ME00521B - Derivati imidazola sa afinitetom prema aktivnosti alfa 2 receptora - Google Patents
Derivati imidazola sa afinitetom prema aktivnosti alfa 2 receptoraInfo
- Publication number
- ME00521B ME00521B MEP-2008-864A MEP86408A ME00521B ME 00521 B ME00521 B ME 00521B ME P86408 A MEP86408 A ME P86408A ME 00521 B ME00521 B ME 00521B
- Authority
- ME
- Montenegro
- Prior art keywords
- compound
- imidazol
- ylmethyl
- pharmaceutically acceptable
- ium chloride
- Prior art date
Links
- 230000000694 effects Effects 0.000 title description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title 1
- 102000005962 receptors Human genes 0.000 title 1
- 108020003175 receptors Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 150000004677 hydrates Chemical class 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims description 17
- 229940079593 drug Drugs 0.000 claims description 14
- 208000019901 Anxiety disease Diseases 0.000 claims description 8
- 230000036506 anxiety Effects 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 206010012335 Dependence Diseases 0.000 claims description 5
- 206010012735 Diarrhoea Diseases 0.000 claims description 5
- 208000010412 Glaucoma Diseases 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 5
- 208000001953 Hypotension Diseases 0.000 claims description 5
- 208000019695 Migraine disease Diseases 0.000 claims description 5
- 208000023178 Musculoskeletal disease Diseases 0.000 claims description 5
- 208000012902 Nervous system disease Diseases 0.000 claims description 5
- 229940124534 adjunct to anesthesia Drugs 0.000 claims description 5
- 239000000556 agonist Substances 0.000 claims description 5
- 238000002680 cardiopulmonary resuscitation Methods 0.000 claims description 5
- 208000010877 cognitive disease Diseases 0.000 claims description 5
- 230000036543 hypotension Effects 0.000 claims description 5
- 208000028867 ischemia Diseases 0.000 claims description 5
- 206010027599 migraine Diseases 0.000 claims description 5
- 239000000133 nasal decongestant Substances 0.000 claims description 5
- 208000020016 psychiatric disease Diseases 0.000 claims description 5
- 239000000932 sedative agent Substances 0.000 claims description 5
- 230000035939 shock Effects 0.000 claims description 5
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 4
- 206010019280 Heart failures Diseases 0.000 claims description 4
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 4
- 206010048010 Withdrawal syndrome Diseases 0.000 claims description 4
- 239000000730 antalgic agent Substances 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000002485 urinary effect Effects 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- 208000025966 Neurological disease Diseases 0.000 claims description 3
- IJVDZNZQEUKGJI-UHFFFAOYSA-N [3-(1h-imidazol-1-ium-4-ylmethyl)-2,3-dihydro-1h-inden-5-yl] acetate;chloride Chemical compound [Cl-].C12=CC(OC(=O)C)=CC=C2CCC1CC1=C[NH2+]C=N1 IJVDZNZQEUKGJI-UHFFFAOYSA-N 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 230000000926 neurological effect Effects 0.000 claims description 3
- 230000001624 sedative effect Effects 0.000 claims description 3
- QOGPGHSEZPBKFX-UHFFFAOYSA-N [3-(1h-imidazol-1-ium-4-ylmethyl)-2,3-dihydro-1h-inden-5-yl] 2,2-dimethylpropanoate;chloride Chemical compound [Cl-].C12=CC(OC(=O)C(C)(C)C)=CC=C2CCC1CC1=C[NH2+]C=N1 QOGPGHSEZPBKFX-UHFFFAOYSA-N 0.000 claims description 2
- QMDUNEFOOFZIPI-UHFFFAOYSA-N [3-(1h-imidazol-1-ium-4-ylmethyl)-2,3-dihydro-1h-inden-5-yl] butanoate;chloride Chemical compound [Cl-].C12=CC(OC(=O)CCC)=CC=C2CCC1CC1=C[NH2+]C=N1 QMDUNEFOOFZIPI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 230000000202 analgesic effect Effects 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229940002612 prodrug Drugs 0.000 abstract description 21
- 239000000651 prodrug Substances 0.000 abstract description 21
- OYKZVKWXOWICFI-UHFFFAOYSA-N 3-(1h-imidazol-1-ium-4-ylmethyl)-2,3-dihydro-1h-inden-5-ol;chloride Chemical compound Cl.C12=CC(O)=CC=C2CCC1CC1=CN=CN1 OYKZVKWXOWICFI-UHFFFAOYSA-N 0.000 abstract description 18
- 125000000217 alkyl group Chemical group 0.000 abstract description 5
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 3
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 3
- 125000003107 substituted aryl group Chemical group 0.000 abstract description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 abstract description 2
