HRP20010828A2 - Novel medicament compositions, based on anticholinergically effective compounds and beta-mimetics - Google Patents
Novel medicament compositions, based on anticholinergically effective compounds and beta-mimetics Download PDFInfo
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- HRP20010828A2 HRP20010828A2 HR20010828A HRP20010828A HRP20010828A2 HR P20010828 A2 HRP20010828 A2 HR P20010828A2 HR 20010828 A HR20010828 A HR 20010828A HR P20010828 A HRP20010828 A HR P20010828A HR P20010828 A2 HRP20010828 A2 HR P20010828A2
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- 239000000203 mixture Substances 0.000 title claims description 18
- 239000003814 drug Substances 0.000 title claims description 11
- 150000001875 compounds Chemical class 0.000 title description 7
- 239000000808 adrenergic beta-agonist Substances 0.000 title 1
- 230000003454 betamimetic effect Effects 0.000 title 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 51
- 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 claims description 30
- 229960000257 tiotropium bromide Drugs 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- OBRNDARFFFHCGE-PERKLWIXSA-N (S,S)-formoterol fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1=CC(OC)=CC=C1C[C@H](C)NC[C@@H](O)C1=CC=C(O)C(NC=O)=C1.C1=CC(OC)=CC=C1C[C@H](C)NC[C@@H](O)C1=CC=C(O)C(NC=O)=C1 OBRNDARFFFHCGE-PERKLWIXSA-N 0.000 claims description 17
- 229960000193 formoterol fumarate Drugs 0.000 claims description 17
- -1 C1-C4-alkyl radical Chemical class 0.000 claims description 16
- 125000001544 thienyl group Chemical group 0.000 claims description 16
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 14
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 claims description 14
- 229960002848 formoterol Drugs 0.000 claims description 14
- 230000001078 anti-cholinergic effect Effects 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Chemical group 0.000 claims description 8
- 239000000460 chlorine Chemical group 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 claims description 7
- 150000001450 anions Chemical class 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 150000003254 radicals Chemical class 0.000 claims description 7
- 229960004017 salmeterol Drugs 0.000 claims description 7
- YUDRVAHLXDBKSR-UHFFFAOYSA-N [CH]1CCCCC1 Chemical compound [CH]1CCCCC1 YUDRVAHLXDBKSR-UHFFFAOYSA-N 0.000 claims description 6
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 6
- 150000001414 amino alcohols Chemical class 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 5
- VPNYRYCIDCJBOM-UHFFFAOYSA-M Glycopyrronium bromide Chemical compound [Br-].C1[N+](C)(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 VPNYRYCIDCJBOM-UHFFFAOYSA-M 0.000 claims description 5
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- 229960002462 glycopyrronium bromide Drugs 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- DBCKRBGYGMVSTI-UHFFFAOYSA-N 2-oxo-7-[2-[2-[3-(2-phenylethoxy)propylsulfonyl]ethylazaniumyl]ethyl]-3h-1,3-benzothiazol-4-olate Chemical compound C1=2SC(=O)NC=2C(O)=CC=C1CCNCCS(=O)(=O)CCCOCCC1=CC=CC=C1 DBCKRBGYGMVSTI-UHFFFAOYSA-N 0.000 claims description 4
- MNJNSRQVLNIPFN-UHFFFAOYSA-N 4-[2-[[4-(benzimidazol-1-yl)-2-methylbutan-2-yl]amino]-1-hydroxyethyl]-2-[(4-methoxyphenyl)methylamino]phenol Chemical compound C1=CC(OC)=CC=C1CNC1=CC(C(O)CNC(C)(C)CCN2C3=CC=CC=C3N=C2)=CC=C1O MNJNSRQVLNIPFN-UHFFFAOYSA-N 0.000 claims description 4
- KOTMQCNDGLTIHR-UHFFFAOYSA-N 4-[2-[[4-(benzimidazol-1-yl)-2-methylbutan-2-yl]amino]-1-hydroxyethyl]-3-fluorophenol Chemical compound C1=NC2=CC=CC=C2N1CCC(C)(C)NCC(O)C1=CC=C(O)C=C1F KOTMQCNDGLTIHR-UHFFFAOYSA-N 0.000 claims description 4
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- 238000000034 method Methods 0.000 claims description 4
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- 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 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
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- RTLJQOLVPIGICL-UHFFFAOYSA-N 4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(methylsulfonylmethyl)phenol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CS(C)(=O)=O)=C1 RTLJQOLVPIGICL-UHFFFAOYSA-N 0.000 claims description 2
- LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 claims description 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- VQDBNKDJNJQRDG-UHFFFAOYSA-N Pirbuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=N1 VQDBNKDJNJQRDG-UHFFFAOYSA-N 0.000 claims description 2
- WKHOPHIMYDJVSA-UHFFFAOYSA-N [3-[2-(tert-butylamino)-1-hydroxyethyl]-5-(2-methylpropanoyloxy)phenyl] 2-methylpropanoate Chemical compound CC(C)C(=O)OC1=CC(OC(=O)C(C)C)=CC(C(O)CNC(C)(C)C)=C1 WKHOPHIMYDJVSA-UHFFFAOYSA-N 0.000 claims description 2
