NO334451B1 - Medication for use in preventing and / or treating hypertension or arteriosclerosis and using the ingredients for the manufacture of a medicament for such use. - Google Patents
Medication for use in preventing and / or treating hypertension or arteriosclerosis and using the ingredients for the manufacture of a medicament for such use. Download PDFInfo
- Publication number
- NO334451B1 NO334451B1 NO20054020A NO20054020A NO334451B1 NO 334451 B1 NO334451 B1 NO 334451B1 NO 20054020 A NO20054020 A NO 20054020A NO 20054020 A NO20054020 A NO 20054020A NO 334451 B1 NO334451 B1 NO 334451B1
- Authority
- NO
- Norway
- Prior art keywords
- use according
- hypertension
- drug
- prophylaxis
- treatment
- Prior art date
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Abstract
En medisin for forhindring og/eller behandling av arteriosl<lerose, hypertensjon, hjertesyl<dommer, nyresyl<dommer eller cerebrovaskulære sykdommer. Det omfatter følgende bestanddeler som aktive bestanddeler: (A) en angiotensin II reseptorantagonist valgt fra gruppen bestående av en forbindelse representert ved følgende formel (I), farmakologisk akseptable estere derav og farmakologisk akseptable salter av disse (for eksempel olmesartanmedoksomil); og (B) en kalsiumantagonist valgt fra gruppen bestående av 1,4-dihydropyridinforbindelser og farmakologisk akseptable salter av disse (for eksempel azelnidipin).A medicine for the prevention and / or treatment of arteriosclerosis, hypertension, heart failure, kidney failure or cerebrovascular disease. It comprises the following ingredients as active ingredients: (A) an angiotensin II receptor antagonist selected from the group consisting of a compound represented by the following formula (I), pharmacologically acceptable esters thereof and pharmacologically acceptable salts thereof (for example olmesartan medoxomil); and (B) a calcium antagonist selected from the group consisting of 1,4-dihydropyridine compounds and pharmacologically acceptable salts thereof (for example azelnidipine).
Description
Teknisk område Technical area
Foreliggende oppfinnelse angår et medikament for profylakse og/eller behandling av hypertensjon eller arteriosklerose. I tillegg angår foreliggende oppfinnelse et medikament for profylakse og/eller medisinsk behandling av sykdommer forårsaket av hypertensjon slik som hjertesykdommer (angina pektoris, myokardialt infarkt, arrytmi (innbefattende plutselig død), hjertesvikt eller hjertehypertrofi), nyresykdommer (diabetisk nefropati, glomerulonefritt eller nefrosklerose) eller cerebrovaskulære sykdommer (cerebral infarkt eller cerebral blødning). The present invention relates to a drug for the prophylaxis and/or treatment of hypertension or arteriosclerosis. In addition, the present invention relates to a drug for the prophylaxis and/or medical treatment of diseases caused by hypertension such as heart diseases (angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure or cardiac hypertrophy), kidney diseases (diabetic nephropathy, glomerulonephritis or nephrosclerosis) or cerebrovascular diseases (cerebral infarction or cerebral haemorrhage).
Kjent teknikk Known technique
For tiden er kalsiumkanalblokkere og inhibitorer av nyre-angiotensinsystemet vidt anvendt klinisk for profylakse og behandling av hypertensjon. Forskjellige typer av kalsiumkanalblokkere anvendes, og blant disse er 1,4-dihydropyridinderivater slik som amoldipin, benidipin, nitrendipin, manidipin, nikardipin, nifedipin, nisoldipin, cilnidipin, lerkanidipin, niguldipin, nimodipin, aranidipin, efonidipin, barnidipin, felodipin, nilvadipin, azelnidipin og lignende lenge-varende kalsiumkanalblokkere og er vidt anvendt klinisk som det første valg av antihypertensive midler. Som inhibitorer av nyre-angiotensinsystemet har en videre klinisk bruk av angiotensin II reseptorantagonister blitt større og større, da for det første angiotensin II reseptorantagonister mangler bivirkninger slik som hoste, som har vært årsak til problemer fremkalt av angiotensinomdannende enzym (ACE) inhibitorer, og for det andre ved at de utviser beskyttende effekt på det kardiovaskulære og renale systemet. Blodtrykket til pasienter med hypertensjon kan imidlertid ikke fult ut kontrolleres med bare en type av disse legemidler i mange tilfeller. Currently, calcium channel blockers and inhibitors of the renal angiotensin system are widely used clinically for the prophylaxis and treatment of hypertension. Different types of calcium channel blockers are used, and among these are 1,4-dihydropyridine derivatives such as amoldipine, benidipine, nitrendipine, manidipine, nicardipine, nifedipine, nisoldipine, cilnidipine, lercanidipine, niguldipine, nimodipine, aranidipine, efonidipine, barnidipine, felodipine, nilvadipine, azelnidipine and similar long-acting calcium channel blockers and are widely used clinically as the first choice of antihypertensive agents. As inhibitors of the renal angiotensin system, further clinical use of angiotensin II receptor antagonists has become greater and greater, as, firstly, angiotensin II receptor antagonists lack side effects such as cough, which have been the cause of problems caused by angiotensin-converting enzyme (ACE) inhibitors, and for the second in that they exhibit a protective effect on the cardiovascular and renal system. However, the blood pressure of patients with hypertension cannot be fully controlled with just one type of these drugs in many cases.
Da kalsiumkanalblokkere utviser natriuretisk virkning i tillegg til vasodillaterende virkning er de også effektive mot hypertensjon forårsaket ved tilbakeholdelse av væske (renin-uavhengig hypertensjon). På den annen side er angiotensin II reseptorantagonister særlig effektive mot renin-avhengig hypertensjon, og i tillegg utviser de glimrende beskyttende aktivitet i flere organer. En stabil og signifikant antihypertensiv effekt utvises derfor ved kombinert administrering av en kalsiumkanalblokker og en angiogensin II reseptorantagonist, uten hensyn til årsaken for hypertensjon. As calcium channel blockers exhibit a natriuretic effect in addition to a vasodilating effect, they are also effective against hypertension caused by fluid retention (renin-independent hypertension). On the other hand, angiotensin II receptor antagonists are particularly effective against renin-dependent hypertension, and in addition they exhibit excellent protective activity in several organs. A stable and significant antihypertensive effect is therefore demonstrated by combined administration of a calcium channel blocker and an angiogenin II receptor antagonist, regardless of the cause of hypertension.
Mange kombinasjonslegemidler omfattende en kalsiumkanalblokker og en angiotensin II reseptorantagonist er blitt foreslått (for eksempel internasjonal publikasjon nr. 01/15674 Official Gazette, internasjonal publikasjon nr. 01/78699 Official Gazette, internasjonal publikasjon nr. 02/43807 Official Gazette, internasjonal publikasjon nr. 01/76632 Official Gazette, internasjonal publikasjon nr. 01/74390 Official Gazette, japansk patentpublikasjon (Kohyo) nr. 2002-524408, internasjonal publikasjon nr. 92/10097 Official Gazette, japansk patentpublikasjon (Kokoku) nr. Hei 7-035372, britisk patentsøknad 2268743 Specification, japansk patentpublikasjon (Kokai) nr. Hei 6-56789, japansk patentpublikasjon (Kokai) nr. Hei 5-155867, US patentsøknad 2001/0004640 Specification, USP 6204281, japansk patent nr. 3057471, japansk patent nr. 2930252, japansk patentpublikasjon (Kohyo) nr. 2002-507213, japansk patentpublikasjon (Kohyo) nr. 2001-513498, japansk patentpublikasjon (Kohyo) nr. 2000-508632, japansk patentpublikasjon (Kokoku) nr. Hei 7-91299, japansk patentpublikasjon (Kokoku) nr. Hei 7-14939, japansk patentpublikasjon (Kokai) nr. Hei 6-65207, japansk patentpublikasjon (Kokai) nr. Hei 5-213894, japansk patentpublikasjon (Kohyo) nr. 2002-518417, japansk patentpublikasjon (Kohyo) nr. 2002-506010 og japansk patentpublikasjon (Kohyo) nr. 2001-522872) og det er beskrevet at optimal antihypertensiv effekt oppnås ved kombinert administrering av en spesifikk kalsiumkanalblokker og en spesifikk angiotensin II reseptorantagonist i noen av disse publikasjoner. Effekten av kombinert administrering av en spesifikk angiotensin II reseptorantagonist og en spesifikk kalsiumkanalblokker ifølge oppfinnelsen er imidlertid ikke kjent. Many combination drugs comprising a calcium channel blocker and an angiotensin II receptor antagonist have been proposed (for example International Publication No. 01/15674 Official Gazette, International Publication No. 01/78699 Official Gazette, International Publication No. 02/43807 Official Gazette, International Publication No. 01/76632 Official Gazette, International Publication No. 01/74390 Official Gazette, Japanese Patent Publication (Kohyo) No. 2002-524408, International Publication No. 92/10097 Official Gazette, Japanese Patent Publication (Kokoku) No. Hi 7-035372, British Patent Application 2268743 Specification, Japanese Patent Publication (Kokai) No. Hei 6-56789, Japanese Patent Publication (Kokai) No. Hei 5-155867, US Patent Application 2001/0004640 Specification, USP 6204281, Japanese Patent No. 3057471, Japanese Patent No. 2930252, Japanese Patent Publication (Kohyo) No. 2002-507213, Japanese Patent Publication (Kohyo) No. 2001-513498, Japanese Patent Publication (Kohyo) No. 2000-508632, Japan sk Patent Publication (Kokoku) No. Hei 7-91299, Japanese Patent Publication (Kokoku) No. Hei 7-14939, Japanese Patent Publication (Kokai) No. Hei 6-65207, Japanese Patent Publication (Kokai) No. Hei 5-213894, Japanese Patent Publication (Kohyo) No. 2002-518417, Japanese Patent Publication (Kohyo) No. 2002-506010 and Japanese Patent Publication (Kohyo) No. 2001-522872) and it is described that optimal antihypertensive effect is achieved by combined administration of a specific calcium channel blocker and a specific angiotensin II receptor antagonist in some of these publications. However, the effect of combined administration of a specific angiotensin II receptor antagonist and a specific calcium channel blocker according to the invention is not known.
På den annen side er karakteristika for patologiske forandringer ved de tidlige tilstander for ateriosklerose unormal fortykning av de middel arterier eller store arterier, og de patologiske forandringer ved den tidlige tilstand for arteriosklerose erkarakterisert vedskade på endotelium, vandring av vaskulære glattmuskelceller (VSMC) til tunika intima av blodkarene, proliferering av vaskulære glattmuskelceller, akkumulering av lipider innen cellene (skumceller) og lignende. Under hypertensive tilstander, som er assosiert med progresjon av arteriosklerose, er det i tillegg kjent at vaskulær cytoarkitektur forandres som svar på forskjellige belastende faktorer på karene og at remodellering av karene finner sted. Remodellering av karene indikerer strukturelle forandringer i karene forårsaket av hemodynamiske forandringer slik som forandringer av blodstrøm og trykk på blodkarvegger. I tillegg til substanser slik som vekstfaktorer og cytokiner, er vasoaktive substanser foreslått å bidra til utviklingen av prosessene. Eksempelvis er det kjent at angiotensin II letter proliferering av vaskulære glattmuskelceller (Medical Clinics of Japan, vol. 21, 1924, 1995), og også letter re-modellering av kar (Journal of Clinical and Experimental Medicine (IGAKU NO AYUMI), vol. 193, 361, 2000). On the other hand, the characteristics of pathological changes in the early states of arteriosclerosis are abnormal thickening of the medium arteries or large arteries, and the pathological changes in the early state of arteriosclerosis are characterized by damage to the endothelium, migration of vascular smooth muscle cells (VSMC) to the tunica intima of the blood vessels, proliferation of vascular smooth muscle cells, accumulation of lipids within the cells (foam cells) and the like. During hypertensive conditions, which are associated with the progression of arteriosclerosis, it is additionally known that vascular cytoarchitecture changes in response to various stress factors on the vessels and that remodeling of the vessels takes place. Remodeling of the vessels indicates structural changes in the vessels caused by hemodynamic changes such as changes in blood flow and pressure on blood vessel walls. In addition to substances such as growth factors and cytokines, vasoactive substances are suggested to contribute to the development of the processes. For example, it is known that angiotensin II facilitates proliferation of vascular smooth muscle cells (Medical Clinics of Japan, vol. 21, 1924, 1995), and also facilitates re-modelling of vessels (Journal of Clinical and Experimental Medicine (IGAKU NO AYUMI), vol. 193, 361, 2000).