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 1
- 230000004410 intraocular pressure Effects 0.000 description 10
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 8
- 239000008363 phosphate buffer Substances 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 230000015556 catabolic process Effects 0.000 description 6
- 238000006731 degradation reaction Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 230000007071 enzymatic hydrolysis Effects 0.000 description 4
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000005192 partition Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 210000001508 eye Anatomy 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 3
- -1 pivaloyl ester Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 206010073261 Ovarian theca cell tumour Diseases 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229940125723 sedative agent Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 2
- 208000001644 thecoma Diseases 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000000384 adrenergic alpha-2 receptor agonist Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 230000007073 chemical hydrolysis Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- YIAPLDFPUUJILH-UHFFFAOYSA-N indan-1-ol Chemical compound C1=CC=C2C(O)CCC2=C1 YIAPLDFPUUJILH-UHFFFAOYSA-N 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 230000003447 ipsilateral effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- HGASFNYMVGEKTF-UHFFFAOYSA-N octan-1-ol;hydrate Chemical compound O.CCCCCCCCO HGASFNYMVGEKTF-UHFFFAOYSA-N 0.000 description 1
- CMHHMUWAYWTMGS-UHFFFAOYSA-N oxybuprocaine Chemical compound CCCCOC1=CC(C(=O)OCCN(CC)CC)=CC=C1N CMHHMUWAYWTMGS-UHFFFAOYSA-N 0.000 description 1
- 229960003502 oxybuprocaine Drugs 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Abstract
Ovaj pronalazak se odnosi na nove proljekove izvedene iz MPV -2426, na postupke za dobijanje navedenih oblika prolijeka, na farmaceutske kompozicije koji sadrže takve oblike prolijeka i na postupke upotrebe tih oblika prolijeka. Jedinjenje opšte formule (I) ili njegove farmaceutski prihvatljive soli ili hidrati, gdje R predstavlja nesupstituisan ili supstituisan niži alkil, nesupstituisan ili supstituisan aril, nesupstituisan ili supstituisan cikloalkil, nesupstituisan ili supstituisan heteroaril, nesupstituisanu ili supstituisanu nižu alkilamino ili zasićenu heterocikličnu grupu sa pet ili šest članova koja sadrži jedan ili dva atoma azota.
Description
OBLAST PRONALASKA
Ovaj pronalazak se odnosi na nove bioreverzibilne prolekove MPV-2426, koji je alfa2 adrenergički agonist, a specifično na estarske derivate, na postupke za dobijanje naveden1H formi proleka, na farmaceutske kompozicije koji sadrže takve forme proleka i na postupke upotrebe formi proleka.
STANJE U STRUCI
MPV-2426[4-(6-hidroksiindan-l-ilmetil)-lH-imidazol-l-ijum hlorid] je opisan u US 6,313,311 BI kao alfa2 agonist koji se upotrebljava u lečenju hipertenzije, glaukoma, migrene, dijareje, ishemije, adikcije na hemijske supstance, anksioznosti, npr. predoperativne anksioznosti, i različit1H neurološk1H, muskuloskeletn1H, ps1Hijatrijsk1H i kognitivn1H poremećaja, a i kao sedativ i analgetičko sredstvo, nazalni dekongestant, i kao dodatak anesteziji. MPV-2426 obezbeđuje prostorno ograničenje i efektivno smanjenje bola sa manjim -neželjenim efektima. Intraspinalno, intratekalno ili epiduralno davanje MPV-2426 je opisano u WO 00/18400 Al. Lečenje hipotenzije i šoka i kardiopulmonarna reanimacija davanjem MPV-2426 opisano je u W001/30347 Al.
Poznato je da alfa2 agonisti smanjuju intraokulami pritisak (IOP). Prvi izveštaj o efektima sniženja IOP ov1H terapeutsk1H agenasa je objavljen 1966. godine [Makabe, R. Dtsch. Med. Wochenschr., 91 (1966) 1686].
Prolekovi su farmakološki neaktivni derivati molekula lekova koji, posle hemijske ili enzimske transformacije oslobađaju aktivan lek koji ispoljava terapijsko fejstvo. Prolekovi su dizajnirani da prebrode različite farmaceutske ili biofarmaceutske probleme vezane za izvorni lek. Prolek sa dobrim prolazom kroz biološke membrane bi trebalo da ispoljava optimalnu lipofilnost. Pored toga, prolek bi trebalo da bude dovoljno stabilan u odnosu na hemijsku
degradaciju i da se vraća u oblik odgovarajućeg aktivnog leka putem enzimske hidrolize u telu tokom ili posle apsorpcije.
