HRP20020363A2 - Use of 2-amino-3,4-dihydro-quinazolines for producing a medicament for treating or preventing diseases caused by ischaemic conditions - Google Patents
Use of 2-amino-3,4-dihydro-quinazolines for producing a medicament for treating or preventing diseases caused by ischaemic conditions Download PDFInfo
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- HRP20020363A2 HRP20020363A2 HR20020363A HRP20020363A HRP20020363A2 HR P20020363 A2 HRP20020363 A2 HR P20020363A2 HR 20020363 A HR20020363 A HR 20020363A HR P20020363 A HRP20020363 A HR P20020363A HR P20020363 A2 HRP20020363 A2 HR P20020363A2
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- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
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- 230000001575 pathological effect Effects 0.000 description 1
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- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000009117 preventive therapy Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000009993 protective function Effects 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
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- 239000002600 sunflower oil Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
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- A61P3/00—Drugs for disorders of the metabolism
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- A61P3/06—Antihyperlipidemics
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- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
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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
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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
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Description
Izum se odnosi na upotrebu 2-amino-3,4-dihidro-kinazolina formule I
[image]
kao i njegovih farmaceutski prihvatljivih soli za proizvodnju lijeka za liječenje ili profilaksu ishemijskih stanja. U formuli I
R1 i R2 predstavljaju vodik, F, Cl, Br, J, ravan ili razgranati C1-C4alkil, C1-C4-alkoksi,
R3 je vodik, ravan ili razgranati C1-C4-alkil ili fenil, pri čemu fenilna jezgra nije supstituirana ili nosi jedan do tri supstituenta odabrana iz skupine koju čine F, Cl, CH3 i CH3O.
Prednost se daje upotrebi spojeva formule I kao i njihovim solima u kojima
R1 i R2 predstavljaju vodik, fluor, klor, ravan ili razgranati C1-C4-alkil, C1-C4-alkoksi;
R3 je vodik ili metil.
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.
Spojevi formule I su poznati iz
EP 530 994, gdje su oni opisani kao inhibitori HIV-reverzne transkriptaze u indikaciji AIDS-a:
US patentnog spisa 3 560 050, u kojem je opisano njihovo analgetsko, diuretsko i anti-upalno djelovanje; i iz
Kosasayama et al., Chem. Phariru Buli. 27, 880 (1979) i Ishikawa et al. Ibid, 28, 1357 (1980), gdje se je za 2-amino-4-fenil-3,4-dihidrokinazolin pokazala inhibicija agregacije trombocita.
Sada je iznenađujuće pronađeno da se ovi već poznati spojevi odlikuju inhibicijom izmjene Na+/H+. Time su oni zbog njihovih farmakoloških svojstava posebno prikladni za proizvodnju antiaritmijskih lijekova 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 nervenog 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.
Osim toga, ovi spojevi formule I upotrijebljeni prema izumu odlikuju se jakim inhibirajućim djelovanjem na proliferaciju stanica, na primjer proliferaciju fibroblasta i proliferaciju glatkih mišićnih stanica krvnih žila. Zbog toga prema izumu upotrijebljeni spojevi formule I dolaze u obzir kao dragocjeni terapeutici za bolesti kod kojih proliferacija stanica predstavlja primarni ili sekundarni uzrok, i oni se stoga mogu upotrijebiti kao anti-aterosklerotici, sredstva protiv diabetskih kasnih komplikacija, bolesti raka, fibroznih bolesti kao što je plućna fibroza, fibroza jetre ili fibroza bubrega, hipertrofije i hiperplazije organa, naročito kod hiperplazije prostate odnosno hipertrofije prostate.
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.
