NO317561B1 - Ipratropiumbromid-enantiomer med forlenget virkningstid - Google Patents
Ipratropiumbromid-enantiomer med forlenget virkningstid Download PDFInfo
- Publication number
- NO317561B1 NO317561B1 NO19980424A NO980424A NO317561B1 NO 317561 B1 NO317561 B1 NO 317561B1 NO 19980424 A NO19980424 A NO 19980424A NO 980424 A NO980424 A NO 980424A NO 317561 B1 NO317561 B1 NO 317561B1
- Authority
- NO
- Norway
- Prior art keywords
- hydroxy
- methyl
- ethanol
- azoniabicyclo
- phenylpropoxy
- Prior art date
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- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical class O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 title description 4
- 230000002035 prolonged effect Effects 0.000 title 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000013543 active substance Substances 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical class CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 3
- 239000000043 antiallergic agent Substances 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 150000003431 steroids Chemical class 0.000 claims description 3
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 claims description 2
- YREYLAVBNPACJM-UHFFFAOYSA-N 2-(tert-butylamino)-1-(2-chlorophenyl)ethanol Chemical compound CC(C)(C)NCC(O)C1=CC=CC=C1Cl YREYLAVBNPACJM-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
- 208000009079 Bronchial Spasm Diseases 0.000 claims description 2
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims description 2
- BQTXJHAJMDGOFI-NJLPOHDGSA-N Dexamethasone 21-(4-Pyridinecarboxylate) Chemical compound O=C([C@]1(O)[C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)COC(=O)C1=CC=NC=C1 BQTXJHAJMDGOFI-NJLPOHDGSA-N 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
- 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 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
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims description 2
- 229960003060 bambuterol Drugs 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
- 229960004620 bitolterol Drugs 0.000 claims description 2
- 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
- 206010006451 bronchitis Diseases 0.000 claims description 2
- 229960004436 budesonide Drugs 0.000 claims description 2
- 229960001386 carbuterol Drugs 0.000 claims description 2
- KEMXXQOFIRIICG-UHFFFAOYSA-N carbuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(NC(N)=O)=C1 KEMXXQOFIRIICG-UHFFFAOYSA-N 0.000 claims description 2
- 230000001684 chronic effect Effects 0.000 claims description 2
- 229960001117 clenbuterol Drugs 0.000 claims description 2
- 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
- 229960000265 cromoglicic acid Drugs 0.000 claims description 2
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 claims description 2
- FIFVQZLUEWHMSV-UHFFFAOYSA-N ethyl n-[4-[2-(tert-butylamino)-1-hydroxyethyl]-2-cyano-6-fluorophenyl]carbamate Chemical compound CCOC(=O)NC1=C(F)C=C(C(O)CNC(C)(C)C)C=C1C#N FIFVQZLUEWHMSV-UHFFFAOYSA-N 0.000 claims description 2
- 229960001022 fenoterol Drugs 0.000 claims description 2
- 229960002848 formoterol Drugs 0.000 claims description 2
- 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 2
- 229960000708 hexoprenaline Drugs 0.000 claims description 2
- OXLZNBCNGJWPRV-UHFFFAOYSA-N hexoprenaline Chemical compound C=1C=C(O)C(O)=CC=1C(O)CNCCCCCCNCC(O)C1=CC=C(O)C(O)=C1 OXLZNBCNGJWPRV-UHFFFAOYSA-N 0.000 claims description 2
- 229950002451 ibuterol Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229960004398 nedocromil Drugs 0.000 claims description 2
- RQTOOFIXOKYGAN-UHFFFAOYSA-N nedocromil Chemical compound CCN1C(C(O)=O)=CC(=O)C2=C1C(CCC)=C1OC(C(O)=O)=CC(=O)C1=C2 RQTOOFIXOKYGAN-UHFFFAOYSA-N 0.000 claims description 2
- 229960005414 pirbuterol Drugs 0.000 claims description 2
- 229960002288 procaterol Drugs 0.000 claims description 2
- 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 claims description 2
- 229960002720 reproterol Drugs 0.000 claims description 2