PREGLED PRONALASKA
Ovaj pronalazak obezbeđuje nove bioreverzibilne estarske prolekove MPV-2426 koji su hemijski stabilni u neenzimskom medijumu, koji imaju pogodnu lipofilnost (sposobni su da prolaze kroz biološke membrane) i koji brzo hidrolizuju u izvorni lek in vivo.
Ovaj pronalazak takođe obezbeđuje jedinjenja za proizvodnju lekova koji se koriste u lečenju hipertenzije, glaukoma, migrene, dijareje, ishemije, adikcije na hemijske supstance, hipotenzije, šoka, kod kardiopulmoname reanimacije, poremećaja kod uriniranja, sindroma odvikavanja, kongestivne srčane mane, anksioznosti, npr. predoperativne anksioznosti ili različit1H neurološk1H, muskuloskeletn1H, ps1Hijatrijsk1H ili kognitivn1H poremećaja, ili kao sedativi ili analgetička sredstva, nazalni dekongestanti ili kao dodaci anesteziji. Pored toga, ovaj pronalazak obezbeđuje farmaceutske kompozicije koje u svojstvu aktivnog agensa sadrže jedinjenje iz ovog pronalaska. Pored toga, ovaj pronalazak obezbeđuje postupke za lečenje oboljenja ili stanja u kojima su alfa2 agonisti indikovani za upotrebu, gde se navedeni postupak sastoji od davanja sisaru kome je potrebno takvo lečenje efektivne količine jedinjenja iz ovog pronalaska.
Dodatna izvođenja ovog pronalaska će biti prikazana delimično u opisu koji sledi, a delimično će biti očigledna iz opisa, ili će moći da se nauče praktikovanjem pronalaska. Izvođenja pronalaska će se realizovati i postizati pomoću elemenata i kombinacija naročito istaknut1H u priključenim zahtevima.
Podrazumeva se da su gornji opšti opis i detaljan opis koji sledi dati samo kao primer i objašnjenje i ne ograničavaju opseg pronalaska dat u zahtevima.
KRATAK OPIS CRTEŽA
Slika 1 pokazuje stvaranje MPV-2426 (□) hidrolizom njegovog pivaloil estra (A) u 80%-nom humanom serumu na 37 °C.
DETALJAN OPIS PRONALASKA
Ovaj pronalazak obezbeđuje nove bioreverzibilne estarske prolekove opšte formule I,
ili nj1Hove farmaceutski pr1Hvatljive soli ili hidrate, gde R predstavlja nesupstituisan ili supstituisan niži alkil, nesupstituisan ili supstituisan aril, nesupstituisan ili supstituisan cikloalkil, nesupstituisan ili supstituisan heteroaril, nesupstituisanu ili supstituisanu nižu alkilamino ili zasićenu heterocikličnu grupu sa pet ili šest članova koja sadrži jedan ili dva atoma azota. Na primer, R predstavlja nesupstituisan ili supstituisan niži alkil ili nesupstituisan ili supstituisan aril, npr. nesupstituisan ili supstituisan niži alkil. Jedinjenje može da bude 4- [6- (2,2-dimetilpropanoiloksi)indan-l-ilmetil]-lH-imidazol-l-ijum hlorid, 4-(6-acetoksiindan-l-ilmetil)-lH-imidazol-l-ijum hlorid ili 4-(6-butiriloksiindan-l-ilmetil)-lH-imidazol-l-ijum hlorid. U definicijama R, termin "niži" označava ostatke sa maksimalno 10 ugljenikov1H atoma, npr. maksimalno 6 ugljenikov1H atoma. Termin "alkil", sam ili u kombinaciji sa terminima kao što su "cikloalkil" ili "alkilamino" označava pravolinijski ili razgranat lanac ugljenikov1H ostataka. Termin "aril" označava karbocikličnu aromatičnu grupu, moguće mono- ili bicikličnu grupu. Termin "heteroaril" označava mono- ili bicikličnu aromatičnu grupu koja sadrži 1 do 3 heteroatoma, koji mogu biti azot i/ili kiseonik i/ili sumpor, npr. 1 ili 2 heteroatoma koji su azot i/ili kiseonik i/ili sumpor. Termin "supstituisan" u vezi sa različitim ostacima odnosi se na supstituente hidroksi, cijano, nitro, halogen, amino, niži alkilamino, di(niži alkiljamino, niži alkoksi, aril ili trifluorometil. Supstituisani ostaci mogu da sadrže 1 do 3 naveden1H supstituenata, npr. 1 ili 2 navedena supstituenta. Termin "halogen" označava fluor, hlor, brom ili jod, npr. hlor ili brom.