Osim toga pronađeno je da prema izumu upotrijebljeni spojevi formule I pokazuju povoljan utjecaj na serum-lipoproteine. Općenito je poznato da za nastanak arterio-sklerotičnih promjena krvnih žila, posebno koronarnih srčanih bolesti, bitan faktor rizika predstavljaju previsoke vrijednosti masti u krvi, takozvane hiperlipo-proteinemije. Zbog toga za profilasku i regresiju aterosklerotičnih promjena izvanredno značenje ima smanjenje povišenih serum-lipoproteina. Osim redukcije ukupnog sadržaja kolesterina u serumu, posebno značenje ima također i smanjenje udjela specifičnih aterogenih frakcija lipida tog ukupnog kolesterina, naročito lipoproteina niske gustoće (LDL) i lipoproteina vrlo niske gustoće (VLDL), jer te frakcije lipida predstavljaju aterogeni faktor rizika. Suprotno tome, lipoproteinima visoke gustoće pripisuje se zaštitnu funkciju protiv koronarnih srčanih bolesti. S tim u skladu, hipolipidemici bi trebali biti u stanju smanjiti ne samo ukupni kolesterin, već posebno VLDL i LDL frakcije kolesterina u serumu. Sada je pronađeno da prema izumu upotrijebljeni spojevi formule I, što se tiče utjecaja na količinu lipida u serumu, pokazuju dragocjena terapeutski korisna svojstva. Tako oni značajno snizuju povišenu koncentraciju LDL i VLDL u serumu, koja se opaža, na primjer, kod povišenog dijetalnog uzimanja hrane bogate kolesterinom i lipidima ili kod patoloških promjena izmjene tvari, na primjer kod genetski uvjetovanih hiperlipidemija. Oni se stoga mogu primijeniti za profilaksu i za regresiju aterosklerotičnih promjena, pri čemu oni isključuju kauzalni faktor rizika. Tu se ne ubrajaju samo primarne hiperlipidamihe, već također i određene sekundarne hiper-lipidemije, koje se pojavljuju npr. kod dijabetesa. Nadalje, prema izumu upotrijebljeni spojevi formule I dovode do vidljivog smanjenja infarkta izazvanog anomalijama izmjene tvari i posebno do značajnog ograničenja veličine induciraneg infarka i stupnja njegove težine. Nadalje, prema izumu upotrijebljeni spojevi formule I dovode do učinkovite zaštite od oštećenja endotela uzrokovanih anomalijama izmjene tvari. S tom zaštitom krvnih žila od sindroma endotelne disfunkcije, spojevi formule I su dragocjeni lijek za prevenciju i za liječenje koronarnih spazmi krvnih žila, aterogeneze i ateroskleroze, lijeve ventrikularne hipertrofije i dilatirajuće kardio-miopatije, i tromboznih oboljenja.
Spojevi I upotrijebljeni prema izumu mogu se stoga korisno upotrijebiti za
za proizvodnju lijeka za liječenje hiperkolesterinemije;
za proizvodnju lijeka za prevenciju aterogeneze;
za proizvodnju lijeka za prevenciju i liječenje ateroskleroze;
za proizvodnju lijeka za prevenciju i liječenje bolesti do kojih dolazi zbog povišene količine kolesterina;
za proizvodnju lijeka za prevenciju i liječenje bolesti do kojih dolazi zbog endotelne disfunkcije;
za proizvodnju lijeka za prevenciju i liječenje s aterosklerozom inducirane hipertonije;
za proizvodnju lijeka za prevenciju i liječenje s aterosklerozom induciranih tromboza;
za proizvodnju lijeka za prevenciju i liječenje ishemijskih ozljeda i postishemijskih reperfuzijskih ozljeda induciranih s hiperkolesterinrmijom i endotelnom disfunkcijom;
za proizvodnju lijeka za prevenciju i liječenje kardijalnih hipertrofija i kardiomiopatija induciranih s hiperkolesterinemijom i endotelnom disfunkcijom;
za proizvodnju lijeka za prevenciju i liječenje koronarnih spazmi krvnih žila i miokardijalnog infarkta induciranih hiperkolesterinemijom i endotelnom disfunkcijom;
za proizvodnju lijeka za liječenje navedenih tegoba u kombinaciji s tvarima koje snizuju krvni tlak, ponajprije s inhibitorima enzima koji pretvara angiotenzin (ACE) i angiotenzin-receptor antagonistima. Kombinacija NHE-inhibitora formule I s aktivnom tvari koja snizuje količinu masnoće u krvi, ponajprije s inhibitorom HMG-CoA-reduktaze (npr. lovastatin ili pravastatin), pri čemu potonji donosi hipolipidemijski učinak i time povisuje hipolipidemijska svojstva NHE-inhibitora formule I, pokazala se je najpovoljnijom kombinacijom s pojačanim učinkom i smanjenom upotrebom aktivne tvari.
