquid placed under pressure.
The compounds listed below may be used in the device according to the invention on their own or in combination. In the compounds mentioned below, W is a pharmacologically active substance and is selected (for exainple) from among the betamimetics, anticholiner-gics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine ago-nists, H1-antihistamines, PAF-antagonists and P13-kinase inhibitors. Moreover, double or triple combinations of W may be combined and used in the device according to the inven-tion. Combinations of W might be, for example:
- W denotes a betamimetic, combined with an anticholinergic, corticosteroid, inhibitor, EGFR-inhibitor or LTD4-antagonist, - W denotes an anticholinergic, combined with a betamimetic, corticosteroid, iiihibitor, EGFR-inhibitor or LTD4-antagonist, PCT P0 ] -2031 2 - W denotes a corticosteroid, combined with a PDE4-inhibitor, EGFR-inhibitor or LTD4-antagonist - W denotes a PDE4-inhibitor, combined with an EGFR-inhibitor or LTD4-antagonist - W denotes an EGFR-inhibitor, combined with an LTD4-antagonist.
The compounds used as betamimetics are preferably compounds selected from among al-buterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ri-todrine, salmefamol, salmeterol, soterenol, sulphonterol, terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035, HOKU-81, KUL-1248 and - 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide - 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-lH-quinolin-2-one - 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone - 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol - 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino] ethanol - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl -2 -propylamino] ethanol - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino] ethanol - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino } ethanol - 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one - 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol - 6-hydroxy-8- { 1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl } -4H-benzo[ 1,4]oxazin-3-one - 6-hydroxy-8-{ 1-hydroxy-2-[2-( ethyl 4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl} -4H-benzo [ 1,4] oxazin-3 -one - 6-hydroxy-8-{ 1-hydroxy-2-[2-(4-phenoxy-acetic acid)-1,1-dimethyl-ethylamino]-ethyi}-4H-benzo[1,4]oxazin-3-one - 8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo [ 1,4] oxazin-3 -one ~
~
- 6-hydroxy-8-{ 1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo [ 1,4] oxazin- 3 -one - 6-hydroxy-8- { 1-hydroxy-2-[2-(4-isopropyl-phenyl)-1. i dimethyl-ethylamino]
-ethyl } -4H-benzo[ 1,4] oxazin-3-one - 8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-benzo[1,4]oxazin-3-one - 8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one - 4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-lo ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid - 8-{2-[2-(3.4-difluoro-phenyl)-l,l-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one - 1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol - 2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino } -ethyl)-benzaldehyde - N-[2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino }-ethyl)-phenyl]-formamide - 8-hydroxy-5-(1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino } -ethyl)-1 H-quinolin-2-one - 8 -hydroxy-5- [1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1 H-quinolin-2-one - 5-[2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1 H-quinolin-2-one - [3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5 -m ethyl-phenyl] -urea - 4-(2- { 6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino } -1-hydroxy-ethyl)-hydroxymethyl-phenol - 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzylsulphonamide - 3 -(3-{ 7-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-3o propyl)-benzylsulphonamide - 4-(2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol - N-Adamantan-2-yl-2-(3 - { 2-[2-hydroxy-2-(4-hydroxy-3 -hydroxymethyl-phenyl)-ethylamino]-propyi } -phenyl)-acetamide optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention the acid addition salts of the betamimetics are prefera-CA 02653422 2008-11-25 pC,h p01-20' ) 1 bly selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hy-drophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hy-drocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
The anticholinergics used are preferably compounds selected from among the tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyr-ronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine. In the above-mentioned salts the cations are the pharmacologically active con-stituents. As anions the above-mentioned salts may preferably contain the chloride, bro-mide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions. Of all the salts the chlorides, bromides, iodides and methanesulphonates are particularly preferred.
Other preferred anticholinergics are selected from among the salts of formula 0N o p X- HO s s AC-i wherein X - denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, iodide, sulphate, phosphate, methanesuipho-nate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, preferably an anion with a single negative charge, particularly pref-erably an anion selected from among the fluoride, chloride, bromide, methanesulphonate and p-toluenesulphonate, particularly preferably bromide, optionally in the form of the ra-cemates, enantiomers or hydrates thereof. Of particular importance are those pharmaceuti-cal combinations which contain the enantiomers of formula AC-1-en PCT PO l -203 l O O
X- HO
s s AC-1-en wherein X may have the above-mentioned meanings. Other preferred anticholinergics are selected from the salts of formula AC-2 OH
N\
R X
wherein R denotes either methyl or ethyl and wherein X may have the above-mentioned meanings. In an alternative embodiment the compound of formula AC-2 may also be pre-1 o sent in the form of the free base AC-2-base.