Jedinjenja formule I mogu da obezbede odgovarajuću lipofdnost i stabilnost u odnosu na hemijsku hidrolizu i da se vrate u aktivan izvoran oblik leka putem enzimske hidrolize.
Ovaj pronalazak može da obezbedi jedinjenja za proizvodnju lekova koji se koriste u lečenju hipertenzije, glaukoma, migrene, dijareje, ishemije, adikcije na hemijske supstance, hipotenzije, šoka, kod kardiopulmoname reanimacije, poremećaja kod uriniranja, sindroma odvikavanja, kongestivne srčane mane, anksioznosti, npr. predoperativne anksioznosti ili različit1H neurološk1H, muskuloskeletn1H, ps1Hijatrijsk1H ili kognitivn1H poremećaja, ili kao sedativi ili analgetička sredstva, nazalni dekongestanti ili kao dodaci anesteziji. Pored toga, ovaj pronalazak obezbeđuje farmaceutske kompozicije koje u svojstvu aktivnog agensa sadrže jedinjenje iz ovog pronalaska. Pored toga, ovaj pronalazak obezbeđuje postupke za lečenje oboljenja ili stanja u kojima su alfa2 agonisti indikovani za upotrebu, gde se navedeni postupak sastoji od davanja sisaru kome je potrebno takvo lečenje efektivne količine jedinjenja iz ovog pronalaska.
Jedinjenja iz ovog pronalaska mogu se dobijati različitim načinima sinteze analogno ili u skladu sa postupcima poznatim iz literature, upotrebom pogodn1H početn1H materijala.
U opštem slučaju, jedinjenja formule I ili nj1Hove farmaceutski pr1Hvatljive soli ili hidrati, mogu se dobijati analogno ili u skladu sa šemom 1, gde je R kao što je definisano gore.
Hidroksiindansko jedinjenje II, ili njegova farmaceutski pr1Hvatljiva so ili hidrat, je rastvoreno u rastvaraču, npr. trifluorosirćetnoj kiselini (TFA) i dodat je hlorid ugljene kiseline. Smesa je mešana, na primer, na sobnoj temperaturi, na primer, 24 sata. Rastvarač je uparen i dobij eno jedinjenje lje izolovano iz reakcione smese na uobičajen način. Jedinjenja iz pronalaska se, po želji, mogu pretvoriti u svoje farmaceutski pr1Hvatljive soli ili hidrate koristeći postupke dobro poznate u struci.
Način sinteze opisan gore služi da ilustruje dobijanje jedinjenja iz pronalaska i dobijanje nije ni na koji način ograničeno na njega, tj. pošto je i drugi mogući postupci sinteze koji spadaju u opšte znanje stručnjaka.
Primer 1
4-(6-acetoksiindan-1 -ilmetil)-1 H-imidazol-1 -ijum hlorid
4-(6-hidroksi-indan-l-ilmetil)-lH-imidazol-l-ijum hlorid (100 mg, 0,399 mmola) je rastvoren u 1 ml trifluorosirćetne kiseline (TFA) i dodat je hlorid sirćetne kiseline (0,510 mmola). Smesa je mešana na sobnoj temperaturi 24 sata. TFA je uparena, a ostatak rastvoren u vodi i zaalkaljen pomoću 2M NH3 (aq.). Vodena faza je ekstrahovana d1Hlorometanom (DCM). Kombinovani ekstrakti su osušeni (Na2SO4) i upareni. Ostatak je rastvoren u dietil etru i rastvor je zasićen suvim hlorovodonikom (gasom). Precipitat je profiltriran i osušen na vakuumu. Dobijen je prinos od 105 mg (82%) bele higroskopne čvrste supstance. 1H NMR (CDCI3, TMS): δ 1,72 (m, 1H), 2,18 - 2,26 (m, 4H), 2,72 - 2,87 (m, 3H), 3,17 (dd, 1H), 3,56 (qui, 1H), 6,85 (m, 2H), 6,92 (s, 1H), 7,16 (d, 1H), 8,61 (s, 1H), 14,44 (s, 2H). 13H NMR (CDCI3, TMS): δ 21,11, 29,60, 30,46, 31,68, 43,93, 115,72, 117,00, 120,29, 125,33 132,32, 132,40, 141,37, 146,32, 149,39, 170,11. HPLC-MS (El): m/z = 257,2 ((M+H)+ - CF). Anal. -Kalk. za C15H16N2OrHCFO,2 CH2C12: C 58,94, H 5,66, N 9,04. Nađeno C 58,66, H 5,78, N 8,83.