Imidlertid er detaljerte mekanismer for utvikling av arteriosklerose fra patogenese til fremskredet sykdom ikke tilstrekkelig klargjort. I tillegg er detaljerte mekanismer for vaskulær remodellering også ukjent. Selv om det finnes enkelte rapporter som beskriver forholdet mellom angiotensin II reseptorantagonister og vaskulære re-modellering (Circulation, 104,2716, 2001) er effekten av kalsiumkanalblokkere på patologiske forandringer i arteriosklerose og vaskulær skade så vel som deres mekanismer lite kjent. Videre er den profylaktiske og terapeutiske effekt av kombinert administrering av en kalsiumkanalblokker og en angiotensin II reseptor-antagonist mot arteriosklerose lite beskrevet, om over hodet. I særdeleshet er effekten av kalsiumkanalblokkere på nyre-angiogensinsystemet og den synergistiske effekt av en kalsiumkanalblokker og en angiotensin II reseptorantagonist lite kjent, til tross for det faktum at de er viktige gjenstander i de terapeutiske aspekter av arteriosklerose. However, detailed mechanisms for the development of arteriosclerosis from pathogenesis to advanced disease have not been sufficiently elucidated. In addition, detailed mechanisms of vascular remodeling are also unknown. Although there are some reports describing the relationship between angiotensin II receptor antagonists and vascular re-modelling (Circulation, 104,2716, 2001), the effect of calcium channel blockers on pathological changes in arteriosclerosis and vascular damage as well as their mechanisms is little known. Furthermore, the prophylactic and therapeutic effect of combined administration of a calcium channel blocker and an angiotensin II receptor antagonist against arteriosclerosis is little described, if over the top. In particular, the effect of calcium channel blockers on the renal angiogenesis system and the synergistic effect of a calcium channel blocker and an angiotensin II receptor antagonist are little known, despite the fact that they are important objects in the therapeutic aspects of arteriosclerosis.
Da perkutan koronar intervensjon (PCI) innbefattende perkutan transluminal koronar angioplasti (PTCA) og stentimplantasjon har lav inntreningsevne inntar de imidlertid en sentral stilling i nåværende terapeutiske strategier mot ischemiske hjertesykdommer. Imidlertid er restenose som fremkommer innen flere måneder etter kirurgi i 30-45 % av pasientene som gjennomgår disse kirurgiske prosedyrer et hovedproblem. Med hensyn til mekanismene for restenose etter PCI er reduksjon i diameterne av helkar i en senere periode etter PCI (dvs. remodellering) betraktet som viktige, i tillegg til hyperplasi og hypertrofi av neointima forårsaket ved profilering av glattmuskelceller og akkumulering av ekstracellulær matriks, som produseres av glattmuskelceller (Coronary Intervention, vol. 1,12, Medical Clinics of Japan, vol. 21,1924, 1995). Under disse omstendigheter er utvikling av nye medikamenter som effektivt kan forhindre restenose av kar etter PCI etterstrebet. Ikke desto mindre er ingen medikamenter med høy virksomhet hittil blitt utviklet. However, as percutaneous coronary intervention (PCI) including percutaneous transluminal coronary angioplasty (PTCA) and stent implantation have a low training capacity, they occupy a central position in current therapeutic strategies against ischemic heart diseases. However, restenosis, which occurs within several months after surgery in 30-45% of patients undergoing these surgical procedures, is a major problem. With regard to the mechanisms of restenosis after PCI, reduction in the diameters of whole vessels in a later period after PCI (i.e. remodeling) is considered important, in addition to hyperplasia and hypertrophy of the neointima caused by the profiling of smooth muscle cells and the accumulation of extracellular matrix, which is produced of smooth muscle cells (Coronary Intervention, vol. 1,12, Medical Clinics of Japan, vol. 21,1924, 1995). Under these circumstances, the development of new drugs that can effectively prevent vessel restenosis after PCI is sought after. Nevertheless, no drugs with high activity have been developed so far.
Beskrivelse av oppfinnelsen Description of the invention
Målet med foreliggende oppfinnelse er å tilveiebringe medikamenter for forhindring og/eller behandling av hypertensjon eller arteriosklerose. Videre er et annet mål med foreliggende oppfinnelse å tilveiebringe medikamenter som forhindre progresjon av arteriosklerose så vel som restenose av kar etter PCI. The aim of the present invention is to provide drugs for the prevention and/or treatment of hypertension or arteriosclerosis. Furthermore, another aim of the present invention is to provide drugs which prevent the progression of arteriosclerosis as well as restenosis of vessels after PCI.
Videre er det et mål med foreliggende oppfinnelse å tilveiebringe medikamenter for profylakse eller behandling av hypertensjon eller sykdommer forårsaket av hypertensjon. Nærmere bestemt er det et mål å tilveiebringe medikamenter for profylakse og/eller medisinsk behandling av sykdommer forårsaket av hypertensjon slik som hjertesykdommer (angina pektoris, myokardialt infarkt, arrytmi (innbefattende plutselig død), hjertesvikt eller hjertehypertropi), nyresykdommer (diabetisk nefropati, glomerulonefritt eller nefrosklerose) eller cerebrovaskulære sykdommer (cerebralt infarkt eller cerebral blødning) (i særdeleshet medikamenter for forhindring eller behandling av hypertensjon). Furthermore, it is an aim of the present invention to provide medicaments for the prophylaxis or treatment of hypertension or diseases caused by hypertension. More specifically, it is an aim to provide medicaments for the prophylaxis and/or medical treatment of diseases caused by hypertension such as heart diseases (angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure or cardiac hypertrophy), kidney diseases (diabetic nephropathy, glomerulonephritis or nephrosclerosis) or cerebrovascular diseases (cerebral infarction or cerebral haemorrhage) (in particular drugs for the prevention or treatment of hypertension).
Foreliggende oppfinnere har grundig studert de ovenfor beskrevne mål, og funnet at kombinert administrering av en spesifikk kalsiumkanalblokker og en spesifikk angiotensin II reseptorantagonist kraftig forhindrer proliferering av vaskulære glattmuskelceller så vel som neointima-dannelse i blodkar, og at den inhiberende virkning av den kombinerte administrering av de to typer av midler ble funnet å være synergistisk, og også funnet at den inhiberende virkning ble kraftig observert ved lavere doser enn deres effektive doser når de ble administrert alene. Enn videre har foreliggende oppfinnere funnet at kombinert administrering som beskrevet ovenfor markert forhindret vaskulær remodellering og at medikamentet effektivt inhiberte restenose etter PCI. The present inventors have thoroughly studied the above-described objectives, and found that combined administration of a specific calcium channel blocker and a specific angiotensin II receptor antagonist strongly prevents the proliferation of vascular smooth muscle cells as well as neointima formation in blood vessels, and that the inhibitory effect of the combined administration of the two types of agents were found to be synergistic, and also found that the inhibitory effect was strongly observed at lower doses than their effective doses when administered alone. Furthermore, the present inventors have found that combined administration as described above markedly prevented vascular remodeling and that the drug effectively inhibited restenosis after PCI.
Videre har foreliggende oppfinnere funnet at kombinert administrering av den spesifikke kalsiumkanalblokker og den spesifikke angiogensin II reseptorantagonist beskrevet Furthermore, the present inventors have found that combined administration of the specific calcium channel blocker and the specific angiogenin II receptor antagonist described
ovenfor kunne føre til glimrende antihypertensiv virkning. I tillegg fant foreliggende oppfinnere at foreliggende medikament er bemerkelsesverdig effektiv for profylakse og/eller behandling av sykdommer forårsaket av hypertensjon slik som hjertesykdommer (angina pektoris, myokardialt infarkt, arrytmi (innbefattende plutselig død), hjertesvikt eller hjertehyptertrofi), nyresykdommer (diabetisk nefropati, glomerulonefritt eller nefrosklerose) eller cerebrovaskulære sykdommer above could lead to an excellent antihypertensive effect. In addition, the present inventors found that the present drug is remarkably effective for the prophylaxis and/or treatment of diseases caused by hypertension such as heart diseases (angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure or cardiac hypertrophy), kidney diseases (diabetic nephropathy, glomerulonephritis or nephrosclerosis) or cerebrovascular diseases
(cerebralt infarkt eller cerebral blødning). Foreliggende oppfinnelse ble således fullført basert på de ovenfor beskrevne oppdagelser. (cerebral infarction or cerebral haemorrhage). The present invention was thus completed based on the above-described discoveries.
Foreliggende oppfinnelse gjelder et medikament for anvendelse til forhindring og/eller behandling av hypertensjon eller arteriosklerose, kjennetegnet ved at det omfatter følgende sammensetning; The present invention relates to a drug for use in the prevention and/or treatment of hypertension or arteriosclerosis, characterized in that it comprises the following composition;
(A) en angiotensin II reseptorantagonist valgt fra gruppen bestående av en forbindelse med generell formel (I), farmakologisk akseptable estere derav og farmakologisk akseptable (A) an angiotensin II receptor antagonist selected from the group consisting of a compound of general formula (I), pharmacologically acceptable esters thereof and pharmacologically acceptable
salter derav; og salts thereof; and
(B) en kalsiumkanalblokker valgt fra gruppen bestående av azelnidipine, amoldipine, og farmakologisk akseptable salter derav som aktive bestanddeler. (B) a calcium channel blocker selected from the group consisting of azelnidipine, amoldipine, and pharmacologically acceptable salts thereof as active ingredients.
Videre tilveiebringer foreliggende oppfinnelse et medikament for forhindring og/eller behandling av hypertensjon eller sykdommer forårsaket av hypertensjon, omfattende følgende forbindelser som aktive bestanddeler; Furthermore, the present invention provides a drug for the prevention and/or treatment of hypertension or diseases caused by hypertension, comprising the following compounds as active ingredients;
(A) en angiotensin II reseptorantagonist valgt fra gruppen bestående av en forbindelse av formel (I) beskrevet ovenfor, farmakalogisk akseptable estere derav og farmakologisk (A) an angiotensin II receptor antagonist selected from the group consisting of a compound of formula (I) described above, pharmacologically acceptable esters thereof and pharmacologically
akseptable salter derav; og acceptable salts thereof; and
(B) en kalsiumkanalblokker valgt fra gruppen bestående av azelnidipine, amoldipine, og farmakologisk akseptable salter derav som aktive bestanddeler; og et medikament for (B) a calcium channel blocker selected from the group consisting of azelnidipine, amoldipine, and pharmacologically acceptable salts thereof as active ingredients; and a drug for
forhindring og/eller behandling av hjertesykdommer (angina pektoris, myokardialt infarkt, arrytmi (innbefattende plutselig død), hjertesvikt, hjertehypertrofi og lignende), nyresykdommer (diabetisk nefropati, glomerulonefritt, nefrosklerose og lignende), eller cerebrovaskulære sykdommer (cerebral infarkt, cerebral blødning og lignende), omfattende følgende forbindelser som aktive bestanddeler; prevention and/or treatment of heart diseases (angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure, cardiac hypertrophy and the like), kidney diseases (diabetic nephropathy, glomerulonephritis, nephrosclerosis and the like), or cerebrovascular diseases (cerebral infarction, cerebral haemorrhage and similar), comprising the following compounds as active ingredients;
(A) en angiotensin II reseptorantagonist valgt fra gruppen bestående av en forbindelse med formel (I) beskrevet ovenfor, farmakologisk akseptable estere derav og farmakologisk (A) an angiotensin II receptor antagonist selected from the group consisting of a compound of formula (I) described above, pharmacologically acceptable esters thereof and pharmacologically
akseptable salter derav; og acceptable salts thereof; and
(B) en kalsiumkanalblokker valgt fra gruppen bestående av azelnidipine, amoldipine, og farmakologisk akseptable salter derav. (B) a calcium channel blocker selected from the group consisting of azelnidipine, amoldipine, and pharmacologically acceptable salts thereof.