Predmet zahtjeva je upotreba inhibitora izmjene natrij-protona formule I za proizvodnju novog lijeka za sniženje povišene količine masnoće u krvi, kao i kombinacija inhibitora izmjene natrij-protona s lijekovima koji snizuju krvni tlak i/ili hipolipidemijski učinkovitim lijekovima.
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 nedvojebnom 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
DMSO dimetilsulfoksid
RT sobna temperatura
EE etil acetat (EtOAc)
tal. talište
ekv. ekvivalent
Primjer 1
2-amino-4-(4-metoksi-fenil)-3,4-dihidro-kinazolin hidroklorid, bezbojna kruta tvar, tal. 169°C, M++H = 254.
Put sinteze
2-amino-fenil-(4-metoksi-fenil)-keton reagira s 1,2 ekv. formamidin-hidroklorida u prisutnosti kalijevog karbonata uz grijanje u DMSO, čime se dobije odgovarajući kinazolin. Nakon vodene obrade sirov proizvod se hidrira s 10% Pd/C u etanolu, zatim se kromatografira na stupcu i proizvod, hidroklorid, se dobije kao kruta tvari s eterskom solnom kiselinom.
Primjer 2
2-amino-4-(3,4-dimetoksi-fenil)-3, 4-dihidro-kinazolinij-fumarat, bezbojna kruta tvar, tal. 179°C, M++H = 284.
Sinteza se odvija analogno primjeru 1 upotrebom 2-amino-fenil-(3,4-dimetoksi-fenil)-ketona. Za tvorbu soli baza reagira s l ekv. fumarne kiseline u EE.
Primjer 3
2-amino-4-(3,4-dimetoksi-fenil)-3-metil-3,4-dihidro-kinazolinij-fumarat, bezbojna kruta tvar, tal. 202°C, M++H=298.
Put sinteze:
Odgovarajući benzhidrilamin proizveden je počevši od 2-amino-fenil-(3,4-dimetnoksi-fenil)-ketona s metilamin/titan-tetrakloridom i zatim redukcijom s natrijevim bor-hidridom. Sirov proizvod se zatim ciklizira sa suviškom bromcijana u 3,4-dihidro-kinazolin i kromatografira na stupcu. Završna tvorba soli vrši se postupkom koji je opisan u primjeru 2.
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 je 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.
Netto 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 3,4 x 10-6
2 3,2 x 10-6
3 4,1 x 10-6
Claims (12)
1. Upotreba spoja formule I
[image]
kao i njegovih farmaceutski prihvatljivih soli, u kojoj formuli
R1 i R2 predstavljaju vodik, F, Cl, Br, J, ravan ili razgranati C1-C4-alkil, C1-C4-alkoksi,
R3 je vodik, ravan ili razgranati C1-C4-alkil ili fenil, pri čemu fenilna jezgra nije supstituirana ili nosi jedan do tri supstituenta odabrana iz skupine koju čine F, Cl, CH3 i CH3O;
naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu ishemijskih stanja.
2. Upotreba prema zahtjevu 1, naznačena time, da u formuli I
R1 i R2 predstavljaju vodik, fluor, klor, ravan ili razgranati C1-C4-alkil, C1-C4-alkoksi;
R3 je vodik ili metil.
3. Upotreba spoja I prema zahtjevima 1 do 2, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu srčanog infarkta.
4. Upotreba spoja I prema zahtjevima 1 do 2, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu angine pektoris.
5. Upotreba spoja I prema zahtjevima 1 do 2, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu ishemijskih stanja srca.
6. Upotreba spoja I prema zahtjevima 1 do 2, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu ishemijskih stanja perifernog i središnjeg nervnog sistema i udara kapi.