Primer 2
4-(6-butiriloksiindan-1 -ilmetil)-1 H-imidazol-1 -ijum hlorid
4-(6-hidroksi-indan-l-ilmetil)-lH-imidazol-l-ijum hlorid (100 mg, 0,399 mmola) i hlorid buteme kiseline (510 mmola) su stavljeni da izreaguju u TFA (1 ml), a zatim su prečišćeni kao što je opisano u primeru 1. Prinos 90 mg (77%) bele higroskopne čvrste supstance. 'H NMR (CDC13, TMS): δ 1,02 (t, 3H), 1,70 - 1,79 (m, 3H), 2,18 - 2,24 (m, 1H), 2,52 (t, 2H), 2,73 - 2,86 (m, 3H), 3,18 (dd, 1H), 3,53 (qui, 1H), 6,84 (dd, 1H), 6,87 (s, 1H), 6,92 (s, 1H), 8,66 (s, 1H), 11,28 (s (široka), 2H). 13C NMR (CDC13, TMS): 6 13,66, 18,45, 29,68, 30,52, 31,68, 36,24, 43,98, 115,79, 117,05, 120,36, 125,36, 132,32, 132,59, 141,32, 146,36, 149,51, 172,85. - HPLC-MS (El): m/z = 285,2 ((M+H)+ - CF). Anal. - Kalk. za C17H20N2O2 HCFO,2 CH2C12: C 61,16, H 6,39, N 8,29. Nađeno C 61,30, H 6,46, N 8,22.
Primer 3
4-[6-(2,2-dimetilpropanoiloksi)indan-l-ilmetil]-1 H-imidazol-1 -ijum hlorid
4-(6-hidroksi-indan-l-ilmetil)-lH-imidazol-l-ijum hlorid (100 mg, 0,399 mmola) i hlorid 2,2-dimetilpropionske kiseline (510 mmola) su stavljeni da izreaguju u TFA (1 ml), a zatim su prečišćeni kao što je opisano u primeru 1. Prinos 74 mg (56%) bele čvrste supstance. T. t. 176 - 177 °C. ’H NMR(CDC13, TMS): δ 1,33 (s, 9H), 1,69-1,78 (m, 1H), 2,16 - 2,25 (m, 1H), 2,74 - 2,88 (m, 3H), 3,23 (dd, 1H), 3,57 (qui, 1H), 6,83 (dd, 1H), 6,89 (s, 1H), 6,93 (s,
1H), 7,16 (d, 1H), 8,85 (s, 1H), 14,38 (s, 1H), 14,47 (s, 1H). 13C NMR (CDC13, TMS): 5 27,17, 29,64, 30,55, 31,57, 39,07, 43,95, 115,69, 116,96, 120,24, 125,33, 132,12, 132,66, 141,20, 146,30, 149,30, 177,87. HPLC-MS (El): m/z = 297,7 (M+- 2H+ - Cl ). Anal. - Kalk. za C18H22N202-HC1: C 64,57, H 6,92, N 8,37. Nađeno C 64,05, H 7,00, N 8,24.
EKSPERIMENTI
Prolek sa dobrim prolazom kroz biološke membrane bi trebalo da ispoljava optimalnu lipofilnost (obično opisanu preko koeficijenta particije oktanol-voda, log Papp). Pored toga, prolek bi trebalo da bude dovoljno stabilan u odnosu na hemijsku degradaciju i da se vraća u oblik odgovarajućeg aktivnog leka putem enzimske hidrolize u telu tokom ili posle apsorpcije.
Eksperiment 1. Lipofilnost
Lipofilnost je procenjena određivanjem prividn1H koeficijenata particije (log Papp) između 1-oktanola i fosfatnog pufera pH 5,0 ili 7,4 na sobnoj temperaturi. Obično se vrednost log Papp u opsegu od 2-3 smatra optimalnom za apsorpciju i za prolaz kroz membranu uopšte.
Postupak
Prividni koeficijenti particije (Papp) su procenjeni iz distribucije testiran1H jedinjenja između 1-oktanola i fosfatnog pufera (0,16 M, pH 5,0 1H pH 7,4, μ = 0,5). Faze pufera i 1-oktanola su zasićene pre upotrebe snažnim mešanjem 24 sata na sobnoj temperaturi. Poznata koncentracija jedinjenja u fosfatnom puferu je mućkana sa odgovarajućom zapreminom 1-oktanola da se postigne ravnoteža. Posle 1 sata mućkanja, faze su razdvojene centrifugiranjem i koncentracija jedinjenja u puferskoj fazi je određena pomoću HPLC.
