HRP20020362A2 - Use of 2-imidazolyl substituted carbinols for production of a medicament for treatment or prohylaxis of disease states as a result of ischaemic conditions - Google Patents
Use of 2-imidazolyl substituted carbinols for production of a medicament for treatment or prohylaxis of disease states as a result of ischaemic conditions Download PDFInfo
- Publication number
- HRP20020362A2 HRP20020362A2 HR20020362A HRP20020362A HRP20020362A2 HR P20020362 A2 HRP20020362 A2 HR P20020362A2 HR 20020362 A HR20020362 A HR 20020362A HR P20020362 A HRP20020362 A HR P20020362A HR P20020362 A2 HRP20020362 A2 HR P20020362A2
- Authority
- HR
- Croatia
- Prior art keywords
- production
- treatment
- compound
- prophylaxis
- phenyl
- Prior art date
Links
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Classifications
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- 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
- A61K31/41—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
- A61K31/4164—1,3-Diazoles
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- A—HUMAN NECESSITIES
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- 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
- A61K31/41—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
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Public Health (AREA)
- Medicinal Chemistry (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Oncology (AREA)
- Immunology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Communicable Diseases (AREA)
- Hospice & Palliative Care (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Nedavno su objavljene patentne prijave u kojima se zahtijevaju spojevi formule I
[image]
U DE-OS 23 05 212 su opisani spojevi slične konstitucije s analgetičkim, anorektičkim, antiflogističkim i antipiretičkim djelovanjem. U DE-OS 2164919 se zahtjeva antikolesteremijski učinak tih spojeva. U WO 97 49 704 su opisani predstavnici tog razreda spojeva u indikaciji bolesti raka, pri čemu oni zahvaćaju u izmjenu vitamina A i kisika. U JP 63270665 je opisano njihovo djelovanje protiv čira.
U nijednoj od tih publikacija nema naznake o djelovanju ovih spojeva kod ishemijskih stanja.
Izum se odnosi na upotrebu s 2-imidazol-supstituiranih karbinola I i njihovih farmaceutski podnošljivih soli, u kojoj formuli
R1 je ravan ili razgranati C1-C8-alkil ili fenil-(CH2)m-;
m je nula, 1 ili 2;
pri čemu fenilna jezgra nije supstituirana ili nosi jedan do tri supstituenta iz skupine koju čine F, Cl, CH3 ili CH3O,
R2 i R3 predstavljaju ravan ili razgranati C1-C6-alkil ili fenil, pri čemu fenilna jezgra nije supstituirana ili nosi jedan do tri supstituenta iz skupine koju čine F, Cl, CH3 ili CH3O; ili
R2 i R3 mogu zajedno tvoriti (C5-C6)-prsten, koji nije supstituiran ili su oni kondenzirani na fenilni prsten, za proizvodnju lijeka za terapiju ili profilaksu ishemijskih stanja.
Upotrebljavaju se ponajprije spojevi I, u kojima:
R1 predstavlja ravan ili razgranati C4-C6-alkil, fenil ili benzil, pri čemu fenilna jezgra nije supstituirana ili ona nosi jedan do tri supstituenta iz skupine koju čine F, Cl, CH3 ili CH3O;
R2 i R3 predstavljaju ravan ili razgranati C1-C6-alkil ili fenil, pri čemu fenilna jezgra nije supstituirana ili nosi jedan do tri supstituenta iz skupine koju čine F, Cl, CH3 ili CH3O; ili
R2 i R3 zajedno sa C atomom na koji su oni povezani tvore fluoren.
Ako jedan od tri supstituenta R1, R2 ili R3 sadrži središte asimetrije, tada u izum spadaju kako spojevi S konfiguracije, tako također i spojevi R konfiguracije. Spojevi koji se upotrebljavaju prema izumu mogu biti prisutni kao optički izomeri, kao diastereoizomeri, kao racemati ili kao njihove smjese.