7. Upotreba spoja I prema zahtjevima 1 do 2, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu ishemijskih stanja, perifernih organa i udova.
8. Upotreba spoja I prema zahtjevima 1 do 2, naznačena time, da se on koristi za proizvodnju lijeka za liječenje stanja šoka.
9. Upotreba spoja, I prema zahtjevima 1do 2, naznačena time, da se on koristi za proizvodnju lijeka za upotrebu pri kirurškim operacijama i transptantacijama organa.
10. Upotreba spoja I prema zahtjevima 1 do 2, naznačena time, da se on koristi za proizvodnju lijeka za konzerviranje i odlaganje transplantata za kirurške zahvate.
11. Upotreba spoja I prema zahtjevima 1 do 2, naznačena time, da se on koristi za proizvodnju lijeka za liječenje bolesti kod kojih proliferacija stanica predstavlja primarni ili sekundarni uzrok.
12. Upotreba spoja I prema zahtjevima 1 do 2, naznačena time, da se on koristi za proizvodnju lijeka za liječenje ili profilaksu poremećaja izmjene masnih tvari.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19951702A DE19951702A1 (de) | 1999-10-27 | 1999-10-27 | Verwendung von 2-Amino-3,4-dihydro-chinazolinen zur Herstellung eines Medikaments zur Behandlung oder Prophylaxe von durch ischämischen Zuständen bewirkten Krankheiten |
| PCT/EP2000/010127 WO2001030328A2 (de) | 1999-10-27 | 2000-10-14 | Verwendung von 2-amino-3,4-dihydro-chinazolinen zur herstellung eines medikaments zur behandlung oder prophylaxe von durch ischämischen zuständen bewirkten krankheiten |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20020363A2 true HRP20020363A2 (en) | 2004-02-29 |
Family
ID=7927021
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR20020363A HRP20020363A2 (en) | 1999-10-27 | 2002-04-25 | Use of 2-amino-3,4-dihydro-quinazolines for producing a medicament for treating or preventing diseases caused by ischaemic conditions |
Country Status (28)
| Country | Link |
|---|---|
| US (1) | US6331546B1 (hr) |
| EP (1) | EP1244454B1 (hr) |
| JP (1) | JP2003512420A (hr) |
| KR (1) | KR20020041831A (hr) |
| CN (1) | CN1181822C (hr) |
| AR (1) | AR026242A1 (hr) |
| AT (1) | ATE324111T1 (hr) |
| AU (1) | AU7664800A (hr) |
| BR (1) | BR0014985A (hr) |
| CA (1) | CA2388965A1 (hr) |
| CZ (1) | CZ20021414A3 (hr) |
| DE (2) | DE19951702A1 (hr) |
| EE (1) | EE200200215A (hr) |
| HK (1) | HK1050480A1 (hr) |
| HR (1) | HRP20020363A2 (hr) |
| HU (1) | HUP0203774A3 (hr) |
| IL (1) | IL149160A0 (hr) |
| MX (1) | MXPA02004035A (hr) |
| NO (1) | NO20021710D0 (hr) |
| NZ (1) | NZ518588A (hr) |
| PL (1) | PL356399A1 (hr) |
| RU (1) | RU2002113667A (hr) |
| SK (1) | SK5582002A3 (hr) |
| TR (1) | TR200201141T2 (hr) |
| TW (1) | TWI227135B (hr) |
| WO (1) | WO2001030328A2 (hr) |
| YU (1) | YU30602A (hr) |
| ZA (1) | ZA200204057B (hr) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| EP1109559B1 (en) * | 1998-08-13 | 2005-10-26 | Hadasit Medical Research Services & Development Co., Ltd. | Inhibition of pathogenic processes related to tissue trauma |
| PL369313A1 (en) * | 2001-12-05 | 2005-04-18 | Aventis Pharma Deutschland Gmbh | Substituted 4-phenyltetrahydroisoquinolines, method for the production thereof, the use thereof as medicaments, in addition to a medicament containing same |