I henhold til en foretrukket utførelsesform av oppfinnelsen er medikamentet beskrevet ovenfor tilveiebrakt som et farmasøytisk preparat omfattende forbindelsen (A) og forbindelsen According to a preferred embodiment of the invention, the drug described above is provided as a pharmaceutical preparation comprising the compound (A) and the compound
(B) som aktive bestanddeler. Dette farmasøytiske preparat kan inneholde en flere eksipienser for formulering. I henhold til en annen foretrukket utførelsesform av oppfinnelsen er et medikament (B) as active ingredients. This pharmaceutical preparation may contain a number of excipients for formulation. According to another preferred embodiment of the invention is a drug
beskrevet ovenfor tilveiebrakt for administrering av forbindelse (A) og forbindelse (B) samtidig eller separat ved visse intervaller. described above provided for the administration of compound (A) and compound (B) simultaneously or separately at certain intervals.
I henhold til en mer foretrukket utførelsesform av oppfinnelsen er videre medikamentet beskrevet ovenfor tilveiebrakt som et farmasøytisk preparat omfattende en angiotensin II reseptorantagonist og en kalsiumkanalblokker, hvor angitte angiotensin II reseptorantagonist er (5-metyl-2-okso-1,3-dioksolen-4-yl)metyl-4-( 1 -hydroksy-1 -metyleyl)-2-propyl-1 -[[2'-(1H-tetrazol-5-yl)bifenyl-4-yl]metyl]imidazol-5-karboksylat (heretter angitt som "olmesartanmedoksomil" i enkelte deler av foreliggende beskrivelse) og angitte kalsiumkanal-blokker er en hvilken som helst valgt fra gruppen av kalsiumkanalbokkere omfattende (+)-2-amino-l,4-dihydro-6-metyl-4-(3-nitrofenyl)-3,5-pyridindikarboksylat-3-(l-difenylmetylazetidin-3-yl)ester-5-isopropylester (heretter angitt som "azelnidipin" i enkelte deler av beskrivelsen) eller amoldipin; og den foretrukne kalsiumkanalblokker er azelnidipin. According to a more preferred embodiment of the invention, the drug described above is further provided as a pharmaceutical preparation comprising an angiotensin II receptor antagonist and a calcium channel blocker, where the specified angiotensin II receptor antagonist is (5-methyl-2-oxo-1,3-dioxolene-4 -yl)methyl-4-(1-hydroxy-1-methylyl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate (hereinafter referred to as "olmesartan medoxomil" in some parts of the present specification) and indicated calcium channel blockers are any selected from the group of calcium channel blockers comprising (+)-2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl)-3,5-pyridinedicarboxylate-3-(1-diphenylmethylazetidin-3-yl)ester-5-isopropyl ester (hereinafter referred to as "azelnidipine" in some parts of the specification) or amoldipine; and the preferred calcium channel blocker is azelnidipine.
Fra et annet aspekt ved foreliggende oppfinnelse tilveiebringer foreliggende oppfinnelse anvendelse av en angiotensin II reseptorantagonist valgt fra gruppen bestående av en forbindelse med formel (I) beskrevet ovenfor, farmakologisk akseptable estere derav og farmakologisk akseptable salter derav, for fremstilling av medikamentet beskrevet ovenfor; og anvendelse av en kalsiumkanalblokker valgt fra gruppen bestående av av azelnidipine, amoldipine, og farmakologisk akseptable salter derav, for fremstilling av medikamentet beskrevet ovenfor. From another aspect of the present invention, the present invention provides the use of an angiotensin II receptor antagonist selected from the group consisting of a compound of formula (I) described above, pharmacologically acceptable esters thereof and pharmacologically acceptable salts thereof, for the preparation of the drug described above; and using a calcium channel blocker selected from the group consisting of azelnidipine, amoldipine, and pharmacologically acceptable salts thereof, for the preparation of the medicament described above.
Videre tilveiebringer foreliggende oppfinnelse medikament for anvendelse i metoder for profylakse og/eller behandling av arteriosklerose, omfattende enhver måte av effektive doser av angitte forbindelse (A) og angitt forbindelse (B) til pattedyr, innbefattende mennesker. Furthermore, the present invention provides a medicament for use in methods of prophylaxis and/or treatment of arteriosclerosis, comprising any manner of effective doses of indicated compound (A) and indicated compound (B) to mammals, including humans.
I foreliggende oppfinnelse er fortrinnsvis den effektive dose av hvert preparat omfattende forbindelse (A) og forbindelse (B) rundt den laveste grense eller rundt den laveste grense av den effektive dose av forbindelse (A) eller forbindelse (B) når de administreres alene. In the present invention, preferably the effective dose of each preparation comprising compound (A) and compound (B) is around the lowest limit or around the lowest limit of the effective dose of compound (A) or compound (B) when administered alone.
Videre tilveiebringer foreliggende oppfinnelse medikament for anvendelse i metoder for profylakse og/eller behandling av hypertensjon eller sykdommer forårsaket av hypertensjon, omfattende enhver metode for administrering av effektive doser av angitte forbindelse (A) og angitte forbindelse (B) til pattedyr, innbefattende mennesker; metoder for profylakse eller behandling av hypertensjon, omfattende enhver metode for administrering av effektive doser av angitte forbindelse (A) og angitte forbindelse (B) til pattedyr, innbefattende mennesker; metoder for profylakse eller behandling av hjertesykdommer, omfattende enhver metode for administrering av effektive doser av angitte forbindelse (A) og angitte forbindelse (B) til pattedyr, innbefattende mennesker; metoder for profylakse eller behandling av angina pektoris, omfattende enhver metode for administrering av effektive doser av angitte forbindelse (A) og angitte forbindelse (B) til pattedyr, innbefattende mennesker; metoder for profylakse eller behandling av myokardialt infarkt, omfattende enhver metode for administrering av effektive doser av angitte forbindelse (A) og angitte forbindelse (B) til pattedyr, innbefattende mennesker; metoder for profylakse eller behandling av arrytmi, omfattende enhver metode for administrering av effektive doser av angitte forbindelse (A) og angitte forbindelse (B) til pattedyr, innbefattende mennesker; metoder for profylakse mot plutselig død, omfattende enhver metode for administrering av effektive doser av angitte forbindelse (A) og angitte forbindelse (B) til pattedyr, innbefattende mennesker; metoder for profylakse eller behandling av hjertesvikt, omfattende enhver metode for administrering av effektive doser av angitte forbindelse (A) og angitte forbindelse (B) til pattedyr, innbefattende mennesker; metoder for profylakse eller behandling av hjertehypertrofi, omfattende enhver metode for administrering av effektive doser av angitte forbindelse (A) og angitte forbindelse (B) til pattedyr, innbefattende mennesker; metoder for profylakse eller behandling av nyresykdommer, omfattende enhver metode for administrering av effektive doser av angitte forbindelse (A) og angitte forbindelse (B) til pattedyr, innbefattende mennesker; metoder for profylakse eller behandling av diabetisk Furthermore, the present invention provides a drug for use in methods of prophylaxis and/or treatment of hypertension or diseases caused by hypertension, including any method of administering effective doses of indicated compound (A) and indicated compound (B) to mammals, including humans; methods for the prophylaxis or treatment of hypertension, including any method for administering effective doses of said compound (A) and said compound (B) to mammals, including humans; methods for the prophylaxis or treatment of heart diseases, including any method for administering effective doses of said compound (A) and said compound (B) to mammals, including humans; methods for the prophylaxis or treatment of angina pectoris, comprising any method of administering effective doses of said compound (A) and said compound (B) to mammals, including humans; methods for the prophylaxis or treatment of myocardial infarction, comprising any method of administering effective doses of said compound (A) and said compound (B) to mammals, including humans; methods for the prophylaxis or treatment of arrhythmia, including any method for administering effective doses of said compound (A) and said compound (B) to mammals, including humans; methods of prophylaxis against sudden death, comprising any method of administering effective doses of said compound (A) and said compound (B) to mammals, including humans; methods for the prophylaxis or treatment of heart failure, comprising any method of administering effective doses of said compound (A) and said compound (B) to mammals, including humans; methods for the prophylaxis or treatment of cardiac hypertrophy, comprising any method of administering effective doses of said compound (A) and said compound (B) to mammals, including humans; methods for the prophylaxis or treatment of kidney diseases, including any method for administering effective doses of said compound (A) and said compound (B) to mammals, including humans; methods for the prophylaxis or treatment of diabetics
nefropati, omfattende enhver metode for administrering av effektive doser av angitte forbindelse nephropathy, including any method of administering effective doses of said compound
(A) og angitte forbindelse (B) til pattedyr, innbefattende mennesker; metoder for profylakse eller behandling av glomerulonefritt, omfattende enhver metode for administrering av effektive doser (A) and said compound (B) to mammals, including humans; methods of prophylaxis or treatment of glomerulonephritis, including any method of administration of effective doses
av angitte forbindelse (A) og angitte forbindelse (B) til pattedyr, innbefattende mennesker; metoder for profylakse eller behandling av nefrosklerose, omfattende enhver metode for administrering av effektive doser av angitte forbindelse (A) og angitte forbindelse (B) til pattedyr, innbefattende mennesker; metoder for profylakse eller behandling av cerebrovaskulære sykdommer, omfattende enhver metode for administrering av effektive doser av angitte forbindelse (A) og angitte forbindelse (B) til pattedyr, innbefattende mennesker; metoder for profylakse eller behandling av cerebralt infarkt, omfattende enhver metode for administrering av effektive doser av angitte forbindelse (A) og angitte forbindelse (B) til pattedyr, innbefattende mennesker; og/eller metoder for profylakse eller behandling av cerebral blødning, omfattende enhver metode for administrering av effektive doser av angitte forbindelse (A) og angitte forbindelse (B) til pattedyr, innbefattende mennesker. of said compound (A) and said compound (B) to mammals, including humans; methods for the prophylaxis or treatment of nephrosclerosis, comprising any method of administering effective doses of said compound (A) and said compound (B) to mammals, including humans; methods for the prophylaxis or treatment of cerebrovascular diseases, including any method for administering effective doses of said compound (A) and said compound (B) to mammals, including humans; methods for the prophylaxis or treatment of cerebral infarction, comprising any method of administering effective doses of said compound (A) and said compound (B) to mammals, including humans; and/or methods for the prophylaxis or treatment of cerebral hemorrhage, comprising any method for administering effective doses of said compound (A) and said compound (B) to mammals, including humans.
Kort beskrivelse av tegningene Brief description of the drawings
Figur 1 indikerer resultatene for inhibering av DNA-syntese i vaskulære glattmuskelceller av en kalsiumkanalblokker, azelnidipin, i et doseområde på 0,1 til 1,0 mg/kg/dag. Figur 2 viser resultatene for inhibering av neointima-dannelse i blodkar av en kalsiumkanalblokker, azelnidipin, i et doseområde på 0,1 til 1,0 mg/kg/dag. Figur 3 representerer resultatene for inhibering DNA-syntese i vaskulære glattmuskelceller av en angiotensin II reseptorantagonist, olmesartan, i et doseområde på 0,5 til 3,0 mg/kg/dag. Figur 4 indikerer resultatene for inhibering av neointima-dannelse i blodkar av en angiotensin II reseptorantagonist, olmesartan, i et doseområde på 0,5 til 3,0 mg/kg/dag. Figur 5 viser resultatene for inhibering av DNA-syntese i vaskulære glattmuskelceller ved samtidig administrering av azelnidipin og olmesartan i doser på 0,1 mg/kg/dag og 0,5 mg/kg/dag (ved hvilke doser de ikke fremkalte noen signifikant effekt hver for seg alene). Figur 6 representerer resultatene for inhibering av neointima-dannelse i blodkar av samtidig administrering av azelnidipin og olmesartan ved doser på 0,1 mg/kg/dag og 0,5 mg/kg/dag (ved hvilke doser de ikke fremkalte noen signifikant effekt hver for seg). Figur 7 indikerer resultatene for inhibering av potensiering av DNA-syntese i dyrkede vaskulære glattmuskelceller fra rotte etter stimulering av angiotensin II reseptorer med azelnidipin i en konsentrasjons-avhengig måte. Figur 8 viser resultatene for signifikant inhibering av DNA-syntese i dyrkede vaskulære glattmuskelceller ved ko-administrering av azelnidipin og olmesartan ved lave konsentrasjoner, ved hvilke konsentrasjoner de ikke fremkalte noen signifikant effekt hver for seg. Figure 1 indicates the results for the inhibition of DNA synthesis in vascular smooth muscle cells by a calcium channel blocker, azelnidipine, in a dose range of 0.1 to 1.0 mg/kg/day. Figure 2 shows the results for the inhibition of neointima formation in blood vessels by a calcium channel blocker, azelnidipine, in a dose range of 0.1 to 1.0 mg/kg/day. Figure 3 represents the results for inhibition of DNA synthesis in vascular smooth muscle cells by an angiotensin II receptor antagonist, olmesartan, in a dose range of 0.5 to 3.0 mg/kg/day. Figure 4 indicates the results for the inhibition of neointima formation in blood vessels by an angiotensin II receptor antagonist, olmesartan, in a dose range of 0.5 to 3.0 mg/kg/day. Figure 5 shows the results for inhibition of DNA synthesis in vascular smooth muscle cells by co-administration of azelnidipine and olmesartan at doses of 0.1 mg/kg/day and 0.5 mg/kg/day (at which doses they produced no significant effect individually). Figure 6 represents the results for the inhibition of neointima formation in blood vessels by co-administration of azelnidipine and olmesartan at doses of 0.1 mg/kg/day and 0.5 mg/kg/day (at which doses they did not produce any significant effect each separately). Figure 7 indicates the results for inhibition of potentiation of DNA synthesis in cultured rat vascular smooth muscle cells after stimulation of angiotensin II receptors with azelnidipine in a concentration-dependent manner. Figure 8 shows the results for significant inhibition of DNA synthesis in cultured vascular smooth muscle cells by co-administration of azelnidipine and olmesartan at low concentrations, at which concentrations they produced no significant effect individually.