Ovi već poznati spojevi iznenađujuće se odlikuju inhibicijom izmjene Na+/H+. Time su oni zbog njihovih farmakoloških svojstava posebno prikladni kao anti-aritmijski lijekovi s kardioprotektivnom komponentom za profilaksu infarkta i za liječenje infarkta kao i za liječenje angine pektoris, pri čemu oni također preventivno inhibiraju ili jako sprečavaju patofiziološke procese kod nastanka ozljeda uzrokovanih ishemijom, posebno kod pojave srčanih aritmija uzrokovanih ishemijom. Zbog njihovog zaštitnog učinka protiv patoloških hipoksičkih i ishemijskih situacija, spojevi formule I, zbog inibicije staničnog mehanizma izmjene Na+/H+ mogu se upotrijebiti kao lijek za liječenje svih akutnih ili kroničnih ozljeda izazvanih ishemijom ili time primarno ili sekundarno induciranih bolesti. To se odnosi na njihovu upotrebu kao lijeka za operativne zahvate, npr. kod transplantacija organa, pri čemu se ovi spojevi mogu upotrijebiti također za zaštitu organa u darovatelju prije i tijekom uzimanja, za zaštitu izvađenih organa, na primjer pri obradi ili njihovom odlaganju u kupelji fiziološke otopine, kao također pri prenošenju u organizam primaoca. Ovi spojevi su također dragocjeni lijekovi protektivnog djelovanja kod provedbe angioplastičnih operativnih zahvata na, primjer na srcu, kao također na perifernim žilama. U skladu s njihovim protektivnim djelovanjem protiv ozljeda induciranih ishemijom, spojevi prema izumu mogu se također prikladno upotrijebiti kao lijekovi za liječenje ishemija nervnog sistema, posebno središnjeg nervnog sistema, pri čemu su oni prikladni npr. za liječenje udara kapi ili moždanog edema. Nadalje, spojevi formule I također su prikladni za liječenje oblika šoka, kao na primjer alergijskog, kardiogenog, hipovolemijskog i bakterijskog šoka.
Prema izumu upotrijebljeni spojevi su učinkoviti inhibitori staničnih natrij-proton-antiportera (izmjenjivači Na+/H+), koji su povišeni kod brojnih oboljenja (esencijalna hipertonija, ateroskleroza, dijabetes itd.) također i u takovim stanicama koje su lako dostupne mjerenju, kao na primjer u eritrocitima, trombocitima ili leukocitima. Zbog toga su spojevi prema izumu prikladni kao istaknuto i jednostavno znanstveno sredstvo, na primjer za njihovu upotrebu kao dijagnostika za određivanje i razlikovanje određenih oblika hipertonije, ali također i ateroskleroze, dijabetesa, itd. Nadalje, spojevi formule I prikladni su za preventivnu terapiju za sprečavanje geneze visokog krvnog tlaka, na primjer esencijalne hipertonije.
Pri tome, lijek koji sadrži spoj I može se dati oralno, parenteralno, intravenski, rektalno ili inhalacijom, pri čemu najpovoljnija aplikacija ovisi u svakom slučaju o pojavnoj slici bolesti. Pri tome, spojevi I mogu doći u primjenu sami ili zajedno s galenskim pomoćnim tvarima, i to kako u veterini, tako također u humanoj medicini.
Izbor pomoćnih tvari koje su prikladne za željenu formulaciju lijeka stručnjaku je moguć na temelju njegovog stručnog znanja. Osim otapala, sredstava za tvorbu gela, osnove za čepiće, pomoćnih tvari za čepiće mogu se upotrijebiti i drugi nosači aktivne tvari kao, na primjer, antioksidanti, disperzanti, emulgatori, sredstva protiv pjenjenja, sredstva za korekciju okusa, konzervansi, sredstva za pospješivanje otapanja ili bojila.
Za oralni oblik aplikacije aktivni spojevi I se pomiješaju s dodatnim tvarima koje su prikladne za tu svrhu, kao što su nosači, stabilizatori ili inertna sredstva za razrjeđivanje i uobičajenim postupcima se dovedu oblike prikladne za davanje, kao tablete, dražeje, utične kapsule, vodene, alkoholne ili uljne otopine. Kao inertni nosači mogu se upotrijebiti npr. guma arabika, magnezijev oksid, magnezijev karbonat, kalijev fosfat, mliječni šećer, glukoza ili škrob, naročito kukuruzni škrob. Pri tome, pripravak se može proizvesti kako kao suhi, tako također i kao mokri granulat. Kao uljni nosači ili kao otapala u obzir dolaze, na primjer, biljna ili životinjska ulja, kao suncokretovo ulje ili riblje jetreno ulje.
Za supkutanu ili intravensku aplikaciju aktivni spojevi I, prema potrebi zajedno s uobičajenim tvarima za tu svrhu kao što su sredstva za pospješivanje otapanja, emulgatori ili druge pomoćne tvari, se dovedu u otopinu, suspenziju ili emulziju. Kao otapala u obzir dolaze npr. voda, fiziološka otopina NaCl ili alkoholi, npr. etanol, propanol, glicerin, te također otopine šećera kao otopina glukoze ili otopina manita, ili također mješavina različitih navedenih otapala.