Rezultati
Log Papp vrednosti jedinjenja su date u Tabeli 1. Lipofilnost jedinjenja je suštinski veća nego ona izvornog leka. Povećana lipofilnost može da izazove povećano prelaženje kroz membranu, kao i duže trajanje aktivnosti kao posledicu izmenjen1H farmakokinetičk1H osobina (duža retencija u telu).
Eksperiment 2. Hemijska stabilnost
Postupak
Odgovarajuća količina testiranog jedinjenja (početne koncentracije su bile 0,1 - 0,4 mM) je rastvorena u prethodno zagrejanom fosfatnom puferu (0,16 M, μ = 0,5, pH 7,4 ili pH 5,0). Rastvor je stavljen u tennostatirano vodeno kupatilo na 37°C, u odgovarajućim vremenskim intervalima su uzimani alikvoti i analizirani pomoću HPLC da bi se odredila brzina raspadanja jedinjenja. Poluvreme degradacije pseudo prvog reda (t1/2) je računato iz linearnog dela nagiba semi-logaritamsk1H kriv1H preostalog jedinjenja u zavisnosti od vremena.
Rezultati
Degradacija jedinjenja u vodenom rastvoru pri pH 5,0 i 7,4 je imala kinetiku pseudo prvog reda. Poluvreme degradacije (t1/2) je prikazano u Tabeli 2. Stabilnost jedinjenja je bila znatno veća na pH 5,0 nego na 7,4.
Tabela 1. Prividni koeficijenti particije (log Papp, srednji ± SD, n = 3) MPV-2426 i njegov1H estara.
Eksperiment 3. Enzimska hidroliza
Da bi ispoljio farmakološki efekat u telu, prolek treba enzimski da se razgradi do izvornog leka. Prema tome, procenjena je podložnost jedinjenja serumskim esterazama.
Postupak
Odgovarajuća količina testiranog jedinjenja je rastvorena u jednoj zapremini (npr. 1 ml) fosfatnog pufera (0,16 M, μ = 0,5, pH 7,4) na 37 °C. Četiri zapremine (npr. 4 ml) prethodno zagrejanog humanog seruma su dodate i rastvori su mešani u vodenom kupatilu na 37 °C (početne koncentracije su bile 0,2 - 0,5 mM). U odgovarajućim intervalima, po 300 μl alikvota je uzimano i deproteinisano pomoću 600 μl acetonitrila. Posle mešanja i centrifugiranja, 600 μl supematanta je upareno do suvog u struji vazduha na 40 °C. Ostatak je ponovo rastvoren u 300 μl mobilne faze i analiziran pomoću HPLC. Poluvreme degradacije pseudo prvog reda (t1/2) je računato iz linearnog dela nagiba semi-logaritamsk1H kriv1H preostalog jedinjenja u zavisnosti od vremena. Određeno je i stvaranje izvornog leka.
Rezultati
Hidroliza prolekova u 80%-nom humanom serumu je imala kinetiku pseudo prvog reda. Poluvreme degradacije (t1/2) je prikazano u Tabeli 2. Svi prolekovi MPV-2426 su kvantitativno oslobađali izvorni lek, MPV-2426, putem enzimske hidrolize u 80%-nom humanom serumu (pH 7,4). Stvaranje MPV-2426 hidrolizom njegovog pivaloil estra u 80%-nom humanom serumu na 37 °C je prikazano na Slici 1.
Tabela 2. Brzina hidrolize u rastvorima fosfatnog pufera (pH 5,0 i 7,4) i u 80%-nom humanom serumu (pH 7,4) na 37 °C.
Eksperiment 4. Studija IOP na kunićima
Studija IOP je pravljena da bi se dokazalo da su prolekovi prema pronalasku sposobni da oslobađaju izvorni lek i da su, prema tome, farmakološki aktivni in vivo. Efekat sniženja IOP koji proizvodi prolek je takođe upoređen sa efektom MPV-2426.
Postupak
Da bi se izveo test sa IOP, kunić je stavljen u plastičnu kutiju smeštenu u t1Hoj sobi. Jedna kap (25 μl) testiranog rastvora je kanuta unilateralno u njegovo levo oko, na gornji
komeosklerični limbus. Za vreme ukapavanja, gornji kapak je blago povučen sa jabučice. IOP je meren pneumatonometrom BioRad (Cambridge, MA) Digilab Modular One. Pre svakog merenja, jedna do dve kapi oksibuprokaina (0,06%) je ukapana u komeu pre tonometrije da bi se uklonila neprijatnost. Gornji i donji kapak su zatim nežno povučeni, i aplanacioni senzor je doveden u kontakt sa centrom komee. Za svako određivanje, urađena su bar dva očitavanja na svakom - tretiranom (ipsilateralnom) i netretiranom (kontralateralnom) - oku, i uzeta je srednja vrednost ov1H očitavanja. IOP kunića je meren na 2,1 i 0 sati pre i na 0,5, 1,2, 3, 4 i 5 sati posle davanja kapi. IOP u vreme administracije kapi (0 h) je korišćen kao bazna vrednost. Sve studije su postavljene uz upotrebu maskiranog i randomiziranog krosover dizajna. Svakom kuniću je ostavljeno najmanje 72 sata između svaka dva doziranja.