Best måte for utførelse av oppfinnelsen Best method for carrying out the invention
Medikamentene ifølge foreliggende oppfinnelse erkarakterisert vedå inneholde The medicines according to the present invention are characterized by containing
(A) en angiotensin II reseptorantagonist valgt fra gruppen bestående av en forbindelse med formel (I) beskrevet ovenfor, farmakologisk akseptable estere derav og farmakologisk (A) an angiotensin II receptor antagonist selected from the group consisting of a compound of formula (I) described above, pharmacologically acceptable esters thereof and pharmacologically
akseptable salter derav; og acceptable salts thereof; and
(B) en kalsiumkanalblokker valgt fra gruppen bestående av azelnidipine, amoldipine, og farmakologisk akseptable salter derav som aktive bestanddeler. (B) a calcium channel blocker selected from the group consisting of azelnidipine, amoldipine, and pharmacologically acceptable salts thereof as active ingredients.
Forbindelsen med formel (I) beskrevet ovenfor, [4-(l-hydroksy-l-metyletyl)-2-propyl-l-[[2'-(lH-tetrazol-5-yl)bifenyl-4-yl]metyl]imidazol-5-karboksylsyre] er en kjent forbindelse og erholdes for eksempel lett ved metoder beskrevet i japansk patentpublikasjon (Kokai) nr. Hei 5-78328 (USP 5 616 599) og lignende. De farmakologisk akseptable salter av forbindelsen av formel (I) beskrevet ovenfor er ikke spesielt begrenset, og disse salter kan velges av fagmannen. Som farmakologisk akseptable salter av forbindelsen av formel (I) beskrevet ovenfor er slike salter for eksempel et alkalimetallsalt slik som natriumsalt, kaliumsalt eller litiumsalt; et jordalkalimetallsalt slik som kalsiumsalt eller magnesiumsalt; et metallsalt slik som aluminiumsalt, jernsalt, sinksalt, kobbersalt, nikkelsak eller koboltsalt; et aminsalt slik som et ammoniumsalt, t-oktylaminslt, dibenzylaminsalt, morfolinsalt, glukosaminsalt, fenylglysin-alkylestersalt, etylendiaminsalt, N-metylglukaminsalt, guanidinsalt, dietylaminsalt, trietylaminsalt, disykloheksylaminsalt, N,N'-dibenzyletylendiaminsalt, klorprokainsalt, prokainsalt, dietanolaminsalt, N-benzylfenetylaminsalt, piperazinsalt, tetrametylammoniumsalt eller tris(hydroksymetyl)aminometansalt. Fortrinnsvis kan alkalimetallsalter anvendes, og særlig foretrukket kan natriumsaltet anvendes. The compound of formula (I) described above, [4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] imidazole-5-carboxylic acid] is a known compound and is, for example, easily obtained by methods described in Japanese patent publication (Kokai) No. Hei 5-78328 (USP 5,616,599) and the like. The pharmacologically acceptable salts of the compound of formula (I) described above are not particularly limited, and these salts can be selected by the person skilled in the art. As pharmacologically acceptable salts of the compound of formula (I) described above, such salts are, for example, an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as calcium salt or magnesium salt; a metal salt such as an aluminum salt, an iron salt, a zinc salt, a copper salt, a nickel salt or a cobalt salt; an amine salt such as an ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N- benzylphenethylamine salt, piperazine salt, tetramethylammonium salt or tris(hydroxymethyl)aminomethane salt. Alkali metal salts can preferably be used, and particularly preferably the sodium salt can be used.
De farmakologisk akseptable estere av forbindelsen av formel (I) omfatter forbindelsen av formel (I) som har karboksylgruppen forestret. De farmakologisk akseptable estere er ikke spesielt begrenset, og kan velges av fagmannen. Når det gjelder slike estere er det foretrukket at slike estere kan spaltes ved en biologisk prosess slik som hydrolyse in vivo. Gruppen som utgjør angitte estere (gruppen vist som R når esterene derav uttrykkes som -COOR) kan for eksempel være en C1-C4alkoksy C1-C4alkylgruppe slik som metoksyetyl, 1-etoksyetyl, 1-metyl-l-metoksyetyl, l-(isopropoksy)etyl, 2-metoksyetyl, 2-etoksyetyl, 1,1-dimetyl-l-metoksymetyl, etoksymetyl, propoksymetyl, isopropoksymetyl, butoksymetyl eller t-butoksymetyl; en C1-C4alkoksylert C1C4alkoksy C1-C4alkylgruppe slik som 2-metoksyetoksymetyl; en C6-C10aryloksy C1-C4alkylgruppe slik som fenoksymetyl; en halogenert C1-C4alkoksy C1C4alkylgruppe slik som 2,2,2-trikloretoksymetyl eller bis(2-kloretoksy)metyl; en C1-C4alkoksykarbonyl C1-C4alkylgruppe slik som metoksykarbonylmetyl; en cyano C1-C4alkylgruppe slik som cyanometyl eller 2-cyanoetyl; en C1-C4alkyltiometylgruppe slik som metyltiometyl eller etyltiometyl; en C6-C10aryltiometylgruppe slik som fenyltiometyl eller naftyltiometyl; en C1-C4alkylsulfonyl Ci-C4lavere alkylgruppe som eventuelt kan være substituert med et halogenatom slik som 2-metansulfonyletyl eller 2-trifluormetansulfonyletyl; en C6-C10arylsulfonyl C1-C4alkylgruppe slik som 2-benzensulfonyletyl eller 2-toluensulfonyletyl; en C1-C7alifatisk acyloksy C1-C4alkylgruppe slik som formyloksymetyl, acetoksymetyl, propionyloksymetyl, butyryloksymetyl, pivaloyloksymetyl, valeryloksymetyl, isovaleryloksymetyl, heksanoyloksymetyl, 1 -formyloksyetyl, 1-acetoksyetyl, 1-propionyloksyetyl, 1-butyryloksyetyl, 1-pivaloyloksyetyl, 1-valeryloksyetyl, 1-isovaleryloksyetyl, 1-heksanoyloksyetyl, 2-formyloksyetyl, 2-acetoksyetyl, 2-propionyloksyetyl, 2-butyryloksyetyl, 2-pivaloyloksyetyl, 2-valeryloksyetyl, 2-isovaleryloksyetyl, 2-heksanoyloksyetyl, 1-formyloksypropyl, 1-acetoksypropyl, 1-propionyloksypropyl, 1-butyryloksypropyl, 1-pivaloyloksypropyl, 1-valeryloksypropyl, 1-isovaleryloksypropyl, 1-heksanoyloksypropyl, 1-acetoksybutyl, 1-propionyloksybutyl, 1-butyryloksybutyl, 1-pivaloyoloksybutyl, 1-acetoksypentyl, 1-propionyloksypentyl, 1-butyryloksypentyl, 1-pivaloyloksypentyl eller 1-pivaloyloksyheksyl; en C5-C6cykloalkylkarbonyloksy C1-C4alkylgruppe slik som syklopentylkarbonyloksymetyl, sykloheksylkarbonyloksymetyl, 1-syklo-pentylkarbonyloksyetyl, 1-sykloheksylkarbonyloksyetyl, 1 -syklopentylkarbonyloksypropyl, 1-sykloheksylkarbonyloksypropyl, 1-syklopentylkarbonyloksybutyl eller 1-sykloheksyl-karbonyloksybutyl; en C6-C10arylkarbonyloksy C1-C4alkylgruppe slik som benzoyloksymetyl; en C1-C6alkoksykarbonyl C1-C4alkylgruppe slik som metoksykarbonyloksymetyl, l-(metoksy-karbonyloksy)etyl, 1 -(metoksykarbonyloksy)propyl, 1 -(metoksykarbonyloksy)butyl, 1 -(metoksykarbonyloksy)pentyl, 1 -(metoksykarbonyloksy)heksyl, etoksykarbonyloksymetyl, The pharmacologically acceptable esters of the compound of formula (I) include the compound of formula (I) having the carboxyl group esterified. The pharmacologically acceptable esters are not particularly limited, and can be chosen by the person skilled in the art. When it comes to such esters, it is preferred that such esters can be split by a biological process such as hydrolysis in vivo. The group constituting indicated esters (the group shown as R when the esters thereof are expressed as -COOR) can for example be a C1-C4 alkoxy C1-C4 alkyl group such as methoxyethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, l-(isopropoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; a C 1 -C 4 alkoxylated C 1 -C 4 alkoxy C 1 -C 4 alkyl group such as 2-methoxyethoxymethyl; a C 6 -C 10 aryloxy C 1 -C 4 alkyl group such as phenoxymethyl; a halogenated C 1 -C 4 alkoxy C 1 C 4 alkyl group such as 2,2,2-trichloroethoxymethyl or bis(2-chloroethoxy)methyl; a C 1 -C 4 alkoxycarbonyl C 1 -C 4 alkyl group such as methoxycarbonylmethyl; a cyano C 1 -C 4 alkyl group such as cyanomethyl or 2-cyanoethyl; a C 1 -C 4 alkylthiomethyl group such as methylthiomethyl or ethylthiomethyl; a C6-C10 arylthiomethyl group such as phenylthiomethyl or naphthylthiomethyl; a C1-C4 alkylsulfonyl C1-C4 lower alkyl group which may optionally be substituted with a halogen atom such as 2-methanesulfonylethyl or 2-trifluoromethanesulfonylethyl; a C6-C10 arylsulfonyl C1-C4 alkyl group such as 2-benzenesulfonylethyl or 2-toluenesulfonylethyl; a C1-C7aliphatic acyloxy C1-C4alkyl group such as formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivalyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivalyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 2-formyloxyethyl, 2-acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-pivaloyloxyethyl, 2-valeryloxyethyl, 2-isovaleryloxyethyl, 2-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1- propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxybutyl, 1-pivaloyloxypentyl or 1-pivaloyloxyhexyl; a C5-C6 cycloalkylcarbonyloxy C1-C4 alkyl group such as cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl or 1-cyclohexylcarbonyloxybutyl; a C 6 -C 10 arylcarbonyloxy C 1 -C 4 alkyl group such as benzoyloxymethyl; a C1-C6 alkoxycarbonyl C1-C4 alkyl group such as methoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(methoxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)butyl, 1-(methoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl, ethoxycarbonyloxymethyl,