- 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 claims description 2
- 229960002052 salbutamol Drugs 0.000 claims description 2
- 229960004017 salmeterol Drugs 0.000 claims description 2
- 229960000195 terbutaline Drugs 0.000 claims description 2
- 238000011282 treatment Methods 0.000 claims description 2
- 229960000859 tulobuterol Drugs 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 2
- 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 1
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 claims 1
- 229940092705 beclomethasone Drugs 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 229960000676 flunisolide Drugs 0.000 claims 1
- 238000011866 long-term treatment Methods 0.000 claims 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 claims 1
- 210000002345 respiratory system Anatomy 0.000 claims 1
- -1 sulfoneterol Chemical compound 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 description 6
- 239000000443 aerosol Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229960001361 ipratropium bromide Drugs 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000003380 propellant Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 230000001078 anti-cholinergic effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- IVWWFWFVSWOTLP-YVZVNANGSA-N (3'as,4r,7'as)-2,2,2',2'-tetramethylspiro[1,3-dioxolane-4,6'-4,7a-dihydro-3ah-[1,3]dioxolo[4,5-c]pyran]-7'-one Chemical compound C([C@@H]1OC(O[C@@H]1C1=O)(C)C)O[C@]21COC(C)(C)O2 IVWWFWFVSWOTLP-YVZVNANGSA-N 0.000 description 1
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960004495 beclometasone Drugs 0.000 description 1
- 230000000572 bronchospasmolytic effect Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 229960003449 epinastine Drugs 0.000 description 1
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000002644 respiratory therapy Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229950007862 sulfonterol Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pulmonology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Oppfinnelsen vedrører (endo, syn)-(-)-3-(3-hydroksy-1-okso-2-fenylpropoksy)-8-metyl-8-(1-metyletyl)-8-azoniabicyklo[3.2.1.]oktan-bromid, anvendelse av (endo, syn)-(-)-3-(3-hydroksy-1-okso-2-fenylpropoksy)-8-metyl-8-(1-metyletyl)-8-azoniabicyklo[3.2.1.]oktan-salter, og inhalerbare farmasøytiske preparater inneholdende disse. Slike salter er bronkospasmolytika med sterk og særlig lenge vedvarende virkning og kan anvendes ved fremstillingen av astmamidler.
Racematet av den ovenfor nevnte forbindelse (som bromid) er i handel under betegnelsen Ipratropiumbromid som virkestoff i anticholinerge legemidler.
Som det nå overraskende ble funnet, er virkningsforholdet av racemat, venstredreiende og høyredreiende enantiomere tydelig forskjellige og viser betydelige særegenheter som avviker fra det normale. Eutomeren (d.v.s. den enantiomere med den ønskete hhv. tilstrebede aktivitet) er L-(-)-enantiomeren. Med reseptorbindingsstudier på CHO-HM reseptoren kunne det måles at L-(-)-enantiomeren sammenliknet med racematet har en rundt dobbelt så høy affinitet. Dette forhold tilsvarer observasjoner som ofte blir gjort ved sammenlikning av virkninger av enantiomere og racemater.
Overraskende er det i foreliggende tilfelle likevel at ved inhalasjonsanvendelse på
(narkotisert) hund ved sammenlikning av eutomeren med racematet i vektsforhold 1 : 2 observeres ikke bare en høyere virkningsstyrke, men også en betydelig forlenget virkningsvarighet.
Det i Figur 1 viste bilde angir den prosentvise hemning av bronkospasmer i avhengighet av tiden. Derunder angir den brutte linje (kurve B) forløpet for (endo, syn)-(-)-3-(3-hydroksy-1-okso-2-fenylpropoksy)-8-metyl-8-(1-metyletyl)-8-azoniabicyklo[3.2.1]oktan og den trukne linje (Kurve A) forløpet for det tilsvarende racemat, hvorunder hydrobromidene ble anvendt. Det ble administrert 5 fig av den rene L-(-)-enantiomeren og - tilsvarende -10 jag av racematet. Eksperimentet ble utført på fem forsøksdyr med den rene L-enantiomeren (BIIH 150 BR), mens racematet ble gitt til syv forsøksdyr.