OH
NJ-"
y AC-2-base Other specified compounds are:
i5 - tropenol 2,2-diphenylpropionate methobromide, - scopine 2,2-diphenylpropionate methobromide, - scopine 2-fluoro-2,2-diphenylacetate methobromide, - tropenol 2-fluoro-2,2-diphenylacetate methobromide;
- tropenol 3,3',4,4'-tetrafluorobenzilate methobromide, 20 - scopine 3,3',4,4'-tetrafluorobenzilate methobromide, - tropenol 4,4'-difluorobenzilate methobromide, - scopine 4,4'-difluorobenzilate methobromide, - tropenol 3,3'-difluorobenzilate methobromide, - scopine 3,3'- difluorobenzilate methobromide;
CA 02653422 2008-11-25 PC'f PO 1-2031 tropenol 9-hydroxy-fluorene-9-carboxylate methobromide;
tropenol9-fluoro-fluorene-9-carboxylate methobromide;
- scopine 9-hydroxy-fluorene-9-carboxylate methobromide=, - scopine 9-fluoro-fluorene-9-carboxylate methobromide;
tropenol 9-methyl-fluorene-9-carboxylate methobromide;
- scopine 9-methyl-fluorene-9-carboxylate methobromide;
- cyclopropyltropine benzilate methobromide;
- cyclopropyltropine 2,2-diphenylpropionate methobromide;
- cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide;
- cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide;
- cyclopropyltropine 9-methyl-xanthene-9-carboxylate methobromide;
- cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide;
- cyclopropyltropine methy14,4'-difluorobenzilate methobromide.
- tropenol 9-hydroxy-xanthene-9-carboxylate methobromide;
- scopine 9-hydroxy-xanthene-9-carboxylate methobromide;
- tropenol 9-methyl-xanthene-9-carboxylate methobromide;
- scopine 9-methyl-xanthene-9-carboxylate methobromide;
- tropenol 9-ethyl-xanthene-9-carboxylate methobromide;
- tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide;
- scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide, The above-mentioned compounds may also be used as salts within the scope of the present invention, wherein instead of the methobromide the salts metho-X are used, wherein X
may have the meanings given hereinbefore for X.
As corticosteroids it is preferable to use compounds selected from among beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etipred-nol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, roflepon-ide, triamcinolone, RPR-4 06541, NS-126, ST-26 and - (S)-fluoromethyl 6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-l6-methyl-3-oxo-androsta-1,4-diene-17-carbothi onate - (S)-(2-oxo-tetrahydro-furan-3S-yl)6,9-difluoro-ll-hydroxy-l6-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate, - cyanomethyl 6a,9a.-difluoro-11 [3-hydroxy-16a-methyl-3-oxo-17a-(2,2,3,3-tertamethylcyclopropylcarbonyl)oxy-androsta-l,4-diene-17(3-carboxylate optionally in the form of the racemates, enantiomers or diastereomers thereof and option-ally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof.
Any reference to steroids includes a reference to any salts or derivatives, hydrates or sol-CA 02653422 2008-11-25 PC']' PO 1-2031 vates thereof which may exist. Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
PDE4-inhibitors which may be used are preferably compounds selected from among en-profyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4418, Bay-198004, BY343, CP-325.366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, C1-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and - N-(3,5-dichloro-l-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide - (-)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,1 Ob-hexahydro-8-methoxy-2-methylbenzo [s] [ 1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide - (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone - 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone - cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-l-carboxylic acid]
- 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy-2 fl phenyl)cyclohexan-l-one - cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l-ol]
- (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate - (S)-(-)-ethyl [4-(3 -cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]
acetate - 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-2 5 a]pyridine - 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine optionally in the form of the racemates, enantiomers or diastereomers thereof and option-ally in the form of the pharmacologically acceptable acid addition salts thereof, the sol-30 vates and/or hydrates thereof. According to the invention the acid addition salts of the PDE4 inhibitors are preferably selected from among the hydrochloride, hydrobromide, hy-driodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydro-maleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuc-cinate, hydrobenzoate and hydro-p-toluenesulphonate.