1 -(etoksykarbonyl)etyl, 1 -(etoksykarbonyloksy)propyl, 1 -(etoksykarbonyloksy)butyl, 1 -(etoksykarbonyloksy)pentyl, 1 -(etoksykarbonyloksy)heksyl, propoksykarbonyloksymetyl, 1 -(propoksykarbonyloksy)etyl, 1 -(propoksykarbonyloksy)propyl, 1 -(propoksykarbonyl-oksy)butyl, isopropoksykarbonyloksymetyl, l-(isopropoksykarbonyloksy)etyl, l-(iso-propoksykarbonyloksy)butyl, butoksykarbonyloksymetyl, 1 -(butoksykarbonyloksy)etyl, 1 -(butoksykarbonyloksy)propyl, 1 -(butoksykarbonyloksy)butyl, isobutoksykarbonyloksymetyl, 1 -(isobutoksykarbonyloksy)etyl, 1 -(isobutoksykarbonyloksy)propyl, 1 -(isobutoksykarbonyl-oksy)butyl, t-butoksykarbonyloksymetyl, 1 -(t-butoksykarbonyloksy)etyl, pentyloksykarbonyl-oksymetyl, 1-(pentyloksykarbonyloksy)etyl, l-(pentyloksykarbonyloksy)propyl, heksyl-oksykarbonyloksymetyl, l-(heksyloksykarbonyloksy)etyl eller l-(heksyloksykarbonyloksy)-propyl; en C5-C6sykloalkyloksykarbonyloksy C1-C4alkylgruppe slik som syklopentyloksy-karbonyloksymetyl, 1 -(syklopentyloksykarbonyloksy)etyl, 1 -(syklopentyloksykarbonyloksy)-propyl, l-(syklopentyloksykarbonyloksy)butyl, sykloheksyloksykarbonyloksymetyl, l-(syklo-heksyloksykarbonyloksy)etyl, 1 -(sykloheksyloksykarbonyloksy)propyl eller 1 -(sykloheksyl-oksykarbonyloksy)butyl; en [5-(C]-C4alkyl)-2-okso-l,3-dioksolen-4-yl]metylgruppe slik som (5-metyl-2-okso-1,3-dioksolen-4-yl)metyl, (5-etyl-2-okso-l ,3-dioksolen-4-yl)metyl, (5-propyl-2-okso-l,3-dioksolen-4-yl)metyl, (5-isopropyl-2-okso-l,3-dioksolen-4-yl)metyl eller (5-butyl-2-okso-l,3-dioksolen-4-yl)metyl; en [5-(fenyl, som eventuelt kan være substituert med en C1-C4alkyl, C1-C4alkoksy eller halogenatome)-2-okso-l,3-dioksolen-4-yl]metylgruppe slik som (5-fenyl-2-okso-l,3-dioksolen-4-yl)metyl, [5-(4-metylfenyl)-2-okso-l,3-dioksolen-4-yl]metyl, [5-(4-metoksyfenyl)-2-okso-l,3-dioksolen-4-yl]metyl, [5-(4-fluorfenyl)-2-okso-l,3-dioksolen-4-yl]metyl eller [5-(4-klorfenyl)-2-okso-l,3-dioksolen-4-yl]metyl; eller en ftalidylgruppe som eventuelt kan være substituert med en C1-C4alkyl eller C1-C4alkoksygruppe, slik som ftalidyl, dimetylftalidyl eller dimetoksyftalidyl, og er fortrinnsvis en pivaloyloksymetylgruppe, ftalidylgruppe eller (5-metyl-2-okso-l,3-dioksolen-4-yl)metylgruppe, og mer fordelaktig en (5-metyl-2-okso-1,3-di oksolen-4-yl)metyl gruppe. 1 -(ethoxycarbonyl)ethyl, 1 -(ethoxycarbonyloxy)propyl, 1 -(ethoxycarbonyloxy)butyl, 1 -(ethoxycarbonyloxy)pentyl, 1 -(ethoxycarbonyloxy)hexyl, propoxycarbonyloxymethyl, 1 -(propoxycarbonyloxy)ethyl, 1 -(propoxycarbonyloxy)propyl , 1 -(propoxycarbonyloxy)butyl, isopropoxycarbonyloxymethyl, l-(isopropoxycarbonyloxy)ethyl, l-(isopropoxycarbonyloxy)butyl, butoxycarbonyloxymethyl, 1 -(butoxycarbonyloxy)ethyl, 1 -(butoxycarbonyloxy)propyl, 1 -(butoxycarbonyloxy)butyl , isobutoxycarbonyloxymethyl, 1 -(isobutoxycarbonyloxy)ethyl, 1 -(isobutoxycarbonyloxy)propyl, 1 -(isobutoxycarbonyloxy)butyl, t-butoxycarbonyloxymethyl, 1 -(t-butoxycarbonyloxy)ethyl, pentyloxycarbonyloxymethyl, 1-(pentyloxycarbonyloxy)ethyl, 1-(pentyloxycarbonyloxy)propyl, hexyloxycarbonyloxymethyl, 1-(hexyloxycarbonyloxy)ethyl or 1-(hexyloxycarbonyloxy)propyl; a C5-C6cycloalkyloxycarbonyloxy C1-C4alkyl group such as cyclopentyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)-propyl, l-(cyclopentyloxycarbonyloxy)butyl, cyclohexyloxycarbonyloxymethyl, l-(cyclohexyloxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy) )propyl or 1-(cyclohexyloxycarbonyloxy)butyl; a [5-(C]-C4alkyl)-2-oxo-1,3-dioxolen-4-yl]methyl group such as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, ( 5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-isopropyl-2-oxo- 1,3-dioxolen-4-yl)methyl or (5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl; a [5-(phenyl, which may optionally be substituted with a C1-C4 alkyl, C1-C4 alkoxy or halogen atom)-2-oxo-1,3-dioxolen-4-yl]methyl group such as (5-phenyl-2-oxo -1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo -1,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl or [5-(4-chlorophenyl)-2-oxo -1,3-dioxolen-4-yl]methyl; or a phthalidyl group which may optionally be substituted with a C1-C4 alkyl or C1-C4 alkoxy group, such as phthalidyl, dimethylphthalidyl or dimethoxyphthalidyl, and is preferably a pivaloyloxymethyl group, phthalidyl group or (5-methyl-2-oxo-1,3-dioxolene-4 -yl)methyl group, and more advantageously a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group.
Idet tilfellet at esterene av forbindelsen av formel (I) beskrevet ovenfor danner farmakologisk akseptable salter, kan de farmakologisk akseptable salter velges av fagmannen. Slike salter kan for eksempel være et hydrohalogensyresalt slik som et hydrofluorid, hydroklorid, hydrobromid eller hydrojodid; et nitrat; et perklorat; et sulfat; et fosfat; et C1-C4alkansulfon-syresalt som eventuelt kan være substituert med et halogenatom slik som et metansulfonat, trifluormetansulfonat eller etansulfonat; et C6-C10arylsulfonsyresalt som eventuelt kan være substituert med C1-C4alkylgruppe, slik som et benzensulfonat eller p-toluensulfonat; et C1-C6alifatisk syresalt slik som et acetat, malat, fumarat, suksinat, citrat, tartrat, okslat eller maleat; eller et aminosyresalt slik som et glysinsalt, lysinsalt, argininsalt, ornitinsalt, glutaminsyresalt eller asparaginsyresalt, og er fortrinnsvis et hydroklorid, nitrat, sulfat eller fosfat, og er særlig fordelaktig et hydroklorid. In the event that the esters of the compound of formula (I) described above form pharmacologically acceptable salts, the pharmacologically acceptable salts can be chosen by the person skilled in the art. Such salts can for example be a hydrohalic acid salt such as a hydrofluoride, hydrochloride, hydrobromide or hydroiodide; a nitrate; a perchlorate; a sulfate; a phosphate; a C 1 -C 4 alkanesulfonic acid salt which may optionally be substituted with a halogen atom such as a methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; a C6-C10 arylsulfonic acid salt which may optionally be substituted with a C1-C4 alkyl group, such as a benzenesulfonate or p-toluenesulfonate; a C1-C6 aliphatic acid salt such as an acetate, malate, fumarate, succinate, citrate, tartrate, oxalate or maleate; or an amino acid salt such as a glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt or aspartic acid salt, and is preferably a hydrochloride, nitrate, sulfate or phosphate, and is particularly advantageously a hydrochloride.
Angiotensin II resetorantagonisten, som anvendes som forbindelse (A), er fortrinnsvis forbindelsen med formel (I) beskrevet ovenfor, eller en farmakologisk akseptabel ester derav, mer foretrukket en farmakologisk akseptabel ester av angitte forbindelse av formel (I), og ytterligere mer foretrukket en pivaloyloksymetylester, ftalidylester eller (5-metyl-2-okso-l,3- dioksolen-4-yl)metylester av forbindelsen av formel (I). Mest foretrukket kan (5-metyl-2-okso-1,3 -dioksolen-4-y l)metyl-4- (1 -hy droksy-1 -mety letyl) -2-propyl-1 - [ [2' -(1 H-tetrazol-5 -yl)bifenyl-4-yl]metyl] imidazol-5-karboksylat anvendes. The angiotensin II receptor antagonist, which is used as compound (A), is preferably the compound of formula (I) described above, or a pharmacologically acceptable ester thereof, more preferably a pharmacologically acceptable ester of said compound of formula (I), and even more preferably a pivaloyloxy methyl ester, phthalidyl ester or (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester of the compound of formula (I). Most preferably, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-( 1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylate is used.
Som forbindelsen valgt fra gruppen bestående av en forbindelse av formel (I) beskrevet ovenfor, en farmakologisk akseptabel ester derav og farmakologisk akseptable salter derav, kan deres hydrater eller solvater også anvendes. I det tilfellet at de farmakologisk akseptable estere av forbindelsen av formel (I) anvendes, kan enkelte forestrede forbindelser ha en eller flere asymmetriske karboner, men rensede optiske isomerer basert på de asymmetriske karboner eller stereoisomerer slik som diastereoisomerer, eller enhver blanding av disse stereoisomerer eller rasemater, kan også anvendes som forbindelse (A). As the compound selected from the group consisting of a compound of formula (I) described above, a pharmacologically acceptable ester thereof and pharmacologically acceptable salts thereof, their hydrates or solvates may also be used. In the event that the pharmacologically acceptable esters of the compound of formula (I) are used, some esterified compounds may have one or more asymmetric carbons, but purified optical isomers based on the asymmetric carbons or stereoisomers such as diastereoisomers, or any mixture of these stereoisomers or racemate, can also be used as compound (A).
En kalsiumkanalblokker innbefattende 1,4-dihydropyridinderivater, som anvendes som forbindelse (B) er en kalsiumkanalblokkerkarakterisert vedå ha 1,4-dihydropyridingruppen eller kjemisk ekvivalent strukturell gruppe av 1,4-dihydropyridingruppen i molekylet. Mange medikamenter er foreslått som kalsiumkanalblokkere, innbefattende 1,4-dihydropyridinderivatene, og anvendes klinisk, og fagmannen kan lett velge enhver egnet forbindelse som utøver effekten ifølge foreliggende beskrivelse. Som 1,4-dihydropyridin kalsiumkanalblokkere kan for eksempel azelnidipin eller amoldipin anvendes. I tillegg kan azelnidipin lett fremstilles i henhold til metodene beskrevet i japansk patentpublikasjon (Kokai) nr. Sho 63-253082 (USP 4 772 596) og lignende. Enn videre kan amlodipin lett fremstilles i henhold til de metoder som er beskrevet i USP 4 572 909 eller USP 4 879 303. A calcium channel blocker including 1,4-dihydropyridine derivatives, which is used as compound (B) is a calcium channel blocker characterized by having the 1,4-dihydropyridine group or chemically equivalent structural group of the 1,4-dihydropyridine group in the molecule. Many drugs have been proposed as calcium channel blockers, including the 1,4-dihydropyridine derivatives, and used clinically, and one skilled in the art can readily select any suitable compound that exerts the effect of the present disclosure. As 1,4-dihydropyridine calcium channel blockers, for example, azelnidipine or amoldipine can be used. In addition, azelnidipine can be easily prepared according to the methods described in Japanese Patent Publication (Kokai) No. Sho 63-253082 (USP 4,772,596) and the like. Furthermore, amlodipine can be easily prepared according to the methods described in USP 4,572,909 or USP 4,879,303.