Det fremgår av Figur 1 at hemningen av den med acetylcholin induserte bronchospase hos hund ved administrering av Ipratropiumbromid-aerosolen (Kurve A) har nådd maksimum etter ca. 10 minutter på ca. 55 % og etter 60 minutter allerede har nådd utgangsnivået igjen. Den samme mengde av eutomer (Kurve B), som racematet innholder, når etter ca. 10 minutter en 60-prosentig hemning, som først etter 180 minutter har nådd utgangsnivået igjen.
Ved hjelp av den målte halveringstiden blir det for eutomeren BlIH 150 BR fastslått en ca. fire ganger lengere virkningsvarighet.
For fremstilling av eutomeren utvinnes eutomeren ut fra racematet ved kombinert anvendelse av høytrykkvæskekromatografi og omkrystallisering i hovedsakelig ren form. Som "eutomer" i betydningen i foreliggende oppfinnelse betegnes også sterkt anrikete produkter (over ca. 90%), fortrinnsvis med over 95, særlig over 97% av L-(-)-enantiomeren. Anionet tilsvarer det i utgangsforbindelsen. Om ønsket kan også en utskifting foretas.
Gjennom det følgende eksempel skal fremstillingen av!_-(-)- og D-(+)-enantiomerene anskueliggjøres nærmere: 18 Gramm Ipratropiumbromid blir separert ved hjelp av høytrykksvæskekromatografi over en Chiralcel OD-kolonne (250x20 mm) med en mobil fase med sammensetningen 600 heksan, 250 metanol, 150 etanol og 1 mettet alkoholisk NaBr-løsning (V:V:V:V:, Gjennomløpshastighet 6 ml/min, bølgelengde 254 nm; ømfintlighet 0,5 A.U.F.S.; innsprøytningsløsning 1 g lpratropiumbromid/5 ml etanol + 5 ml mob. fase + 2,5 ml kons. eddiksyre).
Ved gjentatt kromatografering og omkrystallisering fra etanol oppnås L-(-)-enantiomeren, hvite krystaller, sm.p. 239-40°C (spaltn.), spes. dreining [ afi$ = -24,06° (c = 1,014; H2O), enantiomer renhet 97,4 % (HPLC) og D-(+)-enantiomeren, hvite krystaller, sm.p. 238-39°C (spaltn.), spesif. dreining [a]^° = +24,26° (c = 1,018; H2O), enantiomer renhet 98,9 % (HPLC). Elementanalyse og spektre viser at disse forbindelser foreligger. L-(-)-Eutomeren i form av de forskjellige salter egner seg, som følge av sin natur som anticholinergikum, f.eks. for behandling av kronisk obstruktiv bronkitt og astma gjennom inhalasjonsanvendelse, hvorunder bivirkningene i stor grad uteblir.
For applikasjon blir virkestoffet formulert med kjente hjelpestoffer og/eller bærere til vanlige galeniske preparater, f.eks. til inhalasjonsløsninger, suspensjoner i kondenserte drivgasser, liposom- hhv. proliposomholdige preparater, inhalasjonspulvere (eventuelt i kapsler) for anvendelse i vanlige inhalasjonsapparater.
Formuleringseksempler (Angitt i vektsprosent):
1. Doseringsaerosol
Suspensjonen blir fylt i en vanlig aerosolbeholder med doseringsventil. Pr. gang blir eksempelvis 50 fal suspensjon avgitt. Virkestoffet kan om ønsket også doseres høyere (f.eks. 0,02
vekt-%).
I stedet for de klorholdige drivgasser kan også alternative drivgasser som TG 134a (1,1,1,2-tetrafluoretan) og/eller TG 227 (1,1,1,2,3,3,3-Heptafluorpropan) anvendes.