Kao farmaceutska formulacija za davanje u obliku aerosola ili spreja prikladne su npr. otopine, suspenzije ili emulzije aktivne tvari formule I upotrijebljene prema izumu u farmaceutski nedvojbenom otapalu, kao što je posebno etanol ili voda, ili mješavina takovih otapala.
Formulacija može prema potrebi sadržavati još i druge farmaceutske pomoćne tvari kao tenzide, emulgatore i stabilizatore, te potisni plin. Takav pripravak sadrži aktivnu tvar obično koncentracijom od pribl. 0,1 do 10, naročito od pribl. 0,3 do 3 mas. %.
Doziranje aktivne tvari formule I pri aplikaciji i učestalost davanja ovise o jačini aktivne tvari formule I i o trajanju djelovanja upotrijebljenih spojeva; osim toga, ono također ovisi i o vrsti i jačini bolesti koju se liječi te o spolu, starosti, težini i pojedinačnoj reakciji liječenog sisavca.
U prosjeku, dnevna doza spoja formule I za pacijenta teškog pribl. 75 kg iznosi najmanje 0,001 mg/kg, ponajprije 0,01 mg/kg, do najviše 10 mg/kg, ponajprije 1 mg/kg tjelesne težine. Kod akutnog izbijanja bolesti, eventualno neposredno nakon pretrpljenog srčanog infarkta, može biti potrebno također i više, a prije svega češće doziranje, npr. do 4 pojedinačne doze dnevno. Posebno kod i.v. aplikacije, eventualno kod pacijenta na intenzivnoj njezi, može biti potrebno i do 200 mg dnevno.
Eksperimentalni dio
Popis kratica
RT sobna temperatura
EE etil acetat (EtOAc)
tal. talište
THF tetrahidrofuran
ekv. ekvivalent
Primjer 1
9-(1-benzil-lH-imidazol-2-il)-9H-fluoren-9-ol, bezbojna kruta tvar, talište 149°C, M++H = 339.
[image]
K N-benzil-imidazolu u THF-u pri -70°C doda se 1,2 ekv. n-butil-litija. U roku od jednog sata pusti se zagrijati na -20°C i zatim se ponovno ohladi na -70°C. Nakon dodatka 1 ekv. fluorenona u THF-u u roku od 5 h pusti se zagrijati na sobnu temperaturu. Zatim slijedi vodena obrada, ekstrakcija s EE, i zatim sušenje organske faze preko magnezijevog sulfata i isparavanje otala, nakon čega se dobije kruti žućkasti ostatak. On se protrlja s dietil eterom, nakon čega se dobile krutu tvar koju se odsisa.
Primjer 2
(1-butil-1H-imidazol-2-il)-fenil-4-fluorfenil-karbinol, bezbojna kruta tvar, tal. 138°C, M++H+ = 325.
[image]
Naslovni spoj je dobiven postupkom opisanim pod 1) upotrebom N-n-butil-imidazola i 4-fluorfenil-fenil-ketona.
Farmakološki podaci
Inhibicija Na+/H*-izmjenjivača u eritrocitima kunića
Bijeli novozelandski kunići (Ivanovas) primali su standardnu hranu s 2% kolesterina tijekom šest tjedana da bi se aktiviralo izmjenu Na+/H+ i tako moglo plamenom fotometrijom odrediti dotok Na+ u eritrocite putem izmjene Na+/H+. Krv je uzeta iz usnih arterija i zgrušavanje je spriječeno dodatkom 25 IE kalij-heparina. Dio svakog uzorka je upotrijebljen za dvostruko određivanje hematokrita centrifugiranjem. Alikvoti od po 100 μl poslužili su za mjerenje početnog sadržaja Na+ u eritrocitima.
Da bi se odredilo dotok natrija osjetljiv prema amiloridu, 100 μl svakog uzorka krvi inkubirano j e u 5 ml hiperosmozne otopine sol/saharoze (mmol/1 140 NaCl, 3 KCl, 150 saharoze, 0,1 ouabaina, 20 tris-hidroksimetil-amino-metan) pri pH 7,4 i 37°C. Nakon toga su eritrociti isprani tri puta s ledeno hladnom otopinom MgCl2-ouabaina (mmol/1: 112 MgCl2, 0,1 ouabaina) i hemolizirani u 2,0 ml destilirane vode. Intracelularni sadržaj natrija određen je plamenom fotometrijom.