Da farmakologisk akseptable salter av 1,4-dihydropyridinderivatene ikke er spesielt begrenset, kan ethvert salt derav velges av fagmannen. De farmakologisk akseptable salter kan være syreaddisjonssalter eller baseaddisjonssalter. Disse salter kan for eksempel være et alkalimetallsalt slik som et natriumsalt, kaliumsalt eller litiumsalt; et jordalkalimetallsalt slik som et kalsiumsalt eller magnesiumsalt; et metallsalt slik som et aluminiumsalt, jernsalt, sinksalt, kobbersalt, nikkelsak eller koboltsalt; eller et baseaddisjonssalt, for eksempel et aminsalt slik som et ammoinumsalt, t-oktylaminsalt, dibenzylaminsalt, morfolinsalt, glukosaminsalt, fenyl-glysinalkylestersalt, etylendiaminsalt, N-metylglukaminsalt, guanidinsalt, dietylaminsalt, trietylaminsalt, disykloheksylaminsalt, N,N'-dibenzyletylendiaminsalt, klorprokainsalt, prokainsalt, dietanolaminsalt, N-benzylfenetylaminsalt, piperazinsalt, tetrametylammoniumsalt eller tris(hydroksymetyl)aminometansalt; eller et syreaddisjonsalt, for eksempel et hydro-halogenid slik som et hydrofluorid, hydroklorid, hydrobormid eller hydrojodid; et nitrat; et perklorat; et sulfat; et fosfat; et Ci-C4-alkansulfonat, som kan eventuelt være substituert med et halogenatom slik som et metansulfonat, trifluormetansulfonat eller etansulfonat; et C6-C10arylsulfonat som eventuelt kan være substituert med en C1-C4alkylgruppe slik som et benzensulfonat eller p-toluensulfonat; et C1-C6alifatisk syresalt slik som et acetat, malat, fumarat, suksinat, citrat, tartrat, oksalat eller maleat; eller et aminosyresalt slik som et glysinsalt, lysinsalt, argininsalt, ornitinsalt, glutaminsyresalt eller asparaginsyresalt. Since pharmacologically acceptable salts of the 1,4-dihydropyridine derivatives are not particularly limited, any salt thereof may be selected by the person skilled in the art. The pharmacologically acceptable salts may be acid addition salts or base addition salts. These salts can be, for example, an alkali metal salt such as a sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as a calcium salt or magnesium salt; a metal salt such as an aluminum salt, iron salt, zinc salt, copper salt, nickel or cobalt salt; or a base addition salt, for example an amine salt such as an ammoinum salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chlorprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt or tris(hydroxymethyl)aminomethane salt; or an acid addition salt, for example a hydrohalide such as a hydrofluoride, hydrochloride, hydroborimide or hydroiodide; a nitrate; a perchlorate; a sulfate; a phosphate; a C 1 -C 4 -alkanesulfonate, which may optionally be substituted with a halogen atom such as a methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; a C6-C10 arylsulfonate which may optionally be substituted with a C1-C4 alkyl group such as a benzenesulfonate or p-toluenesulfonate; a C1-C6 aliphatic acid salt such as an acetate, malate, fumarate, succinate, citrate, tartrate, oxalate or maleate; or an amino acid salt such as a glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt or aspartic acid salt.
Som kalsiumkanalblokker innbefattende 1,4-dihydropyridinderivater kan hydrater eller solvater av forbindelsene beskrevet ovenfor, og farmakologisk akseptable salter derav anvendes. I tillegg inneholder enkelte kalsiumkanalblokkere innbefattende 1,4-dihydropyridinderivater en eller flere assymetriske karboner i deres molekyler. I disse tilfeller kan optiske isomerer renset basert på de assymetriske karboner, eller stereoisomerer slik som diastereoisomerer, eller enhver blanding av stereoisomerer, eller rasemater også anvendes som forbindelse (B). Som forbindelse (B) er (+)-2-amino-1,4-dihydro-6-metyl-4-(3-nitrofenyl)-3,5-pyridinkarboksylsyre-3-(l-difenylmetylazetidin-3-yl)ester-5-isopropylester, (R)-2-amino-1,4-dihydro-6-metyl-4-(3-nitrofenyl)-3,5-pyridinkarboksylsyre-3-(l-difenylmetylazetidin-3-yl)ester-5-isopropylester, amlodipinbesylat eller amlodipinmaleat foretrukket. As calcium channel blockers including 1,4-dihydropyridine derivatives, hydrates or solvates of the compounds described above, and pharmacologically acceptable salts thereof can be used. In addition, some calcium channel blockers including 1,4-dihydropyridine derivatives contain one or more asymmetric carbons in their molecules. In these cases, optical isomers purified based on the asymmetric carbons, or stereoisomers such as diastereoisomers, or any mixture of stereoisomers, or racemates can also be used as compound (B). As compound (B) is (+)-2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylic acid 3-(1-diphenylmethylazetidin-3-yl)ester -5-isopropyl ester, (R)-2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylic acid-3-(1-diphenylmethylazetidin-3-yl)ester- 5-isopropyl ester, amlodipine besylate or amlodipine maleate preferred.
Som konkret vist i testeksemplene i foreliggende beskrivelse virker medikamentet ifølge foreliggende oppfinnelse bestående av forbindelse (A) og forbindelse (B) synergistisk og inhiberer neointimadannelse i blodkar og proliferering av vaskulære glattmuskelceller, og inhiberer derfor vaskulær remodellering. Basert på virkningene beskrevet ovenfor kan medikamentene ifølge foreliggende oppfinnelse anvendes for profylakse av restenose etter perkutan koronar intervensjon, i tillegg til profylakse og/eller behandling av arteriosklerose. As concretely shown in the test examples in the present description, the drug according to the present invention consisting of compound (A) and compound (B) acts synergistically and inhibits neointima formation in blood vessels and proliferation of vascular smooth muscle cells, and therefore inhibits vascular remodeling. Based on the effects described above, the drugs according to the present invention can be used for prophylaxis of restenosis after percutaneous coronary intervention, in addition to prophylaxis and/or treatment of arteriosclerosis.
Medikamentet ifølge foreliggende oppfinnelse erkarakterisert vedå utøve glimrende inhiberende effekt på neointimadannelse i blodkar og proliferering av vaskulære glattmuskelceller på grunn av den kombinerte administrering av forbindelse (A) og forbindelse (B) ved deres laveste grensedoser eller lavere enn deres laveste grensedoser for hver av disse administrert alene. I særdeleshet er det fordelaktig å ko-administrere forbindelse (A) og forbindelse (B) ved lave doser ved hvilke ingen effekt fremkalles ved administrering av hver av disse alene. The drug according to the present invention is characterized by exerting an excellent inhibitory effect on neointima formation in blood vessels and proliferation of vascular smooth muscle cells due to the combined administration of compound (A) and compound (B) at their lowest limit doses or lower than their lowest limit doses for each of these administered alone. In particular, it is advantageous to co-administer compound (A) and compound (B) at low doses at which no effect is induced by administering each of these alone.
Som konkret vist i testeksemplene i foreliggende beskrivelse senker medikamentet ifølge foreliggende oppfinnelse blodtrykk mer effektivt ved synergistisk virkning av forbindelse (A) og forbindelse (B). Basert på disse virkninger beskrevet ovenfor kan medikamentet ifølge foreliggende oppfinnelse anvendes for profylakse og/eller behandling av sykdommer forårsaket av hypertensjon slik som hjertesykdommer (angina pektoris, myokardialt infarkt, arrytmi (innbefattende plutselig død), hjertesvikt, hjertehypertrofi og lignende), nyresykdommer (diabetisk nefropati, glomerulonefritt, nefrosklerose og lignende) eller cerebrovaskulære sykdommer (cerebralt infarkt, cerebral blødning og lignende) og fortrinnsvis for behandling. Medikamentet ifølge foreliggende oppfinnelse omfattende en angiotensin II reseptorantagonist og en kaliumkanalblokker utøver mer glimrende effekt ved kombinert administrering av en angiotensin II reseptorantagonist og en kalsiumkanalblokker enn hver av disse midler administrert alene. As concretely shown in the test examples in the present description, the drug according to the present invention lowers blood pressure more effectively through the synergistic action of compound (A) and compound (B). Based on these effects described above, the drug according to the present invention can be used for prophylaxis and/or treatment of diseases caused by hypertension such as heart diseases (angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure, cardiac hypertrophy and the like), kidney diseases (diabetic nephropathy, glomerulonephritis, nephrosclerosis and the like) or cerebrovascular diseases (cerebral infarction, cerebral haemorrhage and the like) and preferably for treatment. The medication according to the present invention comprising an angiotensin II receptor antagonist and a potassium channel blocker exerts a more excellent effect upon combined administration of an angiotensin II receptor antagonist and a calcium channel blocker than each of these agents administered alone.
Medikamentet ifølge foreliggende oppfinnelse kan fremstilles som et farmasøytisk preparat (såkalt en type for "kombinasjonslegemiddel") omfattende forbindelse (A) og forbindelse (B) som aktive bestanddeler. Eksempelvis kan hver aktive bestanddel blandes sammen og kan fremstilles som en fysikalsk enkel formulering. I tillegg kan forbindelse (A) og forbindelse (B) fremstilles separat som en uavhengig formulering og kan tilveiebringes som et medikament inneholdende en kombinasjon av hver type av formulering. De sistnevnte medikament kan anvendes som et medikament for å administrere forbindelse (A) og forbindelse The medicine according to the present invention can be prepared as a pharmaceutical preparation (so-called a type of "combination medicine") comprising compound (A) and compound (B) as active ingredients. For example, each active ingredient can be mixed together and can be produced as a physically simple formulation. In addition, compound (A) and compound (B) can be prepared separately as an independent formulation and can be provided as a drug containing a combination of each type of formulation. The latter drug can be used as a drug to administer compound (A) and compound
(B) samtidig eller separat ved visse intervaller. (B) simultaneously or separately at certain intervals.
Administrering av forbindelse (A) og forbindelse (B) "samtidig" beskrevet i Administration of compound (A) and compound (B) "simultaneously" described in
foreliggende beskrivelse, innbefatter administrering av forbindelse (A) og forbindelse (B) stort sett ved samme tidspunkt, men ikke begrenset til eksakt samme tidspunkt. Det er ingen begrensning på doseringsformen for administrering samtidig, eksempelvis er det innbefattet at en av preparatene administreres oralt og det andre preparat administreres ikke-oralt. Ikke desto mindre er det fordelaktig med et enkelt farmasøytisk preparat og å ta begge preparater samtidig. present description, includes administering compound (A) and compound (B) at substantially the same time, but not limited to the exact same time. There is no restriction on the dosage form for simultaneous administration, for example it is included that one of the preparations is administered orally and the other preparation is administered non-orally. Nevertheless, it is advantageous to have a single pharmaceutical preparation and to take both preparations at the same time.
Uavhengig administrering av forbindelse (A) og forbindelse (B) "ved visse intervaller" som beskrevet i foreliggende beskrivelse, betyr at forbindelse (A) og forbindelse (B) beskrevet ifølge oppfinnelsen, tas uavhengig ved forskjellige tidspunkter. Administreringsmåten for separat administrering ved visse intervaller er ikke begrenset. Eksempelvis er det innbefattet at en antiotensin II reseptorantagonist administreres først, hvorpå, etter et vist intervall, en kalsiumkanalblokker administreres, eller at kalsiumkanalblokkeren administreres først hvorpå en angiotensin II reseptorantagonist administreres deretter ved et vist intervall, men doseringsformen har ingen begrensing. Independent administration of compound (A) and compound (B) "at certain intervals" as described in the present description means that compound (A) and compound (B) described according to the invention are taken independently at different times. The mode of administration for separate administration at certain intervals is not limited. For example, it is included that an antiotensin II receptor antagonist is administered first, after which, after a certain interval, a calcium channel blocker is administered, or that the calcium channel blocker is administered first, after which an angiotensin II receptor antagonist is then administered at a certain interval, but the dosage form has no limitation.