Tabela 3. Promene intraokulamog pritiska (IOP) (srednja vrednost mmHg ± SE, n = 5-6) u prethodno određenim vremenima (h) u tretiranom i netretiranom oku kunića sa normalnim pritiskom posle unilateralnog davanja 25 μl MPV-2426 ili njegov1H pivaloil estarsk1H (PIV) rastvora u fosfatnom puferu na pH 5,0.
Claims (12)
1. Jedinjenje opšte formule I, ili njegove farmaceutski prihvatljive soli ili hidrati, gde R predstavlja C1-C6 alkil.
2. Jedinjenje prema zahtevu 1, gde je navedeno jedinjenje 4-[6-(2, 2-dimetilpropanoiloksi)indan-l-ilmetil]-1H-imidazol-l-ijum hlorid.
3. Jedinjenje prema zahtevu 1, gde je navedeno jedinjenje 4-(6-acetoksiindan-l-ilmetil)-1H-imidazol-l-ijum hlorid.
4. Jedinjenje prema zahtevu 1, gde je navedeno jedinjenje 4-(6-butiriloksiindan-l-ilmetil)-lH-imidazol-l-ijum hlorid.
5. Upotreba jedinjenja formule I, ili njegovih farmaceutski prihvatljivih soli ili hidrata, gde je R kao što je definisano u zahtevu 1, za proizvodnju leka za upotrebu u lečenju hipertenzije, glaukoma, migrene, dijareje, ishemije, adikcije na hemijske supstance, hipotenzije, šoka, kod kardiopulmoname reanimacije, poremećaja kod uriniranja, sindroma odvikavanja, kongestivne srčane mane, anksioznosti ili različitih neuroloških, muskuloskeletnih, psihijatrijskih ili kognitivnih poremećaja, ili kao sedativa ili analgetičkog sredstva, nazalnog dekongestanta ili kao dodatka anesteziji.
6. Upotreba prema zahtevu 5, gde je jedinjenje 4-[6-(2, 2 dimetilpropanoiloksijindan-1 -ilmetil]-1 H-imidazol-1 -ijum hlorid.
7. Upotreba jedinjenja formule I, ili njegov1H farmaceutski prihvatljivih soli ili hidrata, gde je R kao što je defmisano u zahtevu 1, za upotrebu u proizvodnji leka za upotrebu u lečenju hipertenzije, glaukoma, migrene, dijareje, ishemije, adikcije na hemijske supstance, hipotenzije, šoka, kod kardiopulmoname reanimacije, poremećaja kod uriniranja, sindroma odvikavanja, kongestivne srčane mane, anksioznosti ili različitih neurološk1H, muskuloskeletnih, psihijatrijskih ili kognitivn1H poremećaja, ili kao sedativa ili analgetičkog sredstva, nazalnog dekongestanta ili kao dodatka anesteziji.
8. Upotreba prema zahtevu 7, gde je jedinjenje 4-[6-(2,2-dimetilpropanoiloksijindan-1 -ilmetil]-1 H-imidazol-1 -ijum hlorid.
9. Farmaceutska kompozicija koja kao aktivan sastojak sadrži jedinjenje formule I, ili njegove farmaceutski pr1Hvatljive soli ili hidrate, gde je R kao što je defmisano u zahtevu 1 i, po izboru, farmaceutski pr1Hvatljiv ekscipijent.
10. Farmaceutska kompozicija prema zahtevu 9, gde je jedinjenje 4-[6-(2,2-dimetilpropanoiloksi)indan-l-ilmetil]-lFI-imidazol-l-ijum hlorid.
11. Postupak za lečenje oboljenja ili stanja, u kojima su alfa2 agonisti indikovani kao korisni i gde se navedeni postupak sastoji od davanja sisaru kome je potrebno takvo lečenje efektivne količine jedinjenja formule I, ili njegov1H farmaceutski pr1Hvatljiv1H soli ili hidrata, gde je R kao što je definisano u zahtevu 1.