2. Inhalasjonspulver
Mikronisert virkestoffpulver (partikkelstørrelse 0,5 til 7 jim) blir blandet med mikronisert laktose og eventuelt fylt med ytterligere tilsetninger i hårdgelatinkapsler. I hver kapsel fylles eksempelsvis 0,01 mg virkestoff og 5 mg laktose. Pulveret kan inhaleres fra vanlige inhalasjonsapparater, f.eks. ifølge DE-A 3345772.
3. Inhalasjonsløsninger
Vandige løsninger av virkestoffet kan likeledes anvendes, hvorunder det for å danne aerosolen eksempelsvis kan benyttes et apparat ifølge W091/14468. Pr. sprøyteoperasjon appliseres blir f.eks. 0,005 mg virkestoff.
Det ifølge oppfinnelsen anvendbare virkestoff kan med fordel også anvendes i kombinasjon med andre virkestoffer for luftveisterapi. Det må særlig nevnes p2-mimetika, som anvendes i kombinasjoner med 50 -100% av dosen ved engangs anvendelse.
Det nevnes:
Bambuterol
Bitolterol
Carbuterol
Clenbuterol
Fenoterol
Formoterol
Heksoprenalin
Ibuterol
Pirbuterol
Procaterol
Reproterol
Salbutamol
Salmeterol
Sulfonterol
Terbutalin
Tulobuterol
1 -(2-fluor-4-hydroksyfenyl)-2-[4-(1 -benzimidazoly l)-2-metyl-2-butylamino]etanol
erythro-5'-hydroksy-8'-{1 -hydroksy-2-isopropylaminobutyl)-2H-1,4-benzoksazin-3-(4H)-on
1-(4-aminc-3-klor-5-trifluormetyrfenyl)-2-tert.-butylamino)etan 1-(4-etoksykarbonylamino-3-cyan-5-fluorfenyl)-2-(tert.-butylamino)etanol.
Som ytterligere kombinasjonspartnere er inhalerbare steroider som Budesonid, Beclometason (hhv. 17,21-dipropionatet), Dexametason-21-isonicotinat, Flunisolid og antiallergika som dinatriumkromoglikat, Nedokromil, Epinastine egnet. Også ved disse kombinasjonspartnere kan like eller mindre doser enn ved anvendelse av dem alene administreres.
Claims (6)
1. Inhalerbare farmasøytiske preparater med en forlenget aktivitetstid, karakterisert ved at de inneholder (endo, syn)-(-)-3-(3-hydroksy-1 - okso-2-fenylpropoksy)-8-metyl-8-(1-metyletyl)-8-azoniabicyklo[3.2.1.]oktan-salter som inneholder bromid, klorid eller acetat som anioner, med en enantiomer renhet på 90 til 100, eventuelt sammen med vanlige eksipienter og/eller bærere og/eller andre aktive substanser.
2. Anvendelse av (endo, syn)-(-)-3-(3-hydroksy-1-okso-2-fenylpropoksy)-8-metyl-8-(1-metyletyl)-8-azoniabicyklo[3.2.1.]oktan-salter som inneholder bromid, klorid eller acetat som anioner, med en enantiomer renhet på 90 till 00%, eventuelt sammen med vanlige eksipienter og/eller bærere og/eller andre aktive substanser for fremstilling av et farmasøytisk preparat for inhalering, for behandling av sykdommer i luftveiene med en forlenget aktivitetstid.
3. Anvendelse ifølge krav 2 for langvarig behandling av kronisk obstruktiv bronkitt, bronkospasmer eller astma.
4. Anvendelse ifølge krav 2 eller 3, hvori B2-mimetika, steroider eller antiallergiske midler foreligger som ytterligere aktive substanser.