Neto dotok Na+ izračunat je iz razlike početne vrijednosti natrija i sadržaja natrija u eritrocitima nakon inkubacije. Dotok natrija koji se može inhibirati s amiloridom dobije se iz razlike sadržaja natrija u eritrocitima nakon inkubacije sa i bez amilorida 3x10-4 mol/l. Na taj način postupilo se je i sa spojevima prema izumu.
Rezultati
Inhibicija izmjenjivača Na+/H+:
Primjer IC50 (μmol/l)
1 9,3
2 <50
Claims (9)
1. Upotreba spoja I,
[image]
u kojoj
R1 je ravan ili razgranati C1-C8-alkil ili fenil-(CH2)m;
m je nula, 1 ili 2;
pri čemu fenilna jezgra nije supstituirana ili nosi jedan do tri supstituenta iz skupine koju čine F, Cl, CH3 ili CH3O,
R2 i R3 predstavljaju ravan ili razgranati C1-C6-alkil ili fenil,
pri čemu fenilna jezgra nije supstituirana ili nosi jedan do tri supstituenta iz skupine koju čine F, Cl, CH3 ili CH3O; ili
R2 i R3 mogu zajedno tvoriti (C5-C6)-prsten, koji nije supstituiran ili su oni kondenzirani na fenilni prsten, I njegovih farmaceutski podnošljivih soli, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu bolesti uzrokovanih ishemijskim stanjem.
2. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu srčanog infarkta.
3. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu angine pektoris.
4. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu ishemijskih stanja srca.
5. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu ishemijskih stanja perifernog i središnjeg nervnog sistema i udara kapi.
6. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu ishemijskih stanja perifernih organa i udova.
7. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za liječenje stanja šoka.
8. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za upotrebu pri kirurškim operacijama i transplantacijama organa.
9. Upotreba spoja I prema zahtjevu 1, naznačena time, da se on koristi za proizvodnju lijeka za konzerviranje i odlaganje transplantata za kirurške zahvate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19951701A DE19951701A1 (de) | 1999-10-27 | 1999-10-27 | Verwendung von 2-Imidazolyl-substituierten Carbinolen zur Herstellung eines Medikaments zur Behandlung oder Prophylaxe von durch ischämischen Zuständen bewirkten Krankheiten |
| PCT/EP2000/010126 WO2001030327A2 (de) | 1999-10-27 | 2000-10-14 | Verwendung von 2-imidazolyl-substituierten carbinolen zur herstellung eines medikaments zur behandlung oder prophylaxe von durch ischämischen zuständen |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20020362A2 true HRP20020362A2 (en) | 2004-02-29 |
Family
ID=7927020
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR20020362A HRP20020362A2 (en) | 1999-10-27 | 2002-04-25 | Use of 2-imidazolyl substituted carbinols for production of a medicament for treatment or prohylaxis of disease states as a result of ischaemic conditions |
Country Status (30)
| Country | Link |
|---|---|
| US (1) | US6291502B1 (hr) |
| EP (1) | EP1227811B1 (hr) |
| JP (1) | JP2003512419A (hr) |
| KR (1) | KR20020060213A (hr) |
| CN (1) | CN1188125C (hr) |
| AR (1) | AR026241A1 (hr) |
| AT (1) | ATE257702T1 (hr) |
| AU (1) | AU778836B2 (hr) |
| BR (1) | BR0015024A (hr) |
| CA (1) | CA2388956A1 (hr) |
| CZ (1) | CZ295925B6 (hr) |
| DE (2) | DE19951701A1 (hr) |
| DK (1) | DK1227811T3 (hr) |
| EE (1) | EE200200218A (hr) |
| ES (1) | ES2213621T3 (hr) |
| HK (1) | HK1048938B (hr) |
| HR (1) | HRP20020362A2 (hr) |
| HU (1) | HUP0203213A3 (hr) |
| IL (1) | IL149208A0 (hr) |
| NO (1) | NO20021909L (hr) |
| NZ (1) | NZ518586A (hr) |
| PL (1) | PL355911A1 (hr) |
| PT (1) | PT1227811E (hr) |
| RU (1) | RU2257205C2 (hr) |
| SK (1) | SK5512002A3 (hr) |
| TR (1) | TR200201140T2 (hr) |
| TW (1) | TWI246424B (hr) |
| WO (1) | WO2001030327A2 (hr) |
| YU (1) | YU20902A (hr) |