Foreliggende medikament fremstilles ved tidligere kjente metoder i en egnet doseringsform slik som tabletter, kapsler, granuler, pulvere eller siruper for oral administrering, eller som injeksjoner eller stikkpiller for parenteral administrering, ved anvendelse av farmakologisk akseptable og egnede additiver slik som eksipienser, smøremidler, bindemidler, oppbytende midler, demulgeringsmidler, stabiliseringsmidler, smaksstoffer, fortynningsmidler og lignende, og nødvendig, i tillegg til forbindelse (A) og forbindelse (B), som er de aktive bestanddeler. Da forbindelse (A) og forbindelse (B) i medikamentet ifølge foreliggende oppfinnelse er forbindelser som generelt kan administreres oralt, er medikamentet ifølge oppfinnelsen fortrinnsvis oralt administrerbart. The present drug is prepared by previously known methods in a suitable dosage form such as tablets, capsules, granules, powders or syrups for oral administration, or as injections or suppositories for parenteral administration, using pharmacologically acceptable and suitable additives such as excipients, lubricants, binders , bulking agents, demulsifiers, stabilizers, flavourings, diluents and the like, and necessary, in addition to compound (A) and compound (B), which are the active ingredients. Since compound (A) and compound (B) in the drug according to the present invention are compounds which can generally be administered orally, the drug according to the invention is preferably orally administrable.
Som "eksipienser" kan for eksempel nevnes organiske eksipienser innbefattende sukkerderivater slik som laktose, sukkrose, glukose, mannitol eller sorbitol; stivelsesderivater slik som maisstivelse, potetstivelse, a-stivelse eller dekstrin; cellulosederivater slik som krystallinsk cellulose; gummiarabikum; dekstran; eller pullulan; og uorganiske eksipienser innbefattende silikatderivater slik som lett vannfri silisiumsyre, syntetisk aluminiumsilikat, kalsiumsilikat eller magnesiumaluminometasilikat; fosfater slik som kalsiumhydrogenfosfat; karbonater slik som kalsiumkarbonat; eller sulfater slik som kalsiumsulfat. As "excipients" can be mentioned, for example, organic excipients including sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; or pullulan; and inorganic excipients including silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate or magnesium aluminometasilicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; or sulfates such as calcium sulfate.
Som "smøremidler" kan for eksempel nevnes stearinsyre; metallsalter av stearinsyre slik som kalsiumstearat og magnesiumstearat; talkum; kolloidalt silika; vokser slik som bivoks og spermacettvoks; borsyre; adipinsyre; sulfater slik som natriumsulfat; glykol; fumarsyre; natriumbenzoat; DL-leucin; laurylsulfater slik som natriumlaurylsulfat eller magnesium-laurylsulfat; silikater slik som silisiumsyreanhydrid og silisiumhydrat; eller stivelses derivatene beskrevet ovenfor. Examples of "lubricants" include stearic acid; metal salts of stearic acid such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as beeswax and spermacetiwax; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicates such as silicic anhydride and silicon hydrate; or the starch derivatives described above.
Som "bindemidler" kan for eksempel nevnes hydroksypropylcellulose, hydroksypropyl-metylcellulose, poyvinylpyrrolidon, makrogol, eller lignende eksipienser som de som er beskrevet ovenfor. As "binders", mention may be made, for example, of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, macrogol, or similar excipients such as those described above.
Som "oppbrytende midler" kan for eksempel nevnes cellulosederivater slik som lav-substituert hydroksypropylcellulose, karboksymetylcellulose, kalsiumkarboksymetylcellulose eller indre tverrbundet natriumkarboksymetylcellulose; og kjemisk modifiserte stivelse/cellulosederivater slik som karboksymetylstivelse eller natriumkarboksymetylstivelse. As "disintegrating agents" mention can be made, for example, of cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose or internally cross-linked sodium carboxymethyl cellulose; and chemically modified starch/cellulose derivatives such as carboxymethyl starch or sodium carboxymethyl starch.
Som "demulgeringsmidler" kan for eksempel nevnes kolloidal leire slik som bentonitt eller veegum; metallhydroksider slik som magnesiumhydroksid eller aluminiumhydroksid; anioniske overflateaktive midler slik som natriumlaurylsulfat eller kalsiumstearat; kationiske overflateaktive midler slik som benzalkoniumklorid; eller ikke-ioniske overflateaktive midler slik som polyoksyetylenalkyleter, polyoksyetylensorbitan fettsyreester eller sukkroseestere av fettsyrer. As "demulsifiers" can be mentioned, for example, colloidal clay such as bentonite or veegum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzalkonium chloride; or nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid esters or sucrose esters of fatty acids.
Som "stabilisatorer" kan for eksempel nevnes p-hydroksybenzoatestere slik som metylparaben eller propylparaben; alkoholer slik som klorbutanol, benzylalkohol eller fenyletylalkohol; benzalkoniumklorid; fenoler slik som fenol eller kresol; timerosal; dehydroeddiksyre; eller sorbinsyre. As "stabilizers" can be mentioned, for example, p-hydroxybenzoate esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; or sorbic acid.
Som "smaksmidler" kan for eksempel nevnes søtningsmidler slik som sakkarinnatrium eller aspartam; surgjøringsmidler slik som sitronsyre, eplesyre eller vinsyre; eller smaksgjørende midler slik som mentol, sitron eller appelsin. As "flavouring agents" can be mentioned, for example, sweeteners such as saccharin sodium or aspartame; acidulants such as citric, malic or tartaric acid; or flavoring agents such as menthol, lemon or orange.
Som "fortynningsmidler" kan nevnes konvensjonelt anvendte fortynningsmidler, for eksempel laktose, mannitol, glukose, sukkrose, kalsiumsulfat, kalsiumfosfat, hydroksypropylcellulose, mikrokrystallinsk cellulose, vann, etanol, polyetylenglykol, propylenglykol, glyserol, stivelse, polyvinylpyrrolidon, magnesiumaluminometasilikat eller en blanding av disse forbindelser. As "diluents" can be mentioned conventionally used diluents, for example lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone, magnesium aluminum metasilicate or a mixture of these compounds .
Doser av en angiotensin II reseptorantagonist og en kalsiumkanalblokker, som er de aktive bestanddeler, og deres doseringsforhold kan velges på en hensiktsmessig måte avhengig av forskjellige faktorer slik som legemidlenes aktiviteter og symptomene, alder og kroppsvekt av pasienten. Selv om dosen varierer avhengig av symptomer, alder og lignende er den ved oral administrering 0,1 mg (fortrinnsvis 0,5 mg) som en nedre grense, og 1 000 mg (fortrinnsvis 500 mg) som en øvre grense per gan for et voksent menneske en til seks ganger per dag, avhengig av pasientens symptomer, administrert samtidig eller separat ved bestemte intervaller. Når det gjelder parenteral administrering kan 0,01 mg (fortrinnsvis 0,05 mg) som en nedre grense, og 100 mg (fortrinnsvis 50 mg) som en øvre grense per gang for et voksent menneske, en til seks ganger per dag avhengig av pasientens symptomer, samtidig eller separat ved visse intervaller, administreres. Eksempelvis kan doseforholdet mellom forbindelse (A) og forbindelse (B) variere fra 1:10 000 til 10 000:1 i vektforhold, fortrinnsvis i området på 1:1 000 til 1 000:1, og mer foredelaktig innen området på 1:100 til 100:1. Doses of an angiotensin II receptor antagonist and a calcium channel blocker, which are the active ingredients, and their dosage ratio can be appropriately selected depending on various factors such as the activities of the drugs and the symptoms, age and body weight of the patient. Although the dose varies depending on symptoms, age and the like, for oral administration it is 0.1 mg (preferably 0.5 mg) as a lower limit, and 1,000 mg (preferably 500 mg) as an upper limit per dose for an adult human one to six times per day, depending on the patient's symptoms, administered simultaneously or separately at specific intervals. Regarding parenteral administration, 0.01 mg (preferably 0.05 mg) as a lower limit, and 100 mg (preferably 50 mg) as an upper limit per time for an adult human, one to six times per day depending on the patient's symptoms, simultaneously or separately at certain intervals, are administered. For example, the dose ratio between compound (A) and compound (B) can vary from 1:10,000 to 10,000:1 in weight ratio, preferably in the range of 1:1,000 to 1,000:1, and more advantageously within the range of 1:100 to 100:1.
Når medikament ifølge oppfinnelsen anvendes for profylakse og/eller behandling av ateriosklerose, er det generelt ønskelig at blodkonsentrasjonen av forbindelse (A) og forbindelse (B) etter administreringen justeres riktig slik at den er rundt det laveste grense eller under den laveste grense for forbindelse (A) eller forbindelse (B) når de administreres alene. When the drug according to the invention is used for the prophylaxis and/or treatment of atherosclerosis, it is generally desirable that the blood concentration of compound (A) and compound (B) is adjusted correctly after administration so that it is around the lowest limit or below the lowest limit for compound ( A) or compound (B) when administered alone.
Når medikamentet ifølge oppfinnelsen anvendes for profylakse og/eller behandling av hypertensjon kan dosen av angiotensin II reseptorantagonist være foreskrevet ved lavere doser enn dosen av angiotensin II reseptorantagonisten når angiotensin II reseptorantagonisten anvendes alene som et hypotensivt middel, som er dets opprinnelige anvendelse, og dosen av angiotensin II reseptorantagonisten kan være kraftig redusert, fordi glimrende antihypertensiv virkning kan oppnås ved den kombinerte administrering av en angiotensin II reseptorantagonist med en kalsiumkanalblokker. When the drug according to the invention is used for the prophylaxis and/or treatment of hypertension, the dose of angiotensin II receptor antagonist can be prescribed at lower doses than the dose of the angiotensin II receptor antagonist when the angiotensin II receptor antagonist is used alone as a hypotensive agent, which is its original use, and the dose of the angiotensin II receptor antagonist can be greatly reduced, because excellent antihypertensive action can be achieved by the combined administration of an angiotensin II receptor antagonist with a calcium channel blocker.
Eksempler Examples
Foreliggende oppfinnelse beskrives i det følgende mer i detalj ved hjelp av de nedenfor beskrevne eksempler og testeksempler. I testeksemplene er "olmesartanmedoksomil" ganske enkelt kalt "olmesartan". The present invention is described in more detail in the following with the help of the examples and test examples described below. In the test examples, "olmesartan medoxomil" is simply called "olmesartan".
Testeksempel 1: Inhiberende effekter mot arteriosklerose Test example 1: Inhibitory effects against arteriosclerosis
(A) Materialer og Metoder (A) Materials and Methods
(1) Mansj ett-fremkalt vaskulær skademodell (1) Cuff one-induced vascular injury model
C57BL/6 mus med en alder på 10 uker ble anvendt. I en del av denne studie ble en ATla-reseptorgen-utslått (AtlaKO)-mus også anvendt. Inflammatorisk vaskulær skade ble fremkalt i musen ved løst å plassere en polyetylenslange som var kuttet i lengderetningen for å åpne slangen rundt lårarterien av musen. I den skadede arterie ble følgende observasjoner foretatt. Anvendbarheten av denne modell for vaskulær skade for å analysere vaskulær remodellering er tidligere blitt rapportert (Physiol. Genomics., 2, s. 13-30, 2000; Circulation, 104, s. 2716-2721, 2001; Circulation, 106 s, 847-853, 2002). C57BL/6 mice aged 10 weeks were used. In part of this study, an ATla receptor gene-knockout (AtlaKO) mouse was also used. Inflammatory vascular injury was induced in the mouse by loosely placing a polyethylene tube that had been cut longitudinally to open the tube around the femoral artery of the mouse. In the damaged artery the following observations were made. The applicability of this model of vascular injury to analyze vascular remodeling has previously been reported (Physiol. Genomics., 2, pp. 13-30, 2000; Circulation, 104, pp. 2716-2721, 2001; Circulation, 106 pp, 847 -853, 2002).