12. Postupak prema zahtevu 11, gde je jedinjenje 4-[6-(2,2-dimetilpropanoiloksijindan-1 -ilmetil]-1 H-imidazol-1 -ijum hlorid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI20022159A FI20022159A0 (fi) | 2002-12-05 | 2002-12-05 | Uusia farmaseuttisia yhdisteitä |
| PCT/FI2003/000933 WO2004050635A2 (en) | 2002-12-05 | 2003-12-05 | Imidazol derivatives having affinity for alpha 2 receptors activity |
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| Publication Number | Publication Date |
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| ME00521B true ME00521B (me) | 2011-10-10 |
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| Application Number | Title | Priority Date | Filing Date |
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| MEP-2008-864A ME00521B (me) | 2002-12-05 | 2003-12-05 | Derivati imidazola sa afinitetom prema aktivnosti alfa 2 receptora |
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| Country | Link |
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| US (1) | US7759496B2 (me) |
| EP (1) | EP1572198B1 (me) |
| JP (1) | JP4667042B2 (me) |
| KR (1) | KR20050114603A (me) |
| CN (1) | CN100560070C (me) |
| AT (1) | ATE323484T1 (me) |
| BR (1) | BR0317024A (me) |
| CA (1) | CA2508335C (me) |
| CY (1) | CY1105699T1 (me) |
| DE (1) | DE60304741T2 (me) |
| DK (1) | DK1572198T3 (me) |
| EA (1) | EA008251B1 (me) |
| ES (1) | ES2262031T3 (me) |
| FI (1) | FI20022159A0 (me) |
| HR (1) | HRP20050617B1 (me) |
| IL (1) | IL168882A (me) |
| IS (1) | IS2282B (me) |
| ME (1) | ME00521B (me) |
| MX (1) | MXPA05005963A (me) |
| NO (1) | NO330392B1 (me) |
| NZ (1) | NZ540466A (me) |
| PL (1) | PL216530B1 (me) |
| PT (1) | PT1572198E (me) |
| RS (1) | RS52571B (me) |
| SI (1) | SI1572198T1 (me) |
| WO (1) | WO2004050635A2 (me) |
| ZA (1) | ZA200504533B (me) |
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| EP1934203B1 (en) | 2005-08-25 | 2010-08-18 | Schering Corporation | 3,4-dihydro-2H-benzo[1,4]oxazine and 3,4-dihydro-2H-benzo[1,4]thiazine COMPOUNDS AS ALPHA2C ADRENORECEPTOR AGONISTS |
| US7700592B2 (en) | 2005-08-25 | 2010-04-20 | Schering Corporation | α2C adrenoreceptor agonists |
| US8003624B2 (en) | 2005-08-25 | 2011-08-23 | Schering Corporation | Functionally selective ALPHA2C adrenoreceptor agonists |
| WO2010042473A1 (en) | 2008-10-07 | 2010-04-15 | Schering Corporation | Biaryl spiroaminooxazoline analogues as alpha2c adrenergic receptor modulators |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4673679A (en) * | 1986-05-14 | 1987-06-16 | E. I. Du Pont De Nemours And Company | Use of prodrugs of 3-hydroxymorphinans to prevent bitter taste upon buccal, nasal or sublingual administration |
| GB9425211D0 (en) * | 1994-12-14 | 1995-02-15 | Ucb Sa | Substituted 1H-imidazoles |
| GB9520150D0 (en) * | 1995-10-03 | 1995-12-06 | Orion Yhtymae Oy | New imidazole derivatives |
| JPH10195056A (ja) * | 1996-11-12 | 1998-07-28 | Takeda Chem Ind Ltd | 縮合ベンゼン誘導体、その製造法および剤 |
| DK1117399T3 (da) | 1998-09-28 | 2005-03-29 | Orion Corp | Anvendelse af 3-(1H-imidazol-4-ylmethyl)indan-5-ol til fremstilling af et lægemiddel til intraspinal, intrathekal eller epidural indgivelse |
| AU778522B2 (en) | 1999-10-29 | 2004-12-09 | Orion Corporation | Treatment or prevention of hypotension and shock |
| US6388090B2 (en) * | 2000-01-14 | 2002-05-14 | Orion Corporation | Imidazole derivatives |
| FI20000073A0 (fi) * | 2000-01-14 | 2000-01-14 | Orion Yhtymae Oy | Uusia imidatsolijohdannaisia |
| US7091232B2 (en) | 2002-05-21 | 2006-08-15 | Allergan, Inc. | 4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substituted cycloalkenylmethyl) imidazole-2-thiones, 4-(substituted cycloalkylmethyl) imidazol-2-ones and 4-(substituted cycloalkenylmethyl) imidazol-2-ones and related compounds |
| US7439268B2 (en) * | 2003-07-18 | 2008-10-21 | Idexx Laboratories | Compositions containing prodrugs of florfenicol and methods of use |
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