| DE10163914A1 (de) * | 2001-12-22 | 2003-07-03 | Aventis Pharma Gmbh | Substituierte 4-Phenyltetrahydroisochinolinium-Salze, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, sowie sie enthaltendes Medikament |
| DE10312963A1 (de) * | 2003-03-24 | 2004-10-07 | Aventis Pharma Deutschland Gmbh | Substituierte 4-Phenyltetrahydroisochinoline, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, sowie sie enthaltendes Medikament |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3560601A (en) | 1968-11-25 | 1971-02-02 | Ford Motor Co | Process for manufacturing porous thermoplastic sheet material |
| IL102764A0 (en) * | 1991-08-16 | 1993-01-31 | Merck & Co Inc | Quinazoline derivatives,and pharmaceutical compositions containing them |
| WO1994007498A1 (en) * | 1992-10-07 | 1994-04-14 | Sumitomo Pharmaceuticals Company, Limited | Pharmaceutical composition for inhibiting tumor necrosis factor production |
| DE19713427A1 (de) * | 1997-04-01 | 1998-10-08 | Hoechst Ag | Ortho-substituierte Benzoylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament |
-
1999
- 1999-10-27 DE DE19951702A patent/DE19951702A1/de not_active Withdrawn
-
2000
- 2000-10-14 CZ CZ20021414A patent/CZ20021414A3/cs unknown
- 2000-10-14 RU RU2002113667/15A patent/RU2002113667A/ru not_active Application Discontinuation
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- 2000-10-14 CA CA002388965A patent/CA2388965A1/en not_active Abandoned
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- 2000-10-14 WO PCT/EP2000/010127 patent/WO2001030328A2/de active IP Right Grant
- 2000-10-14 EP EP00966165A patent/EP1244454B1/de not_active Expired - Lifetime
- 2000-10-14 KR KR1020027005359A patent/KR20020041831A/ko not_active Application Discontinuation
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- 2000-10-14 BR BR0014985-3A patent/BR0014985A/pt not_active IP Right Cessation
- 2000-10-14 DE DE50012667T patent/DE50012667D1/de not_active Expired - Lifetime
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Also Published As
| Publication number | Publication date |
|---|---|
| US6331546B1 (en) | 2001-12-18 |
| NO20021710L (no) | 2002-04-11 |
| EE200200215A (et) | 2003-06-16 |
| WO2001030328A2 (de) | 2001-05-03 |
| PL356399A1 (en) | 2004-06-28 |
| HUP0203774A3 (en) | 2003-07-28 |
| TR200201141T2 (tr) | 2002-11-21 |
| HUP0203774A2 (en) | 2003-05-28 |
| BR0014985A (pt) | 2003-07-22 |
| ATE324111T1 (de) | 2006-05-15 |
| DE19951702A1 (de) | 2001-05-03 |
| NZ518588A (en) | 2004-06-25 |
| CN1181822C (zh) | 2004-12-29 |
| IL149160A0 (en) | 2002-11-10 |
| JP2003512420A (ja) | 2003-04-02 |
| CA2388965A1 (en) | 2001-05-03 |
| NO20021710D0 (no) | 2002-04-11 |
| TWI227135B (en) | 2005-02-01 |
| WO2001030328A3 (de) | 2002-06-20 |
| DE50012667D1 (de) | 2006-06-01 |
| SK5582002A3 (en) | 2002-08-06 |
| EP1244454A2 (de) | 2002-10-02 |
| CN1384747A (zh) | 2002-12-11 |
| EP1244454B1 (de) | 2006-04-26 |
| YU30602A (sh) | 2004-12-31 |
| ZA200204057B (en) | 2003-02-26 |
| RU2002113667A (ru) | 2004-01-10 |
| AR026242A1 (es) | 2003-02-05 |
| AU7664800A (en) | 2001-05-08 |
| CZ20021414A3 (cs) | 2002-07-17 |
| HK1050480A1 (en) | 2003-06-27 |
| MXPA02004035A (es) | 2002-10-11 |
| KR20020041831A (ko) | 2002-06-03 |
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