(2) Neointima-dannelse i blodkarene og DNA-syntese (2) Neointima formation in the blood vessels and DNA synthesis
En parafin-innstøpt sesjon av den skadede arterie ble fremstilt 14 dager etter mansj ettplasseringen, Elastica van Gieson-beising ble utført, og tverrsnittsarealet av neointima og tunika mediet av blodkarene ble bestemt ved bildeanalyseprogram. For kvantifisering av DNA-syntese ble bromdeoksyuridin (BrdU) injisert i musen 7 dager etter mansj ettplasseringen, og BrdU-indeksen beregnet fra inkorporeringen i kjernen av cellene ble beregnet. (3) Olmesartan, en ATl-reseptorblokker, ble intraperitonealt injisert i villtype mus med osmotisk minipumpe, og doseavhengigheten av olmesartan ble undersøkt som beskrevet i (2). Oral administrering av azelnidipin til villtype musen ble startet etter mansj ettplasseringen, og doseavhengigheten av azelnidipin ble undersøkt som beskrevet i (2). (4) Både olmesartan og azelnidipin ble samtidig administrert til villtype mus, og effekten av ko-administrering av olmesartan eller azelnidipin ble sammenlignet med de av administrering av enten olmesarten eller azelnidipin alene som beskrevet i (2). Effektene av olmesartan og azelnidipin ble undersøkt ved effektive doser av enten olmesartan eller azelnidipin alene og ved utilstrekkelige doser for å fremkalle signifikante effekter med enten olmesarten eller azelnidipin alene, for å bestemme den synergistiske effekt av disse to midler. (5) Ved anvendelse av dyrkede rottevaskulære glattmuskelceller ble effekten av ko-behandling av olmesarten og azelnidipin på lettelsen av DNA-syntesen etter stimulering med angiotensin II (bestemt ved inkorporering av [<3>H]tymidin) ble undersøkt. A paraffin-embedded section of the injured artery was prepared 14 days after cuff placement, Elastica van Gieson staining was performed, and the cross-sectional area of the neointima and tunica media of the blood vessels was determined by image analysis software. For quantification of DNA synthesis, bromodeoxyuridine (BrdU) was injected into the mouse 7 days after cuff placement, and the BrdU index calculated from the incorporation into the nucleus of the cells was calculated. (3) Olmesartan, an AT1 receptor blocker, was intraperitoneally injected into wild-type mice with an osmotic minipump, and the dose dependence of olmesartan was examined as described in (2). Oral administration of azelnidipine to the wild-type mouse was started after cuff placement, and the dose dependence of azelnidipine was examined as described in (2). (4) Both olmesartan and azelnidipine were simultaneously administered to wild-type mice, and the effects of co-administration of olmesartan or azelnidipine were compared with those of administration of either olmesartan or azelnidipine alone as described in (2). The effects of olmesartan and azelnidipine were examined at effective doses of either olmesartan or azelnidipine alone and at doses insufficient to produce significant effects with either olmesartan or azelnidipine alone, to determine the synergistic effect of these two agents. (5) Using cultured rat vascular smooth muscle cells, the effect of co-treatment of olmesartan and azelnidipine on the facilitation of DNA synthesis after stimulation with angiotensin II (determined by incorporation of [<3>H]thymidine) was investigated.
(B) Resultater (B) Results
(1) I den mansj ett-fremkalte vaskulære skademodell av villtype mus ble DNA-syntesen av (1) In the cuff-induced vascular injury model of wild-type mice, DNA synthesis was abolished
vaskulære glattmuskelceller forøket, og neointima-dannelse i blodkarene ble potensielt. Disse forandringer ble inhibert med azelnidipin på en doseavhengig måte ved et doseområde på 0,1 til 1,0 mg/kg/dag, uten noen effekter på blodtrykk (Figur 1 og Figur 2). I tillegg utviste olmesartan-lignende inhiberende effekt på en doseavhengig måte ved et doseområde på 0,5 til 3,0 mg/kg/dag, uten noen effekt på blodtrykk (Figur 3 og Figur 4). Når 0,1 mg/kg/dag av azelnidipin og 0,5 mg/kg/dag av olmesarten (ingen av disse legemidler fremkalte noen signifikant effekt ved disse doser) ble administrert ved samme tidspunkt, ble økningen i DNA-syntese av vaskulær glattmuskelceller og potensieringen av neointima-dannelse i blodtrykk signifikant undertrykket (Figur 5 og Figur 6). Fra disse resultater ble det klart vist in vivo at ko-administrering av azelnidipin og olmesartan arbeider synergistisk, inhiberer proliferering av vaskulære glattmuskelceller og forbedrer vaskulær remodellering. (2) Den synergiske virkning av azelnidipin og olmesartan beskrevet ovenfor ble undersøkt i en in vzYrø-studie. Som vist i Figur 7 ble lettelsen av DNA-syntesen i dyrkede rottevaskulære glattmuskelceller etter stimulering med angiotensin II undertrykket ved administrering av azelnidipin på en konsentrasjons-avhengig måte. Når lave doser av azelnidipin og olmesartan som var utilstrekkelig til å fremkalle noen effekt alene, ble ko-administrert, ble DNA-syntesen av dyrkede rottevaskulære glattmuskelceller signifikant undertrykket (Figur 8). vascular smooth muscle cells increased, and neointima formation in the blood vessels became potentiated. These changes were inhibited by azelnidipine in a dose-dependent manner at a dose range of 0.1 to 1.0 mg/kg/day, without any effects on blood pressure (Figure 1 and Figure 2). In addition, olmesartan exhibited a dose-dependent inhibitory effect at a dose range of 0.5 to 3.0 mg/kg/day, without any effect on blood pressure (Figure 3 and Figure 4). When 0.1 mg/kg/day of azelnidipine and 0.5 mg/kg/day of the olmes species (neither of these drugs produced any significant effect at these doses) were administered at the same time point, the increase in DNA synthesis of vascular smooth muscle cells and the potentiation of neointima formation in blood pressure significantly suppressed (Figure 5 and Figure 6). From these results, it was clearly shown in vivo that co-administration of azelnidipine and olmesartan works synergistically, inhibiting the proliferation of vascular smooth muscle cells and improving vascular remodeling. (2) The synergistic effect of azelnidipine and olmesartan described above was investigated in an in vzYrø study. As shown in Figure 7, the facilitation of DNA synthesis in cultured rat vascular smooth muscle cells after stimulation with angiotensin II was suppressed by administration of azelnidipine in a concentration-dependent manner. When low doses of azelnidipine and olmesartan insufficient to produce any effect alone were co-administered, DNA synthesis of cultured rat vascular smooth muscle cells was significantly suppressed (Figure 8).
Testeksempel 2: Antihypertensiv aktivitet Test example 2: Antihypertensive activity
Kirurgiske operasjoner ble utført i 56 spontant hypertensitve rotter (SHR, SPF kvalitet, Leverandør: Hoshino Laboratory Animals) med en alder på 20 uker, for å implantere sendere for nedtegnelse av deres blodtrykk. Hittil tilfriskning fra de kirurgiske operasjoner ble deres blodtrykk overvåket ved å starte fra deres 24 ukers alder. 0,5 % karboskymetylcellulosenatrium (CMC-Na)-løsning (2 ml/kg) ble oralt administrert i 7 suksessive dager (en gang daglig) med en doseringskanalye. Dyrene ble oppdelt i 7 grupper (8 rotter per gruppe) med homogent blodtrykk i hver gruppe basert på deres blodtrykk bestemt på den 5. og 6. dag fra starten av blodtrykksovervåkningen (sammensetningen i hver gruppe er illustrert i Tabell 1). Enten 0,5 % CMC-Na-løsning (2 ml/kg: kontrollgruppe) eller en testlegemiddelløsning (2 ml/kg) hvor testsubstansen var suspendert i 0,5 % CMC-Na-løsning, ble administrert fra 25 ukers alder i 14 suksessive dager (en gang per dag) og forandringer i blodtrykket ble observert. Forandringer i blodtrykket for gruppe 6 og gruppe 7 er vist i Tabell 2. (Verdiene i tabellene representerer middelverdi + S.D.). Glimrende antihypertensiv effekt ble observert i dyrene i gruppen som ble ko-administrert olmesartan pluss azelnidipin. Surgical operations were performed in 56 spontaneously hypertensive rats (SHR, SPF quality, Supplier: Hoshino Laboratory Animals) with an age of 20 weeks, to implant transmitters for recording their blood pressure. Until recovery from the surgical operations, their blood pressure was monitored starting from their 24 weeks of age. 0.5% carboxymethylcellulose sodium (CMC-Na) solution (2 ml/kg) was orally administered for 7 consecutive days (once daily) using a dosing channel. The animals were divided into 7 groups (8 rats per group) with homogeneous blood pressure in each group based on their blood pressure determined on the 5th and 6th day from the start of blood pressure monitoring (the composition of each group is illustrated in Table 1). Either 0.5% CMC-Na solution (2 ml/kg: control group) or a test drug solution (2 ml/kg) where the test substance was suspended in 0.5% CMC-Na solution was administered from 25 weeks of age for 14 successive days (once per day) and changes in blood pressure were observed. Changes in blood pressure for group 6 and group 7 are shown in Table 2. (The values in the tables represent mean value + S.D.). Excellent antihypertensive effect was observed in the animals in the group co-administered olmesartan plus azelnidipine.
Testeksempel 3: Antihypertensive effekter Test example 3: Antihypertensive effects
Apolipoprotein E (ApoE) utslått hannmus med en alder på 12 uker ble oppdelt i fire grupper (15 mus per gruppe) som følger: kontrollgruppe (administrert 0,5 % karboksymetylcellulose (CMC)-basning), olmesartanmedoksomil (3 mg/kg) administrert gruppe, azelnidipin (3 mg/kg) administrert gruppe og olmesartanmedoksomil (3 mg/kg) pluss azelnidipin (3 mg/kg) administrert gruppe. Enten testsubstans eller bærer (0,5 % CMC-løsning) ble oralt administrert til dyrene i 24 suksessive uker. En høy fettdiett (inneholdende 0,15 % kolesterol og 15 % usaltet smør) ble gitt til alle musene i alle grupper etter starten av testmiddeladministreringen (12 ukers alder). Det systoliske blodtrykk av alle mus ble målt med en blodtrykkmonitor av ikke-foroppvarmende type (BP Monitor for Rotter & Mus, Modell MK-2000, Muromachi Kikai Co., Ltd.) ved 21-24 timer etter legemiddeladministreringen i den 23. uke. Resultatene er vist i Tabell 3 (verdiene i tabellen indikerer middelverdi + S.E.). Apolipoprotein E (ApoE) knockout male mice aged 12 weeks were divided into four groups (15 mice per group) as follows: control group (administered 0.5% carboxymethylcellulose (CMC) bath), olmesartan medoxomil (3 mg/kg) administered group, azelnidipine (3 mg/kg) administered group and olmesartan medoxomil (3 mg/kg) plus azelnidipine (3 mg/kg) administered group. Either test substance or vehicle (0.5% CMC solution) was orally administered to the animals for 24 consecutive weeks. A high fat diet (containing 0.15% cholesterol and 15% unsalted butter) was given to all mice in all groups after the start of test drug administration (12 weeks of age). The systolic blood pressure of all mice was measured with a non-preheating type blood pressure monitor (BP Monitor for Rats & Mice, Model MK-2000, Muromachi Kikai Co., Ltd.) at 21-24 hours after the drug administration in the 23rd week. The results are shown in Table 3 (the values in the table indicate mean value + S.E.).
Som resultatene viser ovenfor ble en merkbar hypotensiv effekt (p = 0,0063; Dunnetts multipel sammenligningstest) observert i den olmesartanmedoksomil og azelnidipin ko-administrete gruppen, ved hvilke doser ikke noe middel alene fremkalte noen signifikant effekt, og effekten fremkalt ved ko-administrering av olmesartanmedoksomil og azelnidipin var synergistisk (p = 0,0065; to-veis variansanalyse). As the results show above, a noticeable hypotensive effect (p = 0.0063; Dunnett's multiple comparison test) was observed in the olmesartan medoxomil and azelnidipine co-administered group, at which doses neither agent alone produced any significant effect, and the effect produced by co-administration of olmesartan medoxomil and azelnidipine was synergistic (p = 0.0065; two-way analysis of variance).
Preparateksempel Preparation example
Tabletter (Kombinasj onslegemiddel) Tablets (Combination medicine)
Pulverne av den ovenfor angitte sammensetning ble blandet og tablettert med tabletteirngsmaskin for å fremstille en tablett inneholdende 350 mg av sammensetningen. The powders of the above composition were mixed and tableted with a tableting machine to prepare a tablet containing 350 mg of the composition.
Tablettene kan sukkerbelegges om nødvendig- The tablets can be sugar-coated if necessary-
Industriell anvendelighet Industrial applicability
Medikamentet ifølge foreliggende oppfinnelse er anvendbart som et profylaktisk og/eller terapeutisk middel mot arteriosklerose og hypertensjon. The medication according to the present invention can be used as a prophylactic and/or therapeutic agent against arteriosclerosis and hypertension.
Claims (41)
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US5492904A (en) * | 1991-05-15 | 1996-02-20 | E. I. Du Pont De Nemours And Company | Composition of angiotensin-II receptor antagonists and calcium channel blockers |
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