| ZA (1) | ZA200203035B (hr) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6726829B2 (en) * | 1997-04-08 | 2004-04-27 | Scimed Life Systems, Inc. | Method of manufacturing a stent |
| EP1911740B1 (en) * | 2002-01-04 | 2013-02-27 | NeuroSearch A/S | Potassium channel modulators |
| US10040767B2 (en) | 2014-05-15 | 2018-08-07 | Peloton Therapeutics, Inc. | Benzimidazole derivatives and uses thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE793407A (fr) * | 1971-12-28 | 1973-06-28 | Hoechst Ag | Imidazolyl - (2) -carbinols ayant une activite hypolipidemique et leur procede de preparation |
| US4152441A (en) | 1972-02-04 | 1979-05-01 | Gist-Brocades N.V. | Analgesic imidazolemethanols |
| BE794940A (fr) * | 1972-02-04 | 1973-08-02 | Gist Brocades Nv | Nouveaux composes anorexigenes |
| US5063220A (en) * | 1988-10-21 | 1991-11-05 | Syntex Pharmaceuticals, Ltd. | Parenteral formulations of 1-diphenylmethyl-4-((2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl)piperazine |
| US5561134A (en) * | 1990-09-25 | 1996-10-01 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Compounds having antihypertensive, cardioprotective, anti-ischemic and antilipolytic properties |
| US6175013B1 (en) * | 1994-06-10 | 2001-01-16 | Eli Lilly And Company | Imidazolinyl tachykinin receptor antagonists |
| CA2258165C (en) | 1996-06-27 | 2009-03-03 | Marc Gaston Venet | N-[4-(heteroarylmethyl)phenyl]-heteroarylamines |
-
1999
- 1999-10-27 DE DE19951701A patent/DE19951701A1/de not_active Withdrawn
-
2000
- 2000-10-14 AT AT00972764T patent/ATE257702T1/de not_active IP Right Cessation
- 2000-10-14 DK DK00972764T patent/DK1227811T3/da active
- 2000-10-14 CA CA002388956A patent/CA2388956A1/en not_active Abandoned
- 2000-10-14 CN CNB008128219A patent/CN1188125C/zh not_active Expired - Fee Related
- 2000-10-14 IL IL14920800A patent/IL149208A0/xx unknown
- 2000-10-14 AU AU11382/01A patent/AU778836B2/en not_active Ceased
- 2000-10-14 PL PL00355911A patent/PL355911A1/xx not_active IP Right Cessation
- 2000-10-14 TR TR2002/01140T patent/TR200201140T2/xx unknown
- 2000-10-14 JP JP2001532747A patent/JP2003512419A/ja not_active Abandoned
- 2000-10-14 BR BR0015024-0A patent/BR0015024A/pt not_active IP Right Cessation
- 2000-10-14 CZ CZ20021452A patent/CZ295925B6/cs not_active IP Right Cessation
- 2000-10-14 HU HU0203213A patent/HUP0203213A3/hu unknown
- 2000-10-14 NZ NZ518586A patent/NZ518586A/en unknown
- 2000-10-14 RU RU2002113666/15A patent/RU2257205C2/ru not_active IP Right Cessation
- 2000-10-14 EP EP00972764A patent/EP1227811B1/de not_active Expired - Lifetime
- 2000-10-14 YU YU20902A patent/YU20902A/sh unknown
- 2000-10-14 ES ES00972764T patent/ES2213621T3/es not_active Expired - Lifetime
- 2000-10-14 PT PT00972764T patent/PT1227811E/pt unknown
- 2000-10-14 WO PCT/EP2000/010126 patent/WO2001030327A2/de active IP Right Grant
- 2000-10-14 DE DE50005040T patent/DE50005040D1/de not_active Expired - Lifetime
- 2000-10-14 KR KR1020027005275A patent/KR20020060213A/ko not_active Application Discontinuation
- 2000-10-14 SK SK551-2002A patent/SK5512002A3/sk unknown
- 2000-10-14 EE EEP200200218A patent/EE200200218A/xx unknown
- 2000-10-24 TW TW089122280A patent/TWI246424B/zh active
- 2000-10-25 AR ARP000105619A patent/AR026241A1/es unknown
- 2000-10-26 US US09/695,920 patent/US6291502B1/en not_active Expired - Fee Related
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2002
- 2002-04-17 ZA ZA200203035A patent/ZA200203035B/en unknown
- 2002-04-23 NO NO20021909A patent/NO20021909L/no unknown
- 2002-04-25 HR HR20020362A patent/HRP20020362A2/hr not_active Application Discontinuation
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2003
- 2003-02-18 HK HK03101149.5A patent/HK1048938B/zh not_active IP Right Cessation
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