The LTD4-antagonists used are preferably compounds selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078.. VUF-K-8707, L-733321 and CA 02653422 2008-11-25 pCT PO 1-20' ) 1 g - 1-(((R)-(3-(2-(6,7-difluoro-2-auinolinyl)ethenyl)phenyl)-3-(2-(2- hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic acid, - 1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid - [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid optionally in the form of the racemates, enantiomers or diastereomers thereof and option-ally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. According to the invention these acid addition salts are preferably se-lected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydro-phosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocit-rate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate. By salts or derivatives which the LTD4-antagonists may optionally be capable of forming are meant, for example: alkali metal salts, such as for example so-dium or potassium salts, alkaline earth metal salts, sulphobenzoates, phosphates, isonicoti-nates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
EGFR-inhibitors which may be used are preferably compounds selected from among cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-l-yl]-2 o amino } -7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{ [4-(N,N-diethylamino)-1-oxo-2-buten-l-yl]-amino } -7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-l-oxo-2-buten-l-yl] amino } -7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-l-yl]amino}-7-cyclopentyloxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ [4-((R)-6-methyl-2-oxo-morpholin-4-yl)-l-oxo-2-buten-l-yl] amino }-7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-l-oxo-2-buten-l-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl)amino]-6- { [4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten- l -yl] amino } -7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-moapholin-4-yl)-ethoxy]-7-methoxy-quinazo line - 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-l-yl} amino)-7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N;N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-cyclopentyloxy-quinazoline CA 02653422 2008-11-25 PCT pO 1-2.031 - 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-to-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-l-yl] amino } -7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-( { 4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-l-yl } amino)-7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-l-oxo-2-buten-l-yl } amino)-7-cyclopropylmethoxy-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-l-yl } amino)-7-cyclopropylmethoxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline - 4- [(3 -chloro-4-fluorophenyl)amino]-6- { [4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-((S)-tetrahydrofuran-3-yloxy)-quinazoline - 4-[(3 -chioro-4-fluorophenyl)amino]-6-( {4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-l-yl } amino)-7-cyclopentyloxy-quinazoline - 4- [(3-chloro-4-fluorophenyl)amino] -6- { [4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-l-yl] amino } -7-cyclopentyloxy-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6- { [4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl]amino } -7-[(R)-(tetrahydrofuran-2-yl)methoxy] -quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl]amino } -7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6.7-to-(2-methoxy-ethoxy)-quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinyl-carbonyl)amino]-quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine - 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-l-yl] amino } -7-ethoxy-quinoline - 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl } -furan-2-yl)quinazoline - 4-[(R)-(1-phenyl-ethyl)amino]-6-{ [4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-3 o buten-l-yl] amino } -7-methoxy-quinazoline - 4- [(3-chloro-4-fluorophenyl)amino]-6-{ [4-(morpholin-4-yl)-1-oxo-2-buten-l-yl]-amino } -7 - [ (tetrahy drofuran-2-yl )methoxy] -quinazoline - 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-to-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-l-yl } amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-buten-l-yl] amino } -quinazo line - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline CA 02653422 2008-11-25 pCT pO 1-2031 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy] -7- [(R)-(tetrahydrofuran-2-yl)methoxy] -quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy] -6- [(S)-(tetrahydrofuran-2-yl)methoxy] -quinazoline 5 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-l-yl]-ethoxy } -7-methoxy-quinazo line - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[ 1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-1 o methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(methoxymethyl)carbonyl]-piperidin-4-yl-2 o oxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-2 5 quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline 30 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-l-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)aznino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-l-yloxy } -7-rnethoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-3 5 cyclohexan-l-vloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylainino-ethoxy)-quinazoline CA 02653422 2008-11-25 pC`j' p01-203 1 ll - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonyl amino-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy } -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4- {N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-1 o methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy- quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-ethoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[ 1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-2 o methoxy-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-[ 1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-y1)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-l-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[2-(2-oxopyrrolidin-l-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3 -ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline CA 02653422 2008-11-25 j>C'j' PO 1 -2203 ) 1 - 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-l-yloxy)-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6- {cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline - 4-[(3-ethynyl-phenyl)amino]-6-{ 1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ 1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy} -7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl) amino] -6- { 1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl] -piperidin-4-yloxy } -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl)amino] -6- {1- [(2-methoxyethyl)carbonyl] -piperidin-4-yloxy} -7-methoxy-quinazoline - 4- [(3 -chloro-4-fl uoro-phenyl)amino] -6- { 1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy} -7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-znethanesulphonyl-N-methyl-amino)-cyclohexan-l-yloxy]-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy] -7-methoxy-quinazoline - 4- [(3 -chloro-4-fluoro-phenyl)amino] -6-(trans-4-methylamino-cyclohexan- 1 -yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-l-yloxy]-7-methoxy-quinazoline CA 02653422 2008-11-25 pC'r'Po]-2031 - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4- {N-[(morpholin-4-yl)carbonyl]-N-methyl-amino } -cyclohexan-l-yloxy)-7-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy] -7- [(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-methoxy-quinazoline - 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hy-dromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofu-marate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
The dopamine agonists used are preferably compounds selected from among bromocriptin, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropini-rol, talipexol, tergurid and viozan, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydrometlianesulphonate, hydronitrate, hydromaleate, hy-droacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydro-benzoate and hydro-p-toluenesulphonate.