5. Anvendelse ifølge krav 4, hvori de anvendte B2-mimetika er bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol
heksoprenalin, ibuterol, pirbuterol, procaterol, reproterol, salbutamol, salmeterol, sulfonterol, terbutalin, tulobuterol, 1-(2-fluor-4-hydroksyfenyl)-2-[4-(1-benzimidazolyl)-2-metyl-2-butylamino]-etanol, erythro-5'-hydroksy-8'-(1-hydroksy-2-isopropylaminobutyl)-2H-1,4-benzoksazin-3-(4H)-on, 1-(4-amino-3-klor-5-trifluormetylfenyl)-2-tert.-butylamino)etanol, 1-(4-etoksykarbonylamino-3-cyan-5-fluorfenyl)-2-(tert.-butylamino)etanol;
steroidet som anvendes er budesonid, beclometason (eller 17,21-dipropionatet), dexametason-21 -isonicotinat eller flunisolid;
og det antiallergiske middel som anvendes er dinatriumkromoglykat, nedokromil eller epinastin.
6. (Endo, syn)-(-)-3-(3-hydroksy-1 -okso-2-fenylpropoksy)-8-metyl-8-(1 - metyletyl)-8-azoniabicyklo[3.2.1 .Joktan-bromid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19528145A DE19528145A1 (de) | 1995-08-01 | 1995-08-01 | Neue Arzneimittel und ihre Verwendung |
| PCT/EP1996/003364 WO1997005136A1 (de) | 1995-08-01 | 1996-07-31 | Ein enantiomer von ipratropiumbromid mit verlängerter wirkungsdauer |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO980424L NO980424L (no) | 1998-01-30 |
| NO980424D0 NO980424D0 (no) | 1998-01-30 |
| NO317561B1 true NO317561B1 (no) | 2004-11-15 |
Family
ID=7768353
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO19980424A NO317561B1 (no) | 1995-08-01 | 1998-01-30 | Ipratropiumbromid-enantiomer med forlenget virkningstid |
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| NZ (1) | NZ315645A (no) |
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| PT (1) | PT843676E (no) |
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| UA (1) | UA55391C2 (no) |
| WO (1) | WO1997005136A1 (no) |
| YU (1) | YU49479B (no) |
| ZA (1) | ZA966494B (no) |
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| US20100197719A1 (en) * | 1999-05-12 | 2010-08-05 | Boehringer Ingelheim Pharma Kg | Medicament compositions containing anticholinergically-effective compounds and betamimetics |
| ES2165768B1 (es) | 1999-07-14 | 2003-04-01 | Almirall Prodesfarma Sa | Nuevos derivados de quinuclidina y composiciones farmaceuticas que los contienen. |
| US6777400B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6787532B2 (en) | 2000-08-05 | 2004-09-07 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivatives |
| GB0019172D0 (en) | 2000-08-05 | 2000-09-27 | Glaxo Group Ltd | Novel compounds |
| US6759398B2 (en) | 2000-08-05 | 2004-07-06 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative |
| US6858593B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6777399B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6858596B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivative |
| US6750210B2 (en) | 2000-08-05 | 2004-06-15 | Smithkline Beecham Corporation | Formulation containing novel anti-inflammatory androstane derivative |
| US20020151541A1 (en) * | 2000-10-31 | 2002-10-17 | Michel Pairet | Pharmaceutical compositions containing tiotropium salts and antihistamines and their use |
| US7776315B2 (en) * | 2000-10-31 | 2010-08-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and additional active ingredients |
| US20100310477A1 (en) * | 2000-11-28 | 2010-12-09 | Boehringer Ingelheim Pharma Gmbh & Co. Kg. | Pharmaceutical compositions based on anticholingerics and additional active ingredients |
| UA77656C2 (en) | 2001-04-07 | 2007-01-15 | Glaxo Group Ltd | S-fluoromethyl ester of 6-alpha, 9-alpha-difluoro-17-alpha-[(2-furanylcarbonyl)oxy]-11-beta-hydroxy-16- alpha-methyl-3-oxoandrosta-1,4-dien-17-beta-carbothioacid as anti-inflammatory agent |