- ANZXOIAKUNOVQU-UHFFFAOYSA-N bambuterol Chemical compound CN(C)C(=O)OC1=CC(OC(=O)N(C)C)=CC(C(O)CNC(C)(C)C)=C1 ANZXOIAKUNOVQU-UHFFFAOYSA-N 0.000 claims description 2
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- FZGVEKPRDOIXJY-UHFFFAOYSA-N bitolterol Chemical compound C1=CC(C)=CC=C1C(=O)OC1=CC=C(C(O)CNC(C)(C)C)C=C1OC(=O)C1=CC=C(C)C=C1 FZGVEKPRDOIXJY-UHFFFAOYSA-N 0.000 claims description 2
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- STJMRWALKKWQGH-UHFFFAOYSA-N clenbuterol Chemical compound CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 STJMRWALKKWQGH-UHFFFAOYSA-N 0.000 claims description 2
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- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 230000003434 inspiratory effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 229960005195 morphine hydrochloride Drugs 0.000 description 1
- XELXKCKNPPSFNN-BJWPBXOKSA-N morphine hydrochloride trihydrate Chemical compound O.O.O.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XELXKCKNPPSFNN-BJWPBXOKSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940105631 nembutal Drugs 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229940120904 succinylcholine chloride Drugs 0.000 description 1
- YOEWQQVKRJEPAE-UHFFFAOYSA-L succinylcholine chloride (anhydrous) Chemical compound [Cl-].[Cl-].C[N+](C)(C)CCOC(=O)CCC(=O)OCC[N+](C)(C)C YOEWQQVKRJEPAE-UHFFFAOYSA-L 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
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Classifications
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Description
Predloženi izum odnosi se na nove pripravke lijekova na osnovi spojeva koji djeluju dugotrajno antiholinergički i p-mimetika koji djeluju dugotrajno, na postupak za njihovu proizvodnju i na njihovu upotrebu u terapiji bolesti dišnih puteva.
Iz stanja tehnike je poznato da se β-mimetici kao također i antiholinergici mogu uspješno upotrijebiti za liječenje opstrukcijskih bolesti dišnih puteva kao što je astma. Međutim, tvari koje djeluju β-simpatomimetički kao npr. također iz stanja tehnike poznata tvar formoterol, kad se daju ljudima mogu biti povezane s neželjenim sporednim učincima.
Kao središnji učinci mogu se pojaviti nemir, uzbuđenost, nesanica, strah, drhtanje prstiju, izbijanje znoja i glavobolja. Pri tome aplikacija inhalacijom ne isključuje te sporedne učinke, no oni su doduše općenito nešto slabiji nego kod peroralne ili parenteralne primjene.
Sporedni učinci β-simpatomimetika kod primjene kao sredstava protiv astme temelje se, međutim, prije svega na više ili manje izraženom β1 stimulirajućem učinku na srce. Oni uzrokuju tahikardiju, lupanje srca, tegobe kao kod angine pektoris, te aritmije [P.T. Ammon (Hrsg.), Arzneimittelnebenwirkungen und -wechselwirkungen, Wissen-schaftliche Verlagsgesellschaft, Stuttgart 1986,S. 584].
Opis izuma
Iznenađujuće je pronađeno da se gore spomenuti sporedni učinci mogu značajno smanjiti s kombinacijom β-simpatomimetika dugotrajnog djelovanja s antiholinergikom dugotrajnog djelovanja.
Pri tome, potpuno iznenađujuće se je također moglo naći da se bronhospazmolitičko djelovanje antiholinergika dugotrajnog djelovanja i β-mimetika dugotrajnog djelovanja pojačava iznad učinka dobivenog zbrajanjem.
Kombinacijom aktivnih tvari prema izumu može se stoga očekivati jasno poboljšanu učinkovitost u usporedbi s poznatim tvarima i kombinacijama iz stanja tehnike – kako kod COPD, tako također i kod astme.
Kao β-mimetici dugotrajnog djelovanja u kombinaciji aktivnih tvari prema izumu mogu se prednosno upotrijebiti slijedeće aktivne tvari:
bambuterol, bitolterol, karbuterol, klenbuterol, fenoterol, formoterol, heksoprenalin, ibuterol, pirbuterol, prokaterol, reproterol, salmeterol, sulfonterol, terbutalin, tolubuterol,
4-hidroksi-7-[2-{[2-{[3-(2-feniletoksi)propil]-sulfonil}etil]-amino}etil]-2(3H)-benzotiazolon,
1-(2-fluor-4-hidroksifenil)-2-[4-(1-benzimidazolil)-2-metil-2-butilamino]etanol,
1-[3-(4-metoksibenzil-amino)-4-hidroksifenil]-2-[4-(1-benzimidazolil)-2-metil-2-butilamino]etanol,
1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-[3-(4-N,N-dimetilaminofenil)-2-metil-2-propilamino]etanol,
1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-[3-(4-metoksifenil)-2-metil-2-propilamino]etanol,
1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-[3-(4-n-butiloksifenil)-2-metil-2-propilamino]etanol,
1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-{4-[3-(4-metoksifenil)-1,2,4-triazol-3-il]-2-metil-2-butil-amino}etanol,
5-hidroksi-8-(1-hidroksi-2-izopropilaminobutil)-2H-1,4-benzoksazin-3-(4H)-on,
1-(4-amino-3-klor-5-trifluormetilfenil)-2-terc-butil-amino)etanol i
1-(4-etoksikarbonilamino-3-cijano-5-fluorfenil)-2-(terc-butilamino)etanol,
prema potrebi u obliku njihovih racemata, njihovih enantiomera, njihovih diastereomera i njihovih smjesa, te prema potrebi njihovih farmakološki nedvojbenih kiselinskih adicijskih soli.
Kao β-mimetici dugotrajnog djelovanja u kombinaciji aktivnih tvari prema izumu prednosni su
formoterol, salmeterol,
4-hidroksi-7-[2-{[2-{[3-(2-feniletoksi)propil]-sulfonil}etil]-amino}etil]-2(3H)-benzotiazolon,
1-(2-fluor-4-hidroksifenil)-2-[4-(1-benzimidazolil)-2-metil-2-butilamino]etanol,
1-[3-(4-metoksibenzil-amino)-4-hidroksifenil]-2-[4-(1-benzimidazolil)-2-metil-2-butilamino]etanol,
1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-[3-(4-N,N-dimetilaminofenil)-2-metil-2-propilamino]etanol,
1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-[3-(4-metoksifenil)-2-metil-2-propilamino]etanol,
1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-[3-(4-n-butiloksifenil)-2-metil-2-propilamino]etanol ili
1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-{4-[3-(4-metoksifenil)-1,2,4-triazol-3-il]-2-metil-2-butil-amino}etanol,
prema potrebi u obliku njihovih racemata, njihovih enantiomera, njihovih diastereomera i njihovih smjesa, te prema potrebi njihovih farmakološki nedvojbenih kiselinskih adicijskih soli.
Kako je gore spomenuto, β-mimetici dugotrajnog djelovanja mogu se prevesti i upotrijebiti u obliku njihovih fiziološki i farmakološki podnošljivih soli. Za proizvodnju kiselinskih adicijskih soli u obzir dolaze, na primjer, solna kiselina, bromovodična kiselina, sumporna kiselina, forfosna kiselina, metansulfonska kiselina, octena kiselina, fumarna kiselina, jantarna kiselina, mliječna kiselina, limunska kiselina, vinska kiselina ili maleinska kiselina. Mogu se, nadalje, upotrijebiti i mješavine gore spomenutih kiselina.
Gledajući sa stajališta sinergisičkog bronho-spazmolitičkog djelovanja, kao β-mimetik dugotrajnog djelovanja posebno povoljan je fumarat formoterola (s kraticom formoterol FU). Pri tome se aktivnu tvar formoterol može upotrijebiti kao smjesu enantiomera, odnosno diastereomera ili u obliku pojedinačnih enantiomera/diastereomera. Kao β-mimetik dugotrajnog djelovanja za izum ima jednako značenje i upotreba salmeterola, prema potrebi u obliku njegovog racemata, enantiomera, od kojih se najveću prednost daje (R)-enantiomeru, te prema potrebi njegovih farmakološki nedvojbenih kiselinskih adicijskih soli.
Kao antiholinergici prikaldni su načelno spojevi koji su već poznati iz stanja tehnike, kao glikopironijev bromid, te esteri bi- i tricikličkih aminoalkohola, kao što su oni koji su poznati iz europske publikacije 0 418 716 i međunarodne patentne prijave WO 92/16528, koje se time ovdje uzimaju u obzir cjelokupnim sadržajem.
U okviru izuma kao antiholinergici dugotrajnog djelovanja u obzir dolazi glikopironijev bromid, kao također i esteri bi- i tricikličkih aminoalkohola spojeva formule (I),
[image] (I)
u kojoj
A predstavlja ostatak opće formule (II)
[image] (II)
u kojoj
Q je dvostruko povezana skupina –СН2-СН2-, -СН2-СН2-СН2-, -СН=СН- ili
[image] ;
R je prema potrebi s halogenim ili s hidroksi substituirani C1-C4-alkilni ostatak,
R’ je C1-C4-alkilni ostatak, a R i R’ mogu također zajedno tvoriti C4-C6-alkilni ostatak, i pozitivan naboj atoma N stoji nasuprot ekvivalentu aniona X,
Z je skupina
[image] (III) ili [image] (IV)
u kojoj
Y je jednostruka veza, atom O ili S ili skupina –СН2-, -CH2-CH2-, -CH=CH-, -OCH2- ili –SCH2-;
R1 je vodik, OH, C1-C4-alkoksi ili C1-C4-alkil, koji može biti prema potrebi supstituiran s hidroksi;
R2 je tienil, fenil, furil, ciklopentil ili cikloheksilni ostatak, pri čemu ti radikali mogu također biti supstituirani s metilom, a tienil i fenil mogu također biti supstituirani s fluorom ili klorom;
R3 je vodik ili tienil ili fenilni ostatak, koji može biti prema potrebi supstituiran s halogenim ili sa C1-C4-alkilom,
prema potrebi u obliku njihovih racemata, njihovih enantiomera, njihovih diastereomera i njihovih smjesa.
U okviru izuma kao antiholinergici dugotrajnog djelovanja posebnu prednost daje se glikopironijevom bromidu, kao također i esterima bi- i tricikličkih aminoalkohola spojeva formule (I), u kojoj
A predstavlja ostatak opće formule (II)
[image] (II)
u kojoj
Q je dvostruko povezana skupina –CH=CH-, –СН2-СН2- ili
[image] ;
R je prema potrebi s fluorom ili s hidroksi substituirana metilna, etilna ili propilna skupina,
R’ je metil, etil ili propil, ponajprije metil, i
pozitivan naboj atoma N stoji nasuprot ekvivalentu aniona X koji je odabran iz skupine koju čine klorid, bromid i metansulfonat, ponajprije bromid,
Z je jedna od skupina
[image] (III) ili [image] (IV)
u kojoj
Y je jednostruka veza ili atom O;
R1 je vodik, OH, metoksi, etoksi, propoksi, metil, etil, propil, hidroksimetil, hidroksietil ili hidroksil-propil;
R2 je tienil, fenil ili cikloheksilni ostatak, pri čemu ti radikali mogu također biti supstituirani s metilom, a tienil i fenil mogu također biti supstituirani s fluorom ili klorom;
R3 je vodik ili tienil ili fenilni ostatak, moji može biti prema potrebi supstituiran s fluorom, klorom ili s metilom,
prema potrebi u obliku njihovih racemata, njihovih enantiomera, njihovih diastereomera i njihovih smjesa.
U okviru izuma posebno su značajni pripravci lijekova u kojima se kao antiholinergik dugotrajnog djelovanja upotrebljava spoj formule (I), u kojoj
A predstavlja ostatak opće formule (II)
[image] (II)
u kojoj
Q je dvostruko povezana skupina –CH=CH-, –СН2-СН2- ili
[image] ;
R je metil ili etil;
R’ je metil; i
pozitivan naboj atoma N stoji nasuprot ekvivalentu aniona X = bromid,
Z je jedna od skupina
[image] (III) ili [image] (IV)
u kojoj
Y je atom O;
R1 je vodik, OH ili hidroksimetil;
R2 je tienil, fenil ili cikloheksilni ostatak;
R3 je vodik, tienil ili fenilni ostatak,
prema potrebi u obliku njihovih racemata, njihovih enantiomera, njihovih diastereomera i njihovih smjesa.
Od gore spomenutih spojeva u okviru predloženog izuma posebnu prednost daje se konfiguraciji 3-α.
Opisane antiholinergne aktivne tvari mogu se upotrijebiti prema potrebi također u obliku čistih enantiomera, te njihovih smjesa, odnosno racemata. S posebnom prednošću kao antiholinergik upotrebljava se tiotropijeva sol, naročito tiotropijev bromid [(1α,2β,4β,5α,7β)-7-[(hidroksi-2-tienilacetil)-oksi]-9,9-dimetil-3-oksa-9-azoniatriciklo[3.3.1.02,4]nonan-bromid monohidrat, čija kratica je tiotropij BR].
Kao skupine za alkiliranje (također ukoliko su one i sastavni dijelovi drugih radikala), ako nije definirano drugačije, uzimaju se u obzir razgranate i nerazgranate alkilne skupine koje imaju 1 do 4 ugljikova atoma. Kao primjeri se navode metil, etil, propil ili butil. Ako nije navedeno drugačije, od prethodno navedenih propila i butila ovaj naziv obuhvaća i pojedinačne moguće izomerne oblike. Naziv propil obuhvaća na primjer obadva radikala, n-propil i izo-propil, naziv butil odnosi se također i na n-butil, izo-butil, sek-butil i terc-butil. Prema potrebi za označavanje gore navedenih alkilnih radikala mogu se također upotrijebiti i uobičajene kratice kao Me za metil, Et za etil itd.
Kao alkoksi skupine (također ako su one sastavni dijelovi drugih radikala), ako nije definirano drugačije, u obzir se uzimaju razgranate i nerazgranate alkilne skupine koje imaju 1 do 4 ugljikova atoma i koje su premoštene s atomom kisika. Kao primjeri se navode metoksi, etoksi, propoksi (= propiloksi) ili butoksi (= butiloksi). I ovdje također, ako nije navedeno drugačije, pod prethodno navedenim nazivima propoksi i butoksi podrazumijevaju se također i dotični mogući izomerni oblici.
Kao alkilenske skupine u obzir dolaze razgranati i nerazgranati alkilenski mostovi. Kao primjeri se navode butilen, pentilen, heksilen. Ako nije navedeno drugačije, prethodno navedeni nazivi butilen, pentilen, heksilen obuhvaćaju dotične moguće izomerne oblike. Tako, na primjer, oznaka butilen obuhvaća izomere n-butilen, 1-metilpropilen, 2-metilpropilen, 1,1-dimetiletilen, 1,2-dimetiletilen itd.
Kao halogeni općenito se označavaju fluor, klor, brom ili jod.
Anion X, ako nije navedeno drugačije, općenito je fluor, klor, brom, jod, metansulfonat, fumarat, citrat. Pripravci aktivnih tvari prema izumu daju se ponajprije u obliku odmjernog aerosola – ali, međutim moguć je također i svaki drugi oblik za parenteralnu ili oralnu aplikaciju. Pri tome, primjena odmjernih aerosola se odnosi na prednosne primjenske oblike posebno kod terapije opstrukcijskih plućnih bolesti ili kod liječenja astme.
Osim primjene u odmjernim aerosolima, koji djeluju na osnovi potisnih plinova, kombinacije aktivnih tvari prema izumu mogu se aplicirati pomoću takozvanih atomizera, s kojima se otopinu farmakološki aktivne tvari brizga pod visokim tlakom tako da nastaje maglica čestica koje se mogu inhalirati. Prednost tog atomizera je u tome da se u potpunosti može izbjeći upotrebu potisnih plinova.
Lijek određen za inhalaciju otopi se na uobičajen način u vodenoj ili etanolnoj otopini, pri čemu, ovisno o svojstvima otapanja aktivne tvari, prikladne su također i mješavine otapala koje se sastoje od vode i etanola.
Atomizeri te vrste opisani su, na primjer, u PCT patentnoj prijavi WO 91/14468 i u međunarodnoj patentnoj prijavi sa brojem spisa PCT/EP96/04351, koje se sadržajno ovdje uzimaju u obzir. U tako opisanim atomizerima, koji su poznati pod nazivom Respimat®, otopinu koja sadrži aktivnu tvar definiranog volumena brizga se djelovanjem visokog pritiska kroz malu mlaznicu tako da nastaje aerosol koji se može inahalirati s pretežnom veličinom čestica između 1 i 10, ponajprije između 2 i 5 mikrometara.
Kao otapalo za pripravak lijeka prikladne su između ostalog i mješavine koje kao otapalo sadrže, na primjer, etanol.
Osim vode, daljnji sastojci otapala su prema potrebi daljnja ko-otapala, dok pripravci lijeka također mogu sadržavati tvari za poboljšanje okusa i daljnje farmakološke pomoćne tvari. Primjeri ko-otapala jesu ona otapala koja sadrže hidroksilne skupine ili druge polarne skupine, na primjer alkoholi, posebno izopropilni alkohol, glikoli, posebno propilen glikol, polietilen glikol, polipropilen glikol, glikol eter, glicerol, polioksietilen alkohol i polioksietilenski ester masne kiseline. Ko-otapala su prikladna za povišenje topivosti pomoćnih tvari i prema potrebi aktivnih tvari.
Mogu se dodati i daljnje farmakološke pomoćne tvari kao na primjer konzervanski, posebno benzalkonijev klorid. Povoljne količine konzervansa, posebno benzalkonijevog klorida jesu između 8 i 12 mg/100 ml otopine.
Za izbjegavanje nepravilnosti kod brizganja, u kombinaciju aktivnih tvari mogu se dodati sredstva za tvorbu komplesa. Prikladna sredstva za tvorbu kompleksa su ona koja su farmakološki podnošljiva, posebna ona koja su dozvoljena u skladu sa zakonima o lijekovima. Posebno je prikladna EDTA, nitrilotrioctena kiselina, limunska kiselina i askorbinska kiselina, kao također i njihove soli. Posebnu prednost daje se dinatrijevoj soli etilen-diamtetraoctene kiseline.
Udio otopljene kombinacije aktivnih tvari u gotovom pripravku lijeka je između 0,001 i 5%, ponajprije između 0,005 i 3%, naročito 0,01 do 2%. Maksimalna koncentracija lijeka ovisi o topivosti u otapalu i o potrebnom doziranju za postizanje željenog terapeutskog učinka.
Slijedeći oblici pripravaka navode se kao primjeri formulacija:
[image]
[image]
Osim toga, kombinacije aktivnih tvari prema izumu mogu se također inhalirati u obliku praha. Proizvodnja takovih oblika za aplikaciju je poznata iz stanja tehnike. Osim kombinacije aktivnih tvari prema izumu, oni sadrže i farmakološki nedvojbeni nosač ili pomoćno sredstvo, kao što je npr. mikrokristalinična laktoza. Doza koja je predviđena za inhalaciju može se puniti, na primjer, u kapsule i ima na primjer slijedeći sastav:
[image]
Eksperimentalni nalazi
Bronhospazmolitički i kardiovaskularni učinak tiotropijevog bromida, formoterol fumarata kao i njihove kombinacije nakon inhalacijske aplikacije vodene otopine pomoću Respimata® na narkotiziranim psima.
Materijal i metode
18 pasa mješanaca tjelesne težine od 27 do 32 kg držano je u pojedinačnim, odnosno skupnim kavezima. Psi su dobivali standardnu tabletiranu hranu, s posljednjim obrokom 15 sati prije početka pokusa, i s vodom za piće bez ograničenja.
Nakon prethodne aplikacije lijeka od 2 mg/kg morfin hidroklorida i.m., životinjama je intravenski polako ubrizgano 30 mg/kg pentobarbital natrija (Nembutal®). Životinje su relaksirane s 1,0 mg/kg i.v. suksametonija.
Nakon intubacije pomoću servo ventilatora 900 С (tvrtke Siemens), životinje su udisale sobni zrak i kisik (4:1) učestalošću od 15/minuti i volumenom udisaja od 6-8 l/min. Da bi se snimio mehanizam disanja, protok disanja utvrđen je pomoću usporne tlačne cijevi (Fleisch br. 1), koja je postavljena neposredno ispred orotrahejne cijevi, uređaja za snimanje diferencijalnog tlaka i pojačala diferencijalnog tlaka DCB-4C. Jedan kateter je stavljen u traheju, a drugi (balonski) kateter je stavljen u plućnom dijelu ezofagusa. Obadva katetera su bila povezana s uređajem za snimanje i uređajem za pojačavanje diferencijalnog tlaka za određivanje transpulmonalnog tlaka. Iz zabilježenih vrijednosti tlaka računalo za mehaniku disanja (IFD-Mühlheim) odredilo je pulmonalnu rezistenciju (R). Iz toga je pomoću računalnog programa VAS-1 LA (IFD-Mühlheim) utvrđeno:
maks. transpulmonalni tlak
pulmonalna rezistencija = ————————————————————————————
protok disanja
Srčana frekvencija zabilježena je preko EKG (sonde II priključene na ekstremitete) i pomoću kardiotahometra.
Po isteku perioda ekvilibracije od 30 minuta, proizvedene su kratkotrajne bronhospazme i.v. injekcijom od 10 μg/kg acetilholin klorida, koje su ponovljene 2 - 3 puta u razmacima od pribl. 10 minuta. Ispitne tvari tiotropij bromid, formoterol fumarat kao i kombinacija obaju tvari date su kao vodene otopine s atomizerom BINEB (Respimat®). Kombinacija je aplicirana s pojedinačnim komponentama u razmaku od pribl. 1 minute. Kod sistema BINEB do aktiviranja mehanizma dolazi na kraju faze ekspiracije i raspršenu tekućinu se potiskuje u traheobronhijalno stablo u slijedećem udisaju s pumpom za disanje.
Doziranje
tiotropij bromid: 3 i 10 μg/15 μl,
formoterol fumarat: 3 i 10 μg/15 μl,
tiotropij bromid + formoterol fumarat: 3 + 3 μg, odnosno 10 + 10 μg/15 μl.
U tablicama 1 - 6 prikazane su polazne vrijednosti i vrijednosti nakon liječenja s tvarima tijekom vremena od 180 minuta. Na slikama 1 i 2 prikazani su postoci inhibicije povišenja pulmonalne rezistencije inducirane s ACh tijekom vremena od 180 minuta.
Rezultati
Rezultati su prikazani u tablicama, kao i na slikama. 3 i 10 μg tropij bromida, odnosno formoterol fumarata jasno inhibira povišenu bronhijalnu rezistenciju induciranu s intravenskom injekcijom Ach-a ovisno o doziranju. Za obadva doziranja maksimalni bronhospazmolitički učinak formoterola FU se uspostavlja brzo, dok se s tiotropijem BR on uspostavlja sporije, nakon otprilike 60 minuta. Trajanje učinka formoterola FU je prije svega pri nižim doziranjima srazmjerno kratko, dok se s tropij bromidom, prema očekivanju, on zadržava sve do kraja pokusa (180 minuta).
S kombinacijom od 3 μg tiotropij bromida + 3 μg formoterola FU postiže se izraženu i vrlo brzo uspostavljenu bronhospazmolizu od 90%, koja ostaje gotovo nepromijenjena sve do kraja pokusa. Protektivan učinak kombinacije je značajno veći od učinka pojedinačnih komponenata, a također je veći i od zbroja pojedinačnih učinaka za 3 μg tiotropij bromida i 3 μg formoterola FU. On je veći i od učinka 10 μg tiotropij bromida, odnosno 10 μg formoterol fumarata (usporedi sliku 2)).
Tiotropij bromid sam nema nikakvog utjecaja na srčanu frekvenciju, kako s 3 μg, tako također i s 10 μg. Suprotno tome, formoterol FU, ovisno o dozi, a prije svega kod viših doziranja povisuje ju najviše do iznad 90%. Na kraju pokusa također su izmjerene još vrijednosti iznad 80%. S kombinacijama 3 + 3 μg, ali također i 10 + 10 μg tiotropij bromida i formoterol fumarata učinci na frekvenciju su također bili jasno slabiji i bili su ispod 50%.
Ocjena
S kombinacijom antiholinergika s β-mimetikom postižu se iznenađujući rezultati u usporedbi s pojedinačnim tvarima:
1. brza pojava djelovanja,
2. dugačko vrijeme djelovanja,
3. a prije svega
4. sinergistički bronhospazmolitički učinak i
5. vidljivo manji porast frekvencije, prije svega s višom dozom formoterola.
S kombiniranim pripravkom može se očekivati jasno poboljšanu terapeutsku učinkovitost, kako kod COPD, tako također i kod astme, a koja je povezana s prednošću manjih kardijalnih sporednih učinaka.
Tablice
Tablica 1: Utjecaj 3 μg tiotropij bromida na srčanu frekvenciju narkotiziranih pasa nakon inhalacijske aplikacije pomoću Respimata®, n = 6.
[image]
[image]
Tablica 2: Utjecaj 10 μg tiotropij bromida na srčanu frekvenciju narkotiziranih pasa nakon inhalacijske aplikacije pomoću Respimata®, n = 6.
[image]
[image]
Tablica 3: Utjecaj 3 μg formoterol fumarata na srčanu frekvenciju narkotiziranih pasa nakon inhalacijske aplikacije pomoću Respimata®, n = 6.
[image]
[image]
Tablica 4: Utjecaj 10 μg formoterol fumarata na srčanu frekvenciju narkotiziranih pasa nakon inhalacijske aplikacije pomoću Respimata®, n = 6.
[image]
[image]
Tablica 5: Utjecaj kombinacije od 3 μg tiotropij bromida + 3 μg formoterol fumarata na srčanu frekvenciju narkotiziranih pasa nakon inhalacijske aplikacije pomoću Respimata®, n = 6.
[image]
[image]
Tablica 6: kombinacije od 10 μg tiotropij bromida + 10 μg formoterol fumarata na srčanu frekvenciju narkotiziranih pasa nakon inhalacijske aplikacije pomoću Respimata®, n = 6.
[image]
[image]
Slike
Slika 1 prikazuje utjecaj 3 μg formoterol fumarata, 3 μg tiotropij bromida kao i kombinacije od 3 μg tiotropij bromida + 3 μg formoterol fumarata na bronhijalnu rezistenciju narkotiziranih pasa, n = 6.
Slika 2 prikazuje utjecaj 3 μg formoterol fumarata, 10 μg tiotropij bromida kao i kombinacije od 10 μg tiotropij bromida + 3 μg formoterol fumarata na bronhijalnu rezistenciju narkotiziranih pasa, n = 6.
Claims (15)
1. Farmaceutski pripravak, naznačen time, da sadrži antiholinergik dugotrajnog djelovanja i β-mimetik dugotrajnog djelovanja.
2. Farmaceutski pripravak prema zahtjevu 1, naznačen time, da sadrži antiholinergik dugotrajnog djelovanja odabran između glikopironijevog bromida ili estera bi- i tricikličkih aminoalkohola formule (I)
[image]
(I)
u kojoj
A predstavlja ostatak opće formule (II)
[image]
(II)
u kojoj
Q je dvostruko povezana skupina –СН2-СН2-, -СН2-СН2-СН2-, -СН=СН- ili
[image]
;
R je prema potrebi s halogenim ili s hidroksi substituirani C1-C4-alkilni ostatak,
R’ je C1-C4-alkilni ostatak, a R i R’ mogu zajedno također tvoriti C4-C6-alkilni ostatak, i
pozitivan naboj atoma N stoji nasuprot ekvivalentu aniona X,
Z je skupina
[image]
(III) ili
[image]
(IV)
u kojoj
Y je jednostruka veza, atom O ili S ili skupina –СН2-, -CH2-CH2-, -CH=CH-, -OCH2- ili –SCH2-;
R1 je vodik, OH, C1-C4-alkoksi ili C1-C4-alkil, koji može biti prema potrebi supstituiran s hidroksi;
R2 je tienil, fenil, furil, ciklopentil ili cikloheksilni ostatak, pri čemu ti radikali mogu također biti supstituirani s metilom, a tienil i fenil mogu također biti supstituirani s fluorom ili klorom;
R3 je vodik ili tienil ili fenilni ostatak, koji može biti prema potrebi supstituiran s halogenim ili sa C1-C4-alkilom,
prema potrebi u obliku njihovih racemata, njihovih enantiomera, njihovih diastereomera i njihovih smjesa.
3. Farmaceutski pripravak prema bilo kojem zahtjevu 1 ili 2, naznačen time, da sadrži antiholinergik dugotrajnog djelovanja odabran između glikopironijevog bromida ili estera bi- i tricikličkih aminoalkohola formule (I) u kojoj
A predstavlja ostatak opće formule (II)
[image]
(II)
u kojoj
Q je dvostruko povezana skupina –CH=CH-, –СН2-СН2- ili
[image]
;
R je prema potrebi s fluorom ili s hidroksi substituirana metilna, etilna ili propilna skupina,
R’ je metil, etil ili propil, ponajprije metil, i
pozitivan naboj atoma N stoji nasuprot ekvivalentu aniona X odabranog iz skupine koju čine klorid, bromid metansulfonat, ponajprije bromid,
Z je jedna od skupina
[image]
(III) ili
[image]
(IV)
u kojoj
Y je jednostruka veza ili atom O;
R1 je vodik, OH, metoksi, etoksi, propoksi, metil, etil, propil, hidroksimetil, hidroksietil ili hidroksi-propil;
R2 je tienil, fenil ili cikloheksilni ostatak, pri čemu ti radikali mogu također biti supstituirani s metilom, a tienil i fenil mogu također biti supstituirani s fluorom ili klorom;
R3 je vodik ili tienil ili fenilni ostatak, moji može biti prema potrebi supstituiran s fluorom, klorom ili s metilom,
prema potrebi u obliku njihovih racemata, njihovih enantiomera, njihovih diastereomera i njihovih smjesa.
4. Farmaceutski pripravak prema bilo kojem zahtjevu 1, 2 ili 3, naznačen time, da sadrži antiholinergik dugotrajnog djelovanja odabran između estera bi- i tricikličkih aminoalkohola formule (I) u kojoj
A predstavlja ostatak opće formule (II)
[image]
(II)
u kojoj
Q je dvostruko povezana skupina –CH=CH-, –СН2-СН2- ili
[image]
;
R je metil ili etil;
R’ je metil; i
pozitivan naboj atoma N stoji nasuprot ekvivalentu aniona X = bromid,
Z je jedna od skupina
[image]
(III) ili
[image]
(IV)
u kojoj
Y je atom O;
R1 je vodik, OH ili hidroksimetil;
R2 je tienil, fenil ili cikloheksilni ostatak;
R3 je vodik, tienil ili fenilni ostatak,
prema potrebi u obliku njihovih racemata, njihovih enantiomera, njihovih diastereomera i njihovih smjesa.
5. Farmaceutski pripravak prema bilo kojem zahtjevu 1, 2, 3 ili 4, naznačen time, da je antiholinergik dugotrajnog djelovanja odabran između soli tiotropija.
6. Farmaceutski pripravak prema bilo kojem zahtjevu 1, 2, 3 ili 5, naznačen time, da je antiholinergik dugotrajnog djelovanja tiotropij bromid.
7. Farmaceutski pripravak prema bilo kojem zahtjevu 1 do 6, naznačen time, da je β-mimetik dugotrajnog djelovanja odabran iz skupine koju čine bambuterol, bitolterol, karbuterol, klenbuterol, fenoterol, formoterol, heksoprenalin, ibuterol, pirbuterol, prokaterol, reproterol, salmeterol, sulfonterol, terbutalin, tolubuterol,
4-hidroksi-7-[2-{[2-{[3-(2-feniletoksi)propil]-sulfonil}etil]-amino}etil]-2(3H)-benzotiazolon,
1-(2-fluor-4-hidroksifenil)-2-[4-(1-benzimidazolil)-2-metil-2-butilamino]etanol,
1-[3-(4-metoksibenzil-amino)-4-hidroksifenil]-2-[4-(1-benzimidazolil)-2-metil-2-butilamino]etanol,
1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-[3-(4-N,N-dimetilaminofenil)-2-metil-2-propilamino]etanol,
1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-[3-(4-metoksifenil)-2-metil-2-propilamino]etanol,
1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-[3-(4-n-butiloksifenil)-2-metil-2-propilamino]etanol,
1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-{4-[3-(4-metoksifenil)-1,2,4-triazol-3-il]-2-metil-2-butil-amino}etanol,
5-hidroksi-8-(1-hidroksi-2-izopropilaminobutil)-2H-1,4-benzoksazin-3-(4H)-on,
1-(4-amino-3-klor-5-trifluormetilfenil)-2-terc-butil-amino)etanol i
1-(4-etoksikarbonilamino-3-cijano-5-fluorfenil)-2-(terc-butilamino)etanol,
prema potrebi u obliku njihovih racemata, njihovih enantiomera, njihovih diastereomera i njihovih smjesa, te prema potrebi njihovih farmakološki nedvojbenih kiselinskih adicijskih soli.
8. Farmaceutski pripravak prema bilo kojem zahtjevu 1 do 7, naznačen time, da je β-mimetik dugotrajnog djelovanja odabran iz skupine koju čine formoterol, salmeterol,
4-hidroksi-7-[2-{[2-{[3-(2-feniletoksi)propil]-sulfonil}etil]-amino}etil]-2(3H)-benzotiazolon,
1-(2-fluor-4-hidroksifenil)-2-[4-(1-benzimidazolil)-2-metil-2-butilamino]etanol,
1-[3-(4-metoksibenzil-amino)-4-hidroksifenil]-2-[4-(1-benzimidazolil)-2-metil-2-butilamino]etanol,
1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-[3-(4-N,N-dimetilaminofenil)-2-metil-2-propilamino]etanol,
1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-[3-(4-metoksifenil)-2-metil-2-propilamino]etanol,
1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-[3-(4-n-butiloksifenil)-2-metil-2-propilamino]etanol i
1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-{4-[3-(4-metoksifenil)-1,2,4-triazol-3-il]-2-metil-2-butil-amino}etanol,
prema potrebi u obliku njihovih racemata, njihovih enantiomera, njihovih diastereomera i njihovih smjesa, te prema potrebi njihovih farmakološki nedvojbenih kiselinskih adicijskih soli.
9. Farmaceutski pripravak prema bilo kojem zahtjevu 1 do 8, naznačen time, da je β-mimetik dugotrajnog djelovanja odabran iz skupine koju čine formoterol i salmeterol prema potrebi u obliku njihovih racemata, njihovih enantiomera, njihovih diastereomera i njihovih smjesa, te prema potrebi njihovih farmakološki nedvojbenih kiselinskih adicijskih soli.
10. Farmaceutski pripravak prema bilo kojem zahtjevu 1 do 9, naznačen time, da je antiholinergik dugotrajnog djelovanja tiotropij bromid, a β-mimetik dugotrajnog djelovanja je formoterol fumarat.
11. Farmaceutski pripravak prema bilo kojem zahtjevu 1 do 9, naznačen time, da je antiholinergik dugotrajnog djelovanja tiotropij bromid, a β-mimetik dugotrajnog djelovanja je salmeterol.
12. Farmaceutski pripravak prema bilo kojem zahtjevu 1 do 11, naznačen time, da je to farmaceutski pripravak koji se može aplicirati inhalacijom.
13. Postupak za proizvodnju farmaceutskog pripravka prema bilo kojem zahtjevu 1 do 12, naznačen time, da se antiholinergik dugotrajnog djelovanja i β-mimetik dugotrajnog djelovanja i prema potrebi daljnje pomoćne tvari i/ili nosači pomiješaju i konfekcioniraju poznatim metodama.
14. Upotreba pripravka prema bilo kojem zahtjevu 1 do 13, naznačena time, da se on koristi za proizvodnju lijeka za liječenje bolesti dišnih puteva.
15. Upotreba prema zahtjevu 14, naznačena time, da se on koristi za proizvodnju lijeka za liječenje astme ili COPD.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19921693A DE19921693A1 (de) | 1999-05-12 | 1999-05-12 | Neuartige Arzneimittelkompositionen auf der Basis von anticholinergisch wirksamen Verbindungen und ß-Mimetika |
| PCT/EP2000/003943 WO2000069468A1 (de) | 1999-05-12 | 2000-05-03 | NEUARTIGE ARZNEIMITTELKOMPOSITIONEN AUF DER BASIS VON ANTICHOLINERGISCH WIRKSAMEN VERBINDUNGEN UND β-MIMETIKA |
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| HRP20010828A2 true HRP20010828A2 (en) | 2003-02-28 |
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| HR20010828A HRP20010828A2 (en) | 1999-05-12 | 2001-11-08 | Novel medicament compositions, based on anticholinergically effective compounds and beta-mimetics |
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