H1-Antihistamines which may be used are preferably compounds selected from among epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ke-totifen, emedastine, dimetindene, clemastine, bamipine, cexchloipheniramine, phenirarnine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, pro-methazine, ebastine, desloratidine and meclozine, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobro-mide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hy-drosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
Any inhalable compounds, including also inhalable macromolecules as disclosed in EP 1 003 478, may be used as pharmaceutically effective substances, formulations or mixtures of substances. Preferably, substances, formulations or mixtures of substances administered by inhalation may be used for treating respiratory complaints.
In addition, the compound may come from the groups of ergot alkaloid derivatives, the triptans, the CGRP-inhibitors, the phosphodiesterase-V inhibitors, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharma-cologically acceptable acid addition salts, the solvates and/or hydrates thereof.
Examples of ergot alkaloid derivatives are dihydroergotamine and ergotamine.
An aim of the invention is to provide an atomizer of the kind mentioned hereinbefore which uniformly and reproducibly nebulises a fluid for absorption through the mucosa in the nasal cavity, without the use of propellant.
According to the invention the aim is achieved by associating a nose piece with the nozzle.
The nose piece can be inserted in at least one of the nostrils and using the atomizer the fluid is uniformly and reproducibly nebulised for absorption through the mucosa. Through the nosepiece inserted in the nostril, the finely divided fluid in the form of fine particles reaches the nasal mucosa, from where, by diffusion, the active substance either reaches its site of activity directly or enters the bloodstream and in this way reaches its target area.
High bioavailability is ensured by distribution over a large surface area of the nasal mu-cosa. Obviously, it is possible to construct the nose piece such that it is designed for inser-tion in both nostrils at the same time or for insertion in one nostril.
To enable the nosepiece to be replaced and/or cleaned as necessary, the nose piece is ad-vantageously attached in removable manner.
According to one feature, the nozzle is arranged in a mouthpiece of the atomizer which carries the nosepiece in sealed manner. Accordingiy, the atomizer is to be used with the mouthpiece in known manner as an inhaler for administering an, in particular, lung-bound CA 02653422 2008-11-25 PCT PO 1 -20' ) j fluid for treatment of the airways and with the nosepiece fitted onto the mouthpiece, which is also referred to as the nasal tube, for the nasal administration of solutions, suspensions and so-called solutions, namely a mixture of solution and suspension. A known atomizer is sold under the brand name "Respimat" by Boehringer Ingelheim KG in the form of an 5 inhaler and is described in WO 91/14468 Al and WO 97/12687 Al.
To avoid undesirable turbulence or loss of the fluid during nasal application, the nose piece preferably has a geometry that is congruent with the mouthpiece in the attachment region associated with the mouthpiece. As a result of this feature, there is no need to provide a 10 seal between the attaclunent region of the nose piece and the mouthpiece.
Rather, an inter-lockingly engaging seal resulting from the contour is obtained after the attachment of the nose piece.
As users find it pleasant to inhale through a mouthpiece adapted to the shape of the mouth, 15 the attachment region of the nose piece is usefully designed to be elliptical as a result of the congruent geometries.
In order to adapt the nose piece to the shape of a human nostril, the nasal insertion region of the nose piece is preferably elliptical in shape. The opening in the nasal insertion region is smaller than the opening in the attachment region. According to a further feature, the cross-section of the nasal section narrows continuously from the attachment region to the nasal insertion region.
Preferably, the pressure generator comprising a piston comprises a holder for the storage container, an associated drive spring with a release button and a conveying tube, while ax-ial tensioning of the drive spring moves the holder with the storage container and the con-veying tube in the opposite direction to the nose piece and sucks fluid out of a storage con-tainer into the pressure chan-iber. According to a further feature the specified amount is adjustable.
Preferably, actuation of the release button causes relaxation of the tensioned drive spring, which moves the conveying tube in the direction of the nose piece and applies pressure to the fluid to expel it through the nozzle. In order to prevent liquid from flowing back out of CA 02653422 2008-11-25 pCT PO 1_2031 16 the pressure chamber into the storage container during the atomization, a non-return valve is associated with the conveying tube.
For using the atomizer for a number of applications that use medicaments, a storage con-tainer for the fluid is replaceably mounted inside a housing. Advantageously, the nozzle comprises a filter system associated with nozzle channels for producing two spray jets that meet to form a spray mist. The nozzle channels are constructed such that two spray jets are formed that meet one another substantially at right angles. The filter system associated with the nozzle channels ensures that solid particles are retained and prevents the nozzle 1 o channels from becoming blocked. Preferably, the nozzle comprises a filter system and at least two nozzle channels for producing at least two spray jets meeting one another in order to produce a spray mist.
It will be appreciated that the features mentioned hereinbefore and those still to be de-scribed hereinafter may be used not only in the particular combination specified but also in other combinations. The scope of the invention is defined only by the claims.
The invention is explained in more detail hereinafter by an illustrative embodiment with reference to the associated drawing. The single Figure of the drawings shows:
Fig. 1 a sectional view of an atomizer according to the invention and Fig. 2 a schematic plan view of a nose piece of the atomizer according to Fig.
1.
The atomizer 1 is used to atomize a fluid 2, particularly a highly effective medicainent, and is in the form of a portable inhaler that operates without propellant gas.
During the atomi-zation of the fluid 2, preferably a liquid, an aerosol is formed which can be breathed in by a user (not shown).
3o The atomizer 1 has a replaceable storage container 3 containing the fluid 2, which is of substantially cylindrical construction and can be inserted in the opened atomizer 1 from below. In the rigid storage container 3 is a bag 4 that holds the fluid 2. For atomizing the fluid 2 in a predetermined adjustable amount, the atomizer 1 has a pressure generator 5 CA 02653422 2008-11-25 PCT p01_2031 comprising a piston 24 with a holder 6 for the container 3, a drive spring 7 with a release button 8 which is to be operated manually to release the tension, a conveying tube 9 with a non-return valve 10 inserted therein, a pressure chamber 11 and a nozzle 12 with an asso-ciated mouthpiece 13.
When the drive spring 7 is axially tensioned by rotating a lower housing part 18 with an inner part 17 releasably attached thereto, relative to an upper housing part 16 formed on the mouthpiece 13, the holder 6 with the storage container 3 and the conveying tube 9 is moved downwards and fluid is sucked out of the container 3 through the non-return valve 10 into the pressure chamber i 1 associated with the piston 24 of the pressure generator 5.
During the subsequent abrupt relaxation of the drive spring 7 by the actuation of the re-lease button 8, the fluid 2 in the pressure chamber 11 is put under pressure by the drive spring 7 moving the conveying tube 9 upwards and is expelled through the nozzle 12, whereupon atomization takes place. The atomization results, for example, in particles in the micron size range, preferably particles about 20 m in size, which form a mist or jet of aerosol. A user can inhale the aerosol, while supply air can be taken in through supply air openings 15 in the mouthpiece 13.
In order to administer fluid 2 as an aerosol through the nose so that it is absorbed through the mucosa in the nasal cavity, a nose piece 19 is removably fitted onto the mouthpiece 13.
The nose piece 19 has a geometry that is congruent with the mouthpiece 13 in the attach-ment region 20 associated with the mouthpiece 13 and is substantially elliptical in cross-section, both in the attachment region 20 and in the nasal insertion region 21. The opening 22 in the nasal insertion region 21 of the nose piece 19 is smaller in size than the opening 23 in the attachment region 20 and broadens out continuously up to the attachment region 20 abutting in sealed manner on the mouthpiece 13. The dimensions of the nose piece 19 are, of course, adapted to the dimensions of a human nostril, the largest and smallest exter-nal diameters being for example 16 mm and 10 mm in size.
Claims (15)
1. Atomiser for delivering a specific amount of a fluid (2), particularly one that con-tains a medicament, as an aerosol through a nozzle (12) from a pressure store, wherein a mechanical pressure generator (5) acts upon the measured amount of fluid (2) in the pressure store which is to be released abruptly for atomization, characterised in that a nosepiece (19) is associated with the nozzle (12).
2. Atomiser according to claim 1, characterised in that the nose piece (19) is remov-ably attached.
3. Atomiser according to claim 1 or 2, characterised in that the nozzle (12) is ar-ranged in a mouthpiece (13) of the atomizer which carries the nose piece (19) in sealed manner.
4. Atomiser according to one of claims 1 to 3, characterised in that the nose piece (19) has a geometry which is congruent to the mouthpiece (13) in the attachment region (20) associated with the mouthpiece (13).
5. Atomiser according to claim 4, characterised in that the attachment region (20) of the nose piece (19) is elliptical in cross-section.
6. Atomiser according to one of claims 1 to 5, characterised in that the nasal inser-tion region (21) of the nose piece (19) is elliptically shaped.
7. Atomiser according to one of claims 1 to 6, characterised in that the opening (22) in the nasal insertion region (21) is smaller in size than the opening (23) in the at-tachment region (20).
8. Atomiser according to claim 7, characterised in that the cross section of the nose piece (19) becomes continuously narrower from the attachment region (20) to the nasal insertion region (21).
9. Atomiser according to claim 1, characterised in that the pressure generator (5) comprising a piston (24) comprises a holder (6) for the storage container (3), an as-sociated drive spring (7) with a release button (8) and a conveying tube (9), while axial tensioning of the drive spring (7) shifts the holder (6) with the storage con-tainer (3) and the conveying tube (9) in the opposite direction to the nose piece (19) and sucks fluid (2) out of the storage container (3) into a pressure chamber (11).
10. Atomiser according to claim 1, characterised in that the specified amount of fluid is adjustable.
11. Atomiser according to claim 10, characterised in that actuation of the release but-ton (8) causes relaxation of the tensioned drive spring (7), which moves the deliv-ery tube (9) in the direction of the nose piece (19) und thereby applies pressure to the fluid (2) to expel it through the nozzle (12).
12. Atomiser according to claim 10 or 12, characterised in that a non-return valve (10) is associated with the conveying tube (9).
13. Atomiser according to claim 1, characterised in that a storage container (3) for the fluid (2) is replaceably mounted inside a housing.
14. Atomiser according to claim 1, characterised in that the nozzle (12) comprises a filter system associated with nozzle channels for producing two spray jets that meet so as to produce a spray mist.
15. Nose piece as an adapter for an atomizer (1) according to one of claims 1 to 14.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102006025871A DE102006025871A1 (en) | 2006-06-02 | 2006-06-02 | atomizer |
| DE102006025871.1 | 2006-06-02 | ||
| PCT/EP2007/055383 WO2007141203A1 (en) | 2006-06-02 | 2007-06-01 | Atomizer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2653422A1 true CA2653422A1 (en) | 2007-12-13 |
Family
ID=38472898
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002653422A Abandoned CA2653422A1 (en) | 2006-06-02 | 2007-06-01 | Atomizer |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP2029205A1 (en) |
| JP (1) | JP2009538656A (en) |
| CA (1) | CA2653422A1 (en) |
| DE (1) | DE102006025871A1 (en) |
| WO (1) | WO2007141203A1 (en) |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7837235B2 (en) | 2004-01-08 | 2010-11-23 | Boehringer Ingelheim International Gmbh | Device for clamping a fluidic component |
| US9265910B2 (en) | 2009-05-18 | 2016-02-23 | Boehringer Ingelheim International Gmbh | Adapter, inhalation device, and nebulizer |
| US9545487B2 (en) | 2012-04-13 | 2017-01-17 | Boehringer Ingelheim International Gmbh | Dispenser with encoding means |
| US9713516B2 (en) | 2013-08-20 | 2017-07-25 | Boehringer Ingelheim Vetmedica Gmbh | Inhaler |
| US9724482B2 (en) | 2009-11-25 | 2017-08-08 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US9744313B2 (en) | 2013-08-09 | 2017-08-29 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US9757750B2 (en) | 2011-04-01 | 2017-09-12 | Boehringer Ingelheim International Gmbh | Medicinal device with container |
| US9827384B2 (en) | 2011-05-23 | 2017-11-28 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US9913952B2 (en) | 2013-08-20 | 2018-03-13 | Boehringer Ingelheim Vetmedica Gmbh | Inhaler |
| US9943654B2 (en) | 2010-06-24 | 2018-04-17 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10004857B2 (en) | 2013-08-09 | 2018-06-26 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10011906B2 (en) | 2009-03-31 | 2018-07-03 | Beohringer Ingelheim International Gmbh | Method for coating a surface of a component |
| US10016568B2 (en) | 2009-11-25 | 2018-07-10 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10046124B2 (en) | 2013-08-20 | 2018-08-14 | Boehringer Ingelheim Vetmedica Gmbh | Inhaler |
| US10099022B2 (en) | 2014-05-07 | 2018-10-16 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10124129B2 (en) | 2008-01-02 | 2018-11-13 | Boehringer Ingelheim International Gmbh | Dispensing device, storage device and method for dispensing a formulation |
| US10124125B2 (en) | 2009-11-25 | 2018-11-13 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10195374B2 (en) | 2014-05-07 | 2019-02-05 | Boehringer Ingelheim International Gmbh | Container, nebulizer and use |
| US10722666B2 (en) | 2014-05-07 | 2020-07-28 | Boehringer Ingelheim International Gmbh | Nebulizer with axially movable and lockable container and indicator |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7963955B2 (en) | 1998-02-27 | 2011-06-21 | Boehringer Ingelheim International Gmbh | Container for a medicinal liquid |
| EP2135632A1 (en) * | 2008-06-20 | 2009-12-23 | Boehringer Ingelheim International Gmbh | Inhalator |
| KR101641520B1 (en) * | 2009-06-25 | 2016-07-21 | 베링거잉겔하임베트메디카게엠베하 | Inhaler |
| DE102013013397A1 (en) * | 2013-08-13 | 2015-03-12 | Epinamics Gmbh | Aerosol dispenser for transdermal pharmaceutical compositions |
| GB201408561D0 (en) * | 2014-05-14 | 2014-06-25 | The Technology Partnership Plc | Aerosolisation engine for liquid drug delivery |
| CN113679910A (en) * | 2020-05-19 | 2021-11-23 | 顾瑜 | Atomization device |
| FR3121047B1 (en) | 2021-03-29 | 2023-07-14 | Aptar France Sas | Nasal powder delivery device |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE788194A (en) * | 1971-08-31 | 1973-02-28 | Thomae Gmbh Dr K | DEVICE FOR THE ADMINISTRATION OF MECHANICALLY DOSE QUANTITIES OF LIQUID OR SOLUTION MEDICINAL PRODUCTS |
| SG45171A1 (en) * | 1990-03-21 | 1998-01-16 | Boehringer Ingelheim Int | Atomising devices and methods |
| GB2291135B (en) * | 1994-07-06 | 1998-02-25 | Boehringer Ingelheim Kg | Device for dispensing fluid |
| DE19708406A1 (en) * | 1997-03-03 | 1998-09-10 | Alfred Von Schuckmann | Device for dispensing substances |
| DE10131178A1 (en) * | 2001-06-29 | 2003-01-16 | Boehringer Ingelheim Pharma | Nebulizer for applying liquids to the eyes |
| DE50311664D1 (en) * | 2002-05-16 | 2009-08-13 | Boehringer Ingelheim Int | SYSTEM COMPRISING A NOZZLE AND A BRACKET SYSTEM |
| WO2005079997A1 (en) * | 2004-02-24 | 2005-09-01 | Boehringer Ingelheim International Gmbh | Atomiser |
| US7448385B2 (en) * | 2004-06-07 | 2008-11-11 | Purepharm Inc. | Nasal adaptation of an oral inhaler device |
-
2006
- 2006-06-02 DE DE102006025871A patent/DE102006025871A1/en not_active Withdrawn
-
2007
- 2007-06-01 EP EP07729784A patent/EP2029205A1/en not_active Withdrawn
- 2007-06-01 WO PCT/EP2007/055383 patent/WO2007141203A1/en active Application Filing
- 2007-06-01 CA CA002653422A patent/CA2653422A1/en not_active Abandoned
- 2007-06-01 JP JP2009512611A patent/JP2009538656A/en active Pending
Cited By (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9027967B2 (en) | 2004-01-08 | 2015-05-12 | Boehringer Ingelheim International Gmbh | Device for clamping a fluidic component |
| US7837235B2 (en) | 2004-01-08 | 2010-11-23 | Boehringer Ingelheim International Gmbh | Device for clamping a fluidic component |
| US10124129B2 (en) | 2008-01-02 | 2018-11-13 | Boehringer Ingelheim International Gmbh | Dispensing device, storage device and method for dispensing a formulation |
| US10011906B2 (en) | 2009-03-31 | 2018-07-03 | Beohringer Ingelheim International Gmbh | Method for coating a surface of a component |
| US9265910B2 (en) | 2009-05-18 | 2016-02-23 | Boehringer Ingelheim International Gmbh | Adapter, inhalation device, and nebulizer |
| US9682202B2 (en) | 2009-05-18 | 2017-06-20 | Boehringer Ingelheim International Gmbh | Adapter, inhalation device, and atomizer |
| US9724482B2 (en) | 2009-11-25 | 2017-08-08 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10016568B2 (en) | 2009-11-25 | 2018-07-10 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10124125B2 (en) | 2009-11-25 | 2018-11-13 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US9943654B2 (en) | 2010-06-24 | 2018-04-17 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US9757750B2 (en) | 2011-04-01 | 2017-09-12 | Boehringer Ingelheim International Gmbh | Medicinal device with container |
| US9827384B2 (en) | 2011-05-23 | 2017-11-28 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10220163B2 (en) | 2012-04-13 | 2019-03-05 | Boehringer Ingelheim International Gmbh | Nebuliser with coding means |
| US9545487B2 (en) | 2012-04-13 | 2017-01-17 | Boehringer Ingelheim International Gmbh | Dispenser with encoding means |
| US9744313B2 (en) | 2013-08-09 | 2017-08-29 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10894134B2 (en) | 2013-08-09 | 2021-01-19 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US11642476B2 (en) | 2013-08-09 | 2023-05-09 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10004857B2 (en) | 2013-08-09 | 2018-06-26 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US10869975B2 (en) | 2013-08-20 | 2020-12-22 | Boehringer Ingelheim Vetmedica Gmbh | Inhaler |
| US9713516B2 (en) | 2013-08-20 | 2017-07-25 | Boehringer Ingelheim Vetmedica Gmbh | Inhaler |
| US10737046B2 (en) | 2013-08-20 | 2020-08-11 | Boehringer Ingelheim Vetmedica Gmbh | Inhaler |
| US10046124B2 (en) | 2013-08-20 | 2018-08-14 | Boehringer Ingelheim Vetmedica Gmbh | Inhaler |
| US9913952B2 (en) | 2013-08-20 | 2018-03-13 | Boehringer Ingelheim Vetmedica Gmbh | Inhaler |
| US11679212B2 (en) | 2013-08-20 | 2023-06-20 | Boehringer Ingelheim Vetmedica Gmbh | Inhaler |
| US11964102B2 (en) | 2013-08-20 | 2024-04-23 | Boehringer Ingelheim Vetmedica Gmbh | Inhaler |
| US10716905B2 (en) | 2014-02-23 | 2020-07-21 | Boehringer Lngelheim International Gmbh | Container, nebulizer and use |
| US10195374B2 (en) | 2014-05-07 | 2019-02-05 | Boehringer Ingelheim International Gmbh | Container, nebulizer and use |
| US10722666B2 (en) | 2014-05-07 | 2020-07-28 | Boehringer Ingelheim International Gmbh | Nebulizer with axially movable and lockable container and indicator |
| US10099022B2 (en) | 2014-05-07 | 2018-10-16 | Boehringer Ingelheim International Gmbh | Nebulizer |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2029205A1 (en) | 2009-03-04 |
| DE102006025871A1 (en) | 2007-12-06 |
| JP2009538656A (en) | 2009-11-12 |
| WO2007141203A1 (en) | 2007-12-13 |
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| FZDE | Discontinued | ||
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| FZDE | Discontinued |
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