| US6455028B1 (en) * | 2001-04-23 | 2002-09-24 | Pharmascience | Ipratropium formulation for pulmonary inhalation |
| US20050070487A1 (en) * | 2001-04-24 | 2005-03-31 | Nyce Jonathan W. | Composition, formulations and kit for treatment of respiratory and lung disease with non-glucocorticoid steroids and/or ubiquinone and a bronchodilating agent |
| US20030018019A1 (en) * | 2001-06-23 | 2003-01-23 | Boehringer Ingelheim Pharma Kg | Pharmaceutical compositions based on anticholinergics, corticosteroids and betamimetics |
| US6702997B2 (en) | 2001-10-26 | 2004-03-09 | Dey, L.P. | Albuterol inhalation solution, system, kit and method for relieving symptoms of pediatric asthma |
| US20030203930A1 (en) * | 2001-10-26 | 2003-10-30 | Imtiaz Chaudry | Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease |
| US20030140920A1 (en) * | 2001-10-26 | 2003-07-31 | Dey L.P. | Albuterol inhalation soultion, system, kit and method for relieving symptoms of pediatric asthma |
| JP2003221335A (ja) | 2001-10-26 | 2003-08-05 | Dey Lp | 慢性閉塞性肺疾患の症状を緩和するためのアルブテロールおよびイプラトロピウム吸入溶液、システム、キットおよび方法 |
| US20030191151A1 (en) * | 2001-10-26 | 2003-10-09 | Imtiaz Chaudry | Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease |
| GB0202635D0 (en) * | 2002-02-05 | 2002-03-20 | Glaxo Wellcome Mfg Pte Ltd | Formulation containing novel anti-inflammatory androstane derivative |
| GB2389530B (en) | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
| US20050043343A1 (en) * | 2003-07-28 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a PDE IV inhibitor |
| US20050026948A1 (en) * | 2003-07-29 | 2005-02-03 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a betamimetic |
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| US20050101545A1 (en) * | 2003-07-31 | 2005-05-12 | Robinson Cynthia B. | Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with an anticholinergic bronchodilator for treatment of asthma or chronic obstructive pulmonary disease |
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| ES2257152B1 (es) * | 2004-05-31 | 2007-07-01 | Laboratorios Almirall S.A. | Combinaciones que comprenden agentes antimuscarinicos y agonistas beta-adrenergicos. |
| PE20060826A1 (es) * | 2004-12-06 | 2006-10-08 | Smithkline Beecham Corp | Derivado oleofinico de 8-azoniabiciclo[3.2.1]octano y combinacion farmaceutica que lo comprende |
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| US20060239935A1 (en) * | 2005-04-23 | 2006-10-26 | Boehringer Ingelheim International Gmbh | Compositions for inhalation |
| EP2100598A1 (en) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
| EP2100599A1 (en) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
| EP2510928A1 (en) | 2011-04-15 | 2012-10-17 | Almirall, S.A. | Aclidinium for use in improving the quality of sleep in respiratory patients |
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| CN110361494B (zh) * | 2019-06-26 | 2023-08-15 | 四川普锐特药业有限公司 | 异丙托溴铵气雾剂中杂质g的检测方法 |
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| US3505337A (en) * | 1967-12-22 | 1970-04-07 | Boehringer Sohn Ingelheim | N - hydrocarbyl-substituted noratropinium,haloalkylates and o-acyl derivatives thereof |
| DE2903957A1 (de) * | 1979-02-02 | 1980-08-07 | Boehringer Sohn Ingelheim | Mittel zur behandlung der nasalen hypersekretion |
| US5225183A (en) * | 1988-12-06 | 1993-07-06 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
| DE4140861C2 (de) * | 1991-12-11 | 2003-12-11 | Boehringer Ingelheim Kg | Verfahren zur Gewinnung von quartären Tropasäurealkaloiden |
| WO1994013263A1 (en) * | 1992-12-09 | 1994-06-23 | Jager Paul D | Stabilized medicinal aerosol solution